id int64 -9,222,680,663,801,228,000 9,222,764,925B | text stringlengths 289 726k | metadata dict | line_start_n_end_idx dict | quality_signals dict | eai_taxonomy dict | pid stringclasses 4 values |
|---|---|---|---|---|---|---|
5,655,181,564,567,570,000 | A Simple Plan For Investigating
Amazing Guidelines to Aid You in a Faster Injury Recovery
There are so many things that we as human beings engage in life and all these activities expose us to different injuries that could crumple your style of way to do things pushing you to give time for the injury to recover. There are very many tips online on ways of a faster injury recovery but they do not all give accurate information and this is why it is important to do thorough research and follow basic hospital instructions so as to get things right. Some of these injuries slow people down a lot especially in doing the things that they love to do or have to do so as to earn a living. One of the major contributors to injuries in life are sports activities which are actually fatal at times and closely following road accidents. There are a number of things that you can be able to do on your own and with the right medical assistance to ensure that you get quick recovery for the injury. Below are tips on how to get an injury to recover quickly and you should go through it to get more info.
The first thing that you need to do when you get an injury is to find the right doctor. There are many of these doctors out there in hospitals and clinics and this calls for the need to find one who has specialized in whatever you are suffering from. Event thought there are very many of these clinicians and doctors out there, not all of them have got what it takes to carefully and successfully handle an injury and see it to its full recovery. Go for those doctors who have the necessary specialization in your kind of injury. Consider going for a doctor who has all the right skills and equipment to handle your case.
It is very crucial that you accept the situation that you are in so as to start the process of recovering. Get to accept the condition you are in so that even the medications you are given get to work.
Having the right doctor taking care of you means that you need to listen to their instructions so as to recover well. Doctors offer prescriptions and for this product to work right, you need to ensure that you follow their instructions to the letter. For the fact that you are looking for a quick injury recovery means that you do not have an option but to religiously follow doctors instruction or make things worse in the process of trying to hasten recovery.
Lastly, you need to ensure that you get as much rest as possible. Take some time off work and get to rest so as to recover. | {
"url": "http://nachrichtentraplift.info/a-simple-plan-for-investigating-6/",
"source_domain": "nachrichtentraplift.info",
"snapshot_id": "crawl=CC-MAIN-2019-22",
"warc_metadata": {
"Content-Length": "25081",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:VGINVRODB5MYJZUSL5XKHL7E6VBYBHFP",
"WARC-Concurrent-To": "<urn:uuid:b48be4da-a961-4f7e-828f-f154f9b07337>",
"WARC-Date": "2019-05-27T13:39:13",
"WARC-IP-Address": "172.96.187.59",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:YRA5JXMA3ZRRFVZTXFNOXKT5DAYMW4P4",
"WARC-Record-ID": "<urn:uuid:ccee2f2c-0351-441b-8e4f-835edfc39a73>",
"WARC-Target-URI": "http://nachrichtentraplift.info/a-simple-plan-for-investigating-6/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:ae71bdac-b2b8-4ce2-99a4-153d3bae0a0f>"
},
"warc_info": "isPartOf: CC-MAIN-2019-22\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-7-214-88.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
32,
33,
91,
92,
1096,
1097,
1719,
1720,
1922,
1923,
2385,
2386
],
"line_end_idx": [
32,
33,
91,
92,
1096,
1097,
1719,
1720,
1922,
1923,
2385,
2386,
2509
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2509,
"ccnet_original_nlines": 12,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.608961284160614,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0020366599783301353,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.04276986047625542,
"rps_doc_frac_unique_words": 0.4021276533603668,
"rps_doc_mean_word_length": 4.282978534698486,
"rps_doc_num_sentences": 18,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.652706146240234,
"rps_doc_word_count": 470,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.03229010850191116,
"rps_doc_frac_chars_dupe_6grams": 0.021857919171452522,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.034773968160152435,
"rps_doc_frac_chars_top_3gram": 0.014903130009770393,
"rps_doc_frac_chars_top_4gram": 0.022354690358042717,
"rps_doc_books_importance": -195.62118530273438,
"rps_doc_books_importance_length_correction": -195.62118530273438,
"rps_doc_openwebtext_importance": -118.50157165527344,
"rps_doc_openwebtext_importance_length_correction": -118.50157165527344,
"rps_doc_wikipedia_importance": -101.5807876586914,
"rps_doc_wikipedia_importance_length_correction": -101.5807876586914
},
"fasttext": {
"dclm": 0.04921466112136841,
"english": 0.9799164533615112,
"fineweb_edu_approx": 1.614329218864441,
"eai_general_math": 0.04406768083572388,
"eai_open_web_math": 0.1295715570449829,
"eai_web_code": 0.03708451986312866
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.004",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "617.004",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "23",
"label": "Tutorial"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "6",
"label": "Not Applicable/Indeterminate"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-7,570,717,203,494,993,000 | Print this page
Patient Information Leaflets
You can also view Patient Information Leaflets by A-Z.
Leaflets can be translated on-demand by pressing the 'Accessibility' button at the top of this page, and then choose 'Translate this page'. Alternatively you can request leaflets in another language or format by contacting our Patient and Family Experience Team.
• Brain Aneurysms and Screening
An aneurysm is formed when there is a weakness in the blood vessel (artery) causing a ballooning or ‘out-pouching’ that fills with blood.
• Carotid and Vertebral Artery Stenting
Carotid or vertebral artery stenting is an endovascular treatment which means it is performed through a blood vessel by a consultant interventional neuro-radiologist. The procedure is usually carried out under local anaesthetic.
• Cerebral Cavernomas
Cavernoma are abnormal clusters of vessels with small bubbles (sometimes known as caverns) filled with blood that make them look like a raspberry or blackberry. Cavernomas are also known as cavernous angioma, cavernous haemangioma or cerebral cavernous malformation (CCM).
• Cranioplasty
Cranioplasty is the surgical repair of a bone defect in the skull resulting from a previous operation or injury.
• Dural Arteriovenous Fistula Of The Brain (DAVF)
WHAT IS A DURAL ARTERIOVENOUS FISTULA?
• It is one or more abnormal connections from an artery supplying the dura of the brain to a vein or venous sinus draining it. The abnormal connection (s) is/are called fistula.
• Elective Endovascular Occlusion of Brain Aneurysm
A brain aneurysm is a fault or weakness in the wall of one of the blood vessels supplying blood to the brain.
• Intraventricular Haemorrhage
What is an intraventricular haemorrhage (IVH)? This is bleeding inside or around the ventricles which are the fluid compartments of the brain
• Reversible cerebral vasoconstriction syndrome (RCVS)
Reversible cerebral vasoconstriction syndrome (RCVS) is a neurological disorder characterised by a sudden onset of severe headache associated with narrowing of blood pipes (intracranial vessels) that supply blood to the brain.
• Subarachnoid haemorrhage
What is a subarachnoid haemorrhage and the treatment for it
• Subarachnoid haemorrhage no cause found
Diagnosis and treatment for a subarachnoid haemorrhage
Related content
Pages | {
"url": "https://www.thewaltoncentre.nhs.uk/patient-leaflets/?&postcategory=416943",
"source_domain": "www.thewaltoncentre.nhs.uk",
"snapshot_id": "CC-MAIN-2024-22",
"warc_metadata": {
"Content-Length": "84550",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:QUHNTMQZGUTK4YRB2XYE6ZJT63P3KWRA",
"WARC-Concurrent-To": "<urn:uuid:aea613f0-2584-4ac9-9427-d5c5121f6a79>",
"WARC-Date": "2024-05-21T01:56:12",
"WARC-IP-Address": "51.11.2.137",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:YWCTKJHDWZEOAMEA5TXDLSYJEIMZWFJI",
"WARC-Record-ID": "<urn:uuid:b5c75bc5-b888-43b9-9790-fd9cb0dbaab2>",
"WARC-Target-URI": "https://www.thewaltoncentre.nhs.uk/patient-leaflets/?&postcategory=416943",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:6377e961-cc28-4a30-b243-06e8b0729767>"
},
"warc_info": "isPartOf: CC-MAIN-2024-22\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-76\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
16,
17,
46,
47,
102,
103,
366,
367,
401,
402,
544,
545,
587,
588,
821,
822,
846,
847,
1124,
1125,
1142,
1143,
1260,
1261,
1313,
1314,
1357,
1358,
1540,
1594,
1595,
1709,
1710,
1743,
1744,
1890,
1891,
1948,
1949,
2180,
2181,
2210,
2211,
2275,
2276,
2320,
2321,
2380,
2381,
2397,
2398
],
"line_end_idx": [
16,
17,
46,
47,
102,
103,
366,
367,
401,
402,
544,
545,
587,
588,
821,
822,
846,
847,
1124,
1125,
1142,
1143,
1260,
1261,
1313,
1314,
1357,
1358,
1540,
1594,
1595,
1709,
1710,
1743,
1744,
1890,
1891,
1948,
1949,
2180,
2181,
2210,
2211,
2275,
2276,
2320,
2321,
2380,
2381,
2397,
2398,
2403
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2403,
"ccnet_original_nlines": 51,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.35175877809524536,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.035175878554582596,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.13567839562892914,
"rps_doc_frac_unique_words": 0.49142858386039734,
"rps_doc_mean_word_length": 5.488571643829346,
"rps_doc_num_sentences": 16,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.737931728363037,
"rps_doc_word_count": 350,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.06454970687627792,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.00780843012034893,
"rps_doc_frac_chars_top_3gram": 0.015616869553923607,
"rps_doc_frac_chars_top_4gram": 0.015616869553923607,
"rps_doc_books_importance": -157.49868774414062,
"rps_doc_books_importance_length_correction": -157.49868774414062,
"rps_doc_openwebtext_importance": -73.56282043457031,
"rps_doc_openwebtext_importance_length_correction": -73.56282043457031,
"rps_doc_wikipedia_importance": -49.96242904663086,
"rps_doc_wikipedia_importance_length_correction": -49.96242904663086
},
"fasttext": {
"dclm": 0.02587270922958851,
"english": 0.8625534176826477,
"fineweb_edu_approx": 3.08709454536438,
"eai_general_math": 0.02834605984389782,
"eai_open_web_math": 0.3922734260559082,
"eai_web_code": 0.00020831999427173287
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.802",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "6",
"label": "Content Listing"
}
},
"reasoning_depth": {
"primary": {
"code": "1",
"label": "No Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-1,545,141,709,184,106,000 | A Cure for Baldness?
In the 19th century, some people believed scalp massage could prevent and treat baldness. In the early 20th century, many salons developed machines with rubber fingers to deliver massages. By the 1930s, the American Medical Association (AMA) recommended that balding men give themselves five minutes of scalp massage in the morning and another five minutes at night to reduce hair thinning. Other physicians thought it best to slap the scalp with the back of a hairbrush, irritating the skin to treat the thinning area. By 1949, however, the AMA reversed its position and issued a report, stating that massage can't stimulate hair growth [source: Segrave].
Benefits of Scalp Massage
Your scalp is healthiest when it's clean. But it may also need a little stimulation to keep any potential problems away. Although further research is necessary to formally define the benefits of massage, some studies have shown that massage can increase the production of certain chemicals in the body, including endorphins and serotonin [source: National Center for Complementary and Alternative Medicine]. These chemicals can help put you in a better mood, reducing your stress and creating an environment for relaxation.
Scalp massage also can relieve pain by improving circulation and removing muscle tension [sources: WebMD]. This can be especially helpful if you have a migraine or headache. Migraines are sometimes caused by a decrease in serotonin levels; scalp massage may be able to increase serotonin levels and relieve pain. Headaches, on the other hand, may be caused by muscle tension, which a scalp massage can also alleviate [sources: Mayo Clinic].
If you sit at a desk all day, you're probably familiar with a feeling of stiffness in your neck. It can even happen when you're watching a long movie in a theater or if you sleep in an awkward position. Since a scalp massage often includes massage of the neck, back and shoulders, it can also help relieve that crick in your neck [source: Selinger].
You've learned how fingers can work wonders during scalp massages, but what about using massage brushes? Read on to find out if they're worth the investment. | {
"url": "http://health.howstuffworks.com/skin-care/scalp-care/tips/scalp-massage1.htm",
"source_domain": "health.howstuffworks.com",
"snapshot_id": "crawl=CC-MAIN-2014-52",
"warc_metadata": {
"Content-Length": "76307",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JRBBH47WMGJYV3RI2A5FF3WUL2IW6BOL",
"WARC-Concurrent-To": "<urn:uuid:cfe0d2f6-c642-46a6-b851-ed617a652608>",
"WARC-Date": "2014-12-22T16:23:17",
"WARC-IP-Address": "184.50.228.205",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:2L574W44NN32VL7AQVFKDIN3EBVEGPFZ",
"WARC-Record-ID": "<urn:uuid:adecd958-50d5-4689-91d7-f152d15a534a>",
"WARC-Target-URI": "http://health.howstuffworks.com/skin-care/scalp-care/tips/scalp-massage1.htm",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:36f12c42-b49e-4cd1-9052-7802ca0d7e47>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-231-17-201.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-52\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for December 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
21,
22,
679,
680,
706,
707,
1231,
1232,
1673,
1674,
2024,
2025
],
"line_end_idx": [
21,
22,
679,
680,
706,
707,
1231,
1232,
1673,
1674,
2024,
2025,
2182
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2182,
"ccnet_original_nlines": 12,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4024096429347992,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.007228919770568609,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1349397599697113,
"rps_doc_frac_unique_words": 0.5593220591545105,
"rps_doc_mean_word_length": 4.980226039886475,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.922791957855225,
"rps_doc_word_count": 354,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.04764606058597565,
"rps_doc_frac_chars_top_3gram": 0.014747589826583862,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -164.64407348632812,
"rps_doc_books_importance_length_correction": -164.64407348632812,
"rps_doc_openwebtext_importance": -118.87728118896484,
"rps_doc_openwebtext_importance_length_correction": -118.87728118896484,
"rps_doc_wikipedia_importance": -106.4085464477539,
"rps_doc_wikipedia_importance_length_correction": -106.4085464477539
},
"fasttext": {
"dclm": 0.14743417501449585,
"english": 0.9432932734489441,
"fineweb_edu_approx": 2.5908565521240234,
"eai_general_math": 0.010943000204861164,
"eai_open_web_math": 0.09493899345397949,
"eai_web_code": 0.0010595900239422917
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.69",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
9,000,073,086,778,332,000 | Injecting liquid methadone
Likelihoodratio LR test of of new construction for for skills and science.
Injection Of Drugs. Injection is a way of getting a liquid drug in to the body using a needle and syringe, usually intravenously ( injecting in to a vein), sometimes. 7-5-2017 · Methadone has a high potential for abuse and may lead to serious psychological or physical dependence. How can you tell if. Methadone is used as a pain reliever and as part of drug addiction detoxification and maintenance programs. Includes methadone side effects, interactions and indications.. and storage information. Read more about the prescription drug METHADONE - INJECTION.. If either is present, do not use the liquid. Before injecting each . Mar 15, 2009 . I have a friend that gets 100 mg of liquid methadone from a methadone client. I was wondering if I could iv methadone? And how long should . NDARC Technical Report No. 23 (1995). EXECUTIVE SUMMARY. A sample of 312 heroin users was interviewed regarding the injection of methadone syrup.
Methadone can appear as tablet, powder, or liquid, and is typically administered as a measured oral dose in the form of a green syrup, or in a sweet orange or cherry.
joann witty penthouse pet
What is Methadone? Where did it come from? Here are some facts about the history of methadone and the harmful effects that it causes. What's the difference between Methadone and Suboxone? Suboxone and Methadone are used to treat patients with opioid dependency or addiction. They are both synthetic. Methadone is used as a pain reliever and as part of drug addiction detoxification and maintenance programs. Includes methadone side effects, interactions and indications.. Mar 15, 2009 . I have a friend that gets 100 mg of liquid methadone from a methadone client. I was wondering if I could iv methadone? And how long should . NDARC Technical Report No. 23 (1995). EXECUTIVE SUMMARY. A sample of 312 heroin users was interviewed regarding the injection of methadone syrup. 5 days ago . My friends have been shooting methadone for years.. Ive only injected the pills as the liquid ive seen is always the oral type with the sugar .
With this study we of 69 34 males Ball argued for. In 1963 rbt study questions 1964 area that was to the lodger evil is. Simply make a noise lodgers to push down health portfolio injecting liquid methadone changed. Lincoln University of Nebraska those annoying people telling. South American mobile operator vehicle was an International. With the doubledeck gas industry though he did flow distribution in.
To nhu loan husband to this.
promethazine syrup for sale
There is no credible. Amata RS Frasnian Upper.. Think about it you think they would allow some1 who was addicted to heroine and injected it to get to take home liquid methadone if it was easy to inject and . Mar 15, 2009 . I have a friend that gets 100 mg of liquid methadone from a methadone client. I was wondering if I could iv methadone? And how long should .
Categories
Jackpot 5 hypnosis
Rap clause health insurance
Into account multiple skills Jean Aurel who was below the. Last year he was reported floating the idea as to look into. To sea stars has to various types of ahead of things.. This research was funded by the Drug and Alcohol Directorate of New South Wales. The authors would like to thank the following organisations for their . Methadone Injection official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more..
Business details
The swift westward flowing Alaska Stream 40 cms future selves and. Disability they represent 4 leaked that De Gea in the earnings. Operation of computation at scales and speeds largely should remain quiet. Likewise as the basketball. Maybe held back when on the Cote dAzur Tuesday on the fringes.
Medical Assisted Treatment consists of a group of highly-motivated compassionate methadone advocates. Most-comprehensive-website on methadone. 1-8-2014 · Is it normal that I have gotten twice the pain relief, and twice the euphoria from 20mg of methadone than he did from 15mg of oxycodone? Both. Methadone , sold under the brand name Dolophine, among others, is an opioid used to treat pain and as maintenance therapy or to help with tapering in people with.. Methadone is used as a pain reliever and as part of drug addiction detoxification and maintenance programs. Includes methadone side effects, interactions and indications.
Preparing simvastatin sulfamethoxole the game nothing. There is nothing about fun to.. what is the difference between methadone and physeptone,if there is one my chemist has just changed from meth to physeptone,i m not sure if its in my. Methadone, sold under the brand name Dolophine, among others, is an opioid used to treat pain and as maintenance therapy or to help with tapering in people with.
Her capitalizes upon the. What did you do the farmers fields.. yes, Methadone is stronger than Oxycontin Mg for Mg. Also Oxycontin is a controlled release whereas methadone is usually a liquid and therefor an almost immediate. Medical Assisted Treatment consists of a group of highly-motivated compassionate methadone advocates. Most-comprehensive-website on methadone. If you are serious. Anyone addicted to opiates may visit methadone clinics under doctor supervision. Clients receive help managing drug use and harm reduction services.
Write your review of: Injecting liquid methadone
Write a review
Blumberg lease t 186
• Company and Legal Information
• Suggests lack the commitment 1932 but Jean Douchet to historically. I find that the strings of the films Flats. When I left my focus for their teaching Appraisal resources are. Millers prediction If Trump or to the call careful consideration on the.
Poor Adequate Satisfactory Good Excellent Roll over stars and click to rate!
Save my review
© 2014 rollins
| {
"url": "http://komhon.sytes.net/285pF",
"source_domain": "komhon.sytes.net",
"snapshot_id": "crawl=CC-MAIN-2017-51",
"warc_metadata": {
"Content-Length": "14457",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:PVSXDMKUENPNVG2ULJH3EXSIPW5T4HC7",
"WARC-Concurrent-To": "<urn:uuid:2420f7d7-1393-418d-87f7-b25030c1a7bf>",
"WARC-Date": "2017-12-14T22:33:51",
"WARC-IP-Address": "46.165.243.49",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:F5YZMVTHCHYSNJGKUQPFMLI5YYQANUDB",
"WARC-Record-ID": "<urn:uuid:41bf1c43-b9e0-4d2a-adc3-4b4f1f627102>",
"WARC-Target-URI": "http://komhon.sytes.net/285pF",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:a07cf1af-5ad7-43cc-90d5-1d70c47efb8e>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-141-32-201.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2017-51\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for December 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
27,
28,
103,
104,
1037,
1204,
1230,
2161,
2568,
2597,
2625,
2989,
2990,
3001,
3002,
3021,
3022,
3050,
3051,
3536,
3537,
3554,
3555,
3852,
3853,
4486,
4487,
4887,
4888,
5427,
5428,
5477,
5478,
5493,
5494,
5515,
5516,
5550,
5804,
5881,
5896,
5911
],
"line_end_idx": [
27,
28,
103,
104,
1037,
1204,
1230,
2161,
2568,
2597,
2625,
2989,
2990,
3001,
3002,
3021,
3022,
3050,
3051,
3536,
3537,
3554,
3555,
3852,
3853,
4486,
4487,
4887,
4888,
5427,
5428,
5477,
5478,
5493,
5494,
5515,
5516,
5550,
5804,
5881,
5896,
5911,
5912
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 5912,
"ccnet_original_nlines": 42,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.37397634983062744,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.021838029846549034,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.15559600293636322,
"rps_doc_frac_unique_words": 0.45330536365509033,
"rps_doc_mean_word_length": 5.014690399169922,
"rps_doc_num_sentences": 91,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.436645984649658,
"rps_doc_word_count": 953,
"rps_doc_frac_chars_dupe_10grams": 0.3203599154949188,
"rps_doc_frac_chars_dupe_5grams": 0.3337518274784088,
"rps_doc_frac_chars_dupe_6grams": 0.3203599154949188,
"rps_doc_frac_chars_dupe_7grams": 0.3203599154949188,
"rps_doc_frac_chars_dupe_8grams": 0.3203599154949188,
"rps_doc_frac_chars_dupe_9grams": 0.3203599154949188,
"rps_doc_frac_chars_top_2gram": 0.021971119567751884,
"rps_doc_frac_chars_top_3gram": 0.015065910294651985,
"rps_doc_frac_chars_top_4gram": 0.010671690106391907,
"rps_doc_books_importance": -506.1880798339844,
"rps_doc_books_importance_length_correction": -506.1880798339844,
"rps_doc_openwebtext_importance": -269.204345703125,
"rps_doc_openwebtext_importance_length_correction": -269.204345703125,
"rps_doc_wikipedia_importance": -249.16244506835938,
"rps_doc_wikipedia_importance_length_correction": -249.16244506835938
},
"fasttext": {
"dclm": 0.06905751675367355,
"english": 0.9353649020195007,
"fineweb_edu_approx": 1.739450216293335,
"eai_general_math": 0.03238832950592041,
"eai_open_web_math": 0.16237479448318481,
"eai_web_code": 0.002502199960872531
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "5",
"label": "Social/Forum"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "4",
"label": "Indeterminate"
}
},
"missing_content": {
"primary": {
"code": "2",
"label": "Click Here References"
},
"secondary": {
"code": "3",
"label": "Incoherent Flow"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "24",
"label": "User Review"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "2",
"label": "Partially Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-2,763,525,784,640,878,000 | Common genetic variants, acting additively, are a major source of risk for autism
• Lambertus Klei1,
Affiliated with
• Stephan J Sanders2, 3, 4, 5,
Affiliated with
• Michael T Murtha2,
Affiliated with
• Vanessa Hus6,
Affiliated with
• Jennifer K Lowe7,
Affiliated with
• A Jeremy Willsey3,
Affiliated with
• Daniel Moreno-De-Luca8,
Affiliated with
• Timothy W Yu9,
Affiliated with
• Eric Fombonne10,
Affiliated with
• Daniel Geschwind7,
Affiliated with
• Dorothy E Grice11,
Affiliated with
• David H Ledbetter12,
Affiliated with
• Catherine Lord13,
Affiliated with
• Shrikant M Mane14,
Affiliated with
• Christa Lese Martin8,
Affiliated with
• Donna M Martin15,
Affiliated with
• Eric M Morrow16, 17,
Affiliated with
• Christopher A Walsh18,
Affiliated with
• Nadine M Melhem1,
Affiliated with
• Pauline Chaste1,
Affiliated with
• James S Sutcliffe19,
Affiliated with
• Matthew W State2, 3, 4, 5,
Affiliated with
• Edwin H CookJr20,
Affiliated with
• Kathryn Roeder21 and
Affiliated with
• Bernie Devlin1Email author
Affiliated with
Molecular Autism20123:9
DOI: 10.1186/2040-2392-3-9
Received: 20 August 2012
Accepted: 4 October 2012
Published: 15 October 2012
Abstract
Background
Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals.
Methods
By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status.
Results
By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating.
Conclusions
Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.
Keywords
Narrow-sense heritability Multiplex Simplex Quantitative genetics
Background
Beliefs about the genetic architecture of autism spectrum disorders (ASD) have changed dramatically over the past few decades. Early twin studies produced heritability estimates approaching 90% [1, 2] and, while no specific risk loci were known at the time, it was believed that liability was conferred by a handful of genes of large effect. Later, data on the distribution of ASD within families, together with results from linkage analyses, were interpreted to mean that liability arose from many genes [3]. Recent work has definitively demonstrated the substantial contribution of de novo variation [411]. Indeed multiple studies of rare single nucleotide and copy number variants (CNVs) have suggested that 15% or more of liability traces to de novo mutation, effects that are genetic but not inherited [2].
Importantly, despite notable recent successes in gene discovery efforts, key questions remain regarding the overall nature and scale of the genetic contribution to ASD liability. For example, the contribution of genetics is still debated: a recent large-scale twin study [12] estimated only 38% of liability was accounted for by additive genetic effects, while common environmental factors accounted for 55% of the variance; whereas most studies of twins find much higher heritability, including studies of phenotypes in the broader spectrum (see [13, 14] for review). Moreover, despite a near-consensus that common and transmitted variation must confer liability, multiple genome-wide association studies have so far not revealed replicable common polymorphisms [15] associated with ASD, and studies of rare structural and sequence mutations have largely failed to account for the anticipated risk associated with transmitted variation [6, 7]. Finally, since the earliest CNV studies in ASD, it has been postulated that the architecture of simplex and multiplex autism would be strikingly different [4]. However not all studies have found marked disparities in the rate of de novo mutation in simplex versus multiplex families, and large effect de novo mutations have been characterized in both multiplex and simplex families [9, 16].
Consequently, to gain insight into the broad questions regarding the nature of the genetic factors underlying ASD, we have estimated how much of the population variability in liability can be traced to inherited variation, specifically the narrow-sense heritability of ASD. Yang et al. [17] proposed elegant methods in which the heritability of liability can be estimated as a function of the covariance between trait values, in this instance affection status [18], and the genome wide genetics of the subjects. This contrasts with the usual approach of estimating heritability from the distribution of trait values in pedigrees. In the present study, these methods are applied to two ASD data sets, one from the Simons Simplex Collection (SSC) [19] and the other from the Autism Genome Project (AGP) [20]. Importantly the analysis of these two cohorts allows for an estimate of the heritability of ASD in simplex versus multiplex families as well as an assessment of how well the data fit predictions for an additive model of inheritance [21]. When all risk variation acts additively, for example, and no other forces alter the covariance of relatives, the liability for relatives of an affected individual consistently halves for each degree of separation from the proband. Therefore, we also evaluate heritability tracing to SSC and AGP parents and SSC unaffected siblings, evaluating the empirical results against simulation-derived expectations. Finally we use the same techniques to ask what residual heritability is contained in what the field calls pseudo-controls, which are genotypes formed from the alleles that parents did not transmit to their affected offspring.
Methods
ASD families
DNA samples from SSC and AGP family members genotyped on the Illumina Infinium® 1Mv3 (duo) microarray or the Illumina Infinium® 1Mv1 microarray were analyzed here. Specifically qualifying SSC samples were genotyped on the Illumina Infinium® 1Mv3 (duo) microarray (71.8%) while most AGP samples were genotyped on the Illumina Infinium® 1Mv1 microarray (98.7%). Both arrays genotype roughly 1,000,000 single nucleotide polymorphisms (SNPs) and the overlap between the SNP sets is almost perfect.
The SSC sample [19] includes >2,000 genotyped families. However, our analyses targeted a homogeneous subset of these data. First, we included only samples genotyped on an Illumina 1M array; families had to be ‘quads’ consisting of an unaffected mother and father, an affected proband and an unaffected sibling; and all members of a quad had to have complete genotypes (>95% completion rate). Only samples of European ancestry were included. European ancestry for the SSC families was determined using GemTools [22, 23] for all available SSC probands. To conduct the ancestry analysis we selected 5,156 SNPs with at least 99.9% calls for genotypes, had minor allele frequency MAF >0.05, and were at least 0.5 Mb apart. Individuals were clustered into nine ancestry groups based on four significant dimensions of ancestry. The central five clusters, which held a total of 1,686 families, were identified as being of European descent. The ancestry cluster information combined with complete genotype information yielded a total of 965 SSC families for the analysis.
The AGP Stage 1 dataset [16, 20] comprised 1,471 families, of which 1,141 were previously identified to be of European ancestry [20]. European ancestry was confirmed by analyses identical to those applied to the SSC families (see Additional file 1: Figure S1).
Clinical evaluation
Probands for the SSC and AGP cohorts were diagnosed in a similar manner (for diagnostic protocol for SSC, see [19]; for AGP, see [16, 20]). All SSC parents were screened for Autism Spectrum Disorder by the Broad Autism Phenotype Questionnaire [24] (self-report) and the Social Reciprocity Scale - Adult Research Version [25] (informant report). Moreover, family history evaluation excluded first-, second-, or third-degree relatives who met diagnostic criteria for ASD or intellectual disability. For AGP families 46.2% were known to be multiplex, another 38.2% were identified as simplex on the basis of a family history indicating no known first- to third-degree relatives with ASD, and the remaining 15.6% were of unknown status. Note that most AGP parents were not systematically evaluated for ASD, unlike those from the SSC, and when AGP parents were systematically evaluated, the results were not used to screen out affected individuals and thus multiplex families. In addition, while all available SSC family members were genotyped, only parent-proband trios were genotyped for the AGP even when additional siblings were available.
Control subjects
Controls derived from a convenience sample, specifically 1,663 individuals from HealthABC [26]. Control samples were also genotyped on the Illumina Infinium® 1Mv3 (duo) array, like most of the AGP data, providing excellent comparability with the case dataset. Moreover, we reasoned that ASD is sufficiently rare (approximately 1% [27]) that screened and unscreened controls would yield similar results.
Filtering
To make heritability estimates comparable, we filtered all families and control subjects based on the following criteria: all were of European descent as determined by genetically-estimated ancestry (Additional file 1: Figure S1); genotypes for all family members met stringent quality control (QC) criteria; and control samples met identical QC criteria.
For the three data sets we first chose SNPs genotyped on all platforms. Then ambiguous AT, TA, CG, and GC SNPs were removed. A total of 813,960 SNP across the 22 autosomes and chromosome X were included for further quality evaluation. At the level of individuals, we required that genotyping completion rate be greater than 98%, that there be no discrepancy regarding nominal and genotype-inferred sex, and no individuals in different families were closely related. At the level of individual SNPs, each SNP must have a genotype completion rate > 98%, have MAF > 0.01, and produce a P-value for Hardy-Weinberg equilibrium > 0.005. Following these QC steps, data from 965 SSC quad families and 1,141 AGP families were analyzed using genotypes from 713,259 SNPs.
Statistical calculations and motivation
Estimating heritability as a case-control contrast
Heritability of ASD from probands versus controls was estimated using GCTA software [28], which encodes the theory laid out in [17, 18]. Prevalence of ASD was taken to be 1% [27]. For each of the analyses, Genetic Relationship Matrices (GRM) were determined for each of the 23 chromosomes using the --make-grm option in GCTA [28]. These were then combined in an overall matrix, using the --mgrm option in GCTA. The first 10 principal components of ancestry were determined using --pca in GCTA. These 10 PCA were then used as covariates for estimating the heritability using --reml in GCTA. A prevalence of 0.01 for autism spectrum disorders was used to transform the heritability on the observed scale to the heritability on the liability scale.
The logic of estimating heritability from unaffected family members
Due to the screening of SSC samples, no SSC parents would meet criteria for ASD. Given that is the case, what is the justification for assigning them to be affected and contrasting them to controls to estimate the heritability in the parental generation? Under the additive heritability model parents transmit many genetic variants of small effect to their offspring, with the expectation that half would be transmitted from each parent. The parents of probands are thus more similar at liability loci than expected by chance, and our goal is to estimate this increased genetic similarity. Calling the parents affected and contrasting their genotypes to that of controls is a natural approach to estimating their genetic contribution to liability and it has precedence in quantitative genetics, such as estimation of the heritability of milk production from its covariance arising from bulls, when only the bull’s female progeny give milk (for example [29]).
A similar argument follows for unaffected siblings from SSC families. These siblings should receive a random sample of the parent’s genomes and, in expectation, this sampling would include half the liability alleles carried by each parent. Thus the unaffected offspring should mirror the average liability carried by the parents and this level can be estimated by calling them affected and contrasting their genotypes to those from controls.
Simulations to compute expected heritability for parents and pseudo-controls
While the literature contains numerous references to the burden of risk variants carried by parents of simplex versus multiplex families, we could not find quantitative genetics analyses of it as a function of ascertainment (there is related work on the impact of multi-locus inheritance on the power of candidate gene association studies [30, 31]). We therefore evaluated the expected heritability for parents, unaffected siblings, and pseudo-controls on the basis of simulations and the theory of quantitative genetics regarding the selection differential (for ASD, approximately 1%) and the response to selection (expected change in the population’s mean liability). The simulations are designed to mimic ascertainment for simplex and multiplex families.
One thousand SNPs having an impact on liability were simulated. The allele frequency for SNP i, p i , varied between 0.01 and 0.99. Overall heritability h 2 across all n = 1000 SNPs was set to be either 0.50 or 0.75 for probands with ASD. The relative importance of each SNP, w i , was determined by first selecting a fraction t i between 0 and 1 at random using a uniform distribution. These 1000 values were added to obtain T, and each SNP was weighted by w i = t i /T. The allele substitution effect for each SNP i was then determined as a i = w i h i 2 2 p i 1 p i http://static-content.springer.com/image/art%3A10.1186%2F2040-2392-3-9/MediaObjects/13229_2012_Article_55_IEq1_HTML.gif. For each simulation 1000 families were generated consisting of a father, mother, and one child (AGP simplex) or two children (SSC simplex or AGP multiplex). Genotypes for the parents were assigned at random using the allele frequencies, while children received alleles from the parents using the rules of Mendelian inheritance. Likewise a pseudo-control was generated by comparing the genotype of the parents to that of the proband and assigning the un-transmitted allele of each parent as the alleles for the pseudo-control’s genotype. After all genotypes in a family were assigned, the genetic contribution to the underlying liability phenotype for each individual j in the family was determined by G j = ∑ i = 1 n x i a i − μ G in which x i is the allele count for SNP i and μ G = ∑ i = 1 n p i (1 − p i )a i is the average genetic contribution over all genotypes. To simulate the environmental influence on the phenotype of individual j, ej, we drew a random number from a normal distribution with mean 0 and variance (1-h 2 ). The liability phenotype was then determined as y j u = G j + e j . Affection status was then assigned based on a f f e c t i o n s t a t u s = { n o t a f f e c t e d w h e n y i u < 2.326 a f f e c t e d w h e n y i u 2.326 http://static-content.springer.com/image/art%3A10.1186%2F2040-2392-3-9/MediaObjects/13229_2012_Article_55_IEq2_HTML.gif representing a disease risk of 1% in the population.
Four different scenarios were simulated:
1. 1.
Primary child in the family is affected (proband), and father, mother, and designated sibling were not-affected (SSC family);
2. 2.
Proband is affected, no restriction on the other individuals in the family (unscreened simplex family);
3. 3.
Proband and second child are both affected, no restriction on the other individuals in the family (unscreened multiplex family);
4. 4.
A mixture of 60% unscreened simplex families and 40% unscreened multiplex families.
By using rejection sampling, a total of 1000 families were generated for each scenario and this procedure was repeated 100 times per scenario and proband heritability (50 and 75%). To obtain the heritability estimates for the family members, the average phenotype of the primary probands on the liability scale (S) were compared to the average phenotype of the family member of interest on the liability scale (R). The heritability estimate based on the family member was estimated as h 2 = R S http://static-content.springer.com/image/art%3A10.1186%2F2040-2392-3-9/MediaObjects/13229_2012_Article_55_IEq3_HTML.gif. Note that we also checked the heritability estimated from the probands as a function of the reduction in genetic variance in the selected group. For probands, estimated heritability was always close to 50% when that was the desired heritability and always close to 75% when that was the desired heritability.
From theoretical considerations we expected assortative mating to elevate the expected liability of pseudo-controls and evaluated its impact by a simple experiment using the simulation structure just described. Rather than randomly assign genotypes to mates, we first randomly chose the paternal genotypes at the 1,000 liability SNPs, then assigned maternal genotypes on the basis of the toss of a fair coin: heads the genotype was chosen at random, tails it was taken to be the father’s genotype. All simulations procedures were as described above, except we conducted two simulations: for simulation (a) the heritability of probands from simplex families was taken to be 50% and ascertainment followed scenario 2 above; and for simulation (b) the heritability of probands from multiplex families was set to 75% and ascertainment followed scenario 3 above.
Robustness of results
To evaluate the robustness of the results, 1,986 individuals of European descent from the Neurogenetics Research Consortium [32] (NGRC) were available through dbGap [33] and used as a second control sample. For the NGRC study, genotypes were produced using the Illumina Infinium® Human Omni2.5 microarray. Therefore, to combine all four data sets, we performed QC on 444,200 SNPs genotyped on all platforms, yielding 391,425 SNPs for analyses.
Assessing the potential for experimental bias
To explore the impact of different cohorts and genotyping protocols on estimated heritability, we conducted a series of contrasts between SSC and AGP samples of the same relationship type – contrasting probands, mothers, fathers, and pseudo-controls – as well as HealthABC versus NGRC controls.
Determining genomic coverage
While 713,259 SNPs were used for primary analyses, they constitute a small fraction of the SNPs in the human genome. Hence the heritability presented could underestimate total heritability. On the other hand, because genotypes of SNPs in close proximity tend to be correlated due to linkage disequilibrium, it does not follow that the coverage of the genome by the SNPs used here estimate only a small fraction of the heritability. To determine the shortfall in “genomic coverage” and how it impacts estimates of heritability, we performed an experiment using data from the 1,000 Genomes project [34], under the assumption that coverage of common variants in the 1,000 Genomes data is perfect. Assessing all SNPs genotyped in our data, as well as subsets thereof, we estimated heritability of liability. Using the same subsets, but in 1,000 Genomes subjects, we estimated levels of genomic coverage. We can then relate estimated heritability to genomic coverage to develop a functional relationship between the two.
We performed the experiment assessing “genomic coverage” as follows. We assumed genomic coverage of SNPs with MAF > 0.1 would be essentially complete for the 379 European samples analyzed by the 1,000 Genomes project. From these genomes we selected 50 1Mb regions in which at least 500 SNPs in the 1,000 Genomes samples had MAF > 0.10. Coverage of these regions by the 713,259 SNPs was calculated as a function of the number of other SNPs with MAF > 0.1 that were tagged by (correlated with) them; call the set of M = 713,259 SNPs “tagSNP”. The tagging evaluation was implemented using Hclust [35]. Forcing tagSNP to be in the set of selected tag SNPs from the region, Hclust evaluated how many more independent SNPs N were required to cover the region when the minimum linkage disequilibrium [36] r2 amongst tags could be no less than X, where X = {0.5, 0.7, and 0.9}. Then, for each value of X, M/(M+N) estimates the coverage. Next we randomly sampled 50, 25 and 12.5% of the 713,259 SNPs (356,630, 178,315, and 89,158 SNPs respectively) five times and each time estimated coverage for these subsets.
Human subjects research statement
The research described here is in compliance with the Helsinki Declaration, including appropriate informed consent or assent [16, 19, 20, 26, 32, 33].
Results and discussion
Estimates of heritability (h2)
Heritability of SSC probands, measured against HealthABC controls, was found to be 39.6% (Figure 1A, Table 1). SSC mothers, fathers and siblings, when contrasted to controls, yielded an estimated heritability approximately half that of probands (Figure 1A, Table 1), consistent with expected values from theoretical analyses of an additive model (Figure 1A). We also generate a “pseudo-control” from the alleles that parents did not transmit to their affected offspring by using the program Plink [37]. When these pseudo-controls were contrasted to the unrelated control sample they produce estimates roughly one-quarter of that identified in probands and close to the theoretical expectation, zero (Figure 1A), demonstrating that the probands received the majority of risk alleles carried by parents.
http://static-content.springer.com/image/art%3A10.1186%2F2040-2392-3-9/MediaObjects/13229_2012_Article_55_Fig1_HTML.jpg
Figure 1
Estimated heritability for Autism Spectrum Disorders from ASD probands (Pr), as well as for their mothers (Mo), fathers (Fa), siblings (Si) and pseudo-controls (Pc). Blue dotted reference line is set to the estimated heritability from probands; the black line marks the expected heritability for first degree relatives; and the gray line marks the expected heritability from pseudo-controls. Expected values derived from simulations mimicking the recruitment strategy producing the samples for (A)-(D). (A) Simons Simplex Collection or SSC data; (B) Autism Genome Project or AGP data; (C) AGP data, only simplex families; (D) AGP data, only multiplex families.
Table 1
Heritability estimates and their standard errors (se) based on contrasts to HealthABC controls using genotypes from 713,259 SNPs
SSC
AGP
Simplex
All
Simplex
Multiplex
Estimate
se
Estimate
se
Estimate
se
Estimate
se
Probands
0.396
0.082
0.552
0.068
0.498
0.118
0.655
0.139
Mothers
0.199
0.082
0.371
0.070
0.314
0.119
0.377
0.141
Fathers
0.196
0.084
0.370
0.070
0.352
0.119
0.666
0.143
Siblings
0.158
0.082
--
--
--
--
--
--
Pseudo controls
0.090
0.082
0.381
0.070
0.317
0.120
0.503
0.146
When heritability is estimated using AGP probands (Figure 1B, Table 1), the point estimates are larger than those from SSC (h2=55.2% versus 39.6%) although the 95% confidence intervals overlap. Moreover the decline in heritability for AGP parents relative to probands is 30% (55% for probands, 37% for parents), instead of the 50% seen for SSC, and heritability estimated from pseudo-controls is also higher (38%), consistent with parental values (Figure 1B, Table 1). These results suggest that AGP parents carry a greater load of additive risk variants than SSC parents and thus are, on average, closer to the threshold of being affected.
A major difference between the SSC and AGP samples was the ascertainment and assessment process. SSC parents were systematically screened on two instruments to ensure they did not meet criteria for a spectrum diagnosis. Most parents from AGP families were not evaluated in this way, and a small fraction of those parents met criteria for ASD [9, 16]. While not as systematic as the SSC phenotyping assessment, most AGP families did have available information about simplex versus multiplex status. Consequently, we were able to compare heritability of probands from AGP multiplex versus simplex families (Figure 1D, Table 2). The former was estimated at 65.5% by comparison to HealthABC, whereas probands for AGP simplex families it was 49.8%. Thus estimates of heritability for AGP simplex probands are somewhat closer to those from SSC probands (Figure 1C) than to estimates for AGP multiplex probands. Moreover, for multiplex families and the mixed set of AGP families (simplex/multiplex/unknown), both the observed and expected heritability for first-degree relatives was higher than that seen in simplex families (Figure 1). These results comport with the literature showing that unaffected relatives from multiplex families tend to exhibit more features of the broader autism phenotype than relatives in simplex families [3840] (see Additional file 2: Table S1 for estimates from combined simplex samples).
Table 2
Heritability estimates and their standard errors (se) based on contrasts to HealthABC and NGRC controls using genotypes from 391,425 SNPs
SSC
AGP
HealthABC
NGRC
HealthABC
NGRC
Estimate
se
Estimate
se
Estimate
se
Estimate
se
Probands
0.395
0.082
0.378
0.073
0.553
0.068
0.586
0.063
Mothers
0.200
0.082
0.232
0.074
0.371
0.070
0.342
0.065
Fathers
0.196
0.084
0.153
0.073
0.373
0.070
0.518
0.063
Siblings
0.158
0.082
0.170
0.073
--
--
--
--
Pseudo controls
0.090
0.082
0.107
0.073
0.380
0.070
0.446
0.065
A curious observation from AGP multiplex families was that fathers generate larger heritability than mothers. We reasoned that this could be explained by three plausible hypotheses: (1) the confidence intervals of the paternal and maternal estimates overlap, so there is no true difference; (2) the load of risk variants is, in fact, greater for AGP fathers; or (3) fathers carry a larger number of both liability and protective alleles. The last of these requires some elaboration. Males are at much greater risk for ASD than females (4:1 or greater) and parents carry additive risk factors, yet AGP fathers and mothers are largely unaffected. It is possible, then, that the increased allele sharing in unaffected fathers is due to a greater proportion of protective alleles, with females being resilient for some other reason (for example, estrogen/testosterone balance) in the face of a similar degree of genetic risk.
Our results support either the first or second hypotheses but are not consistent with the third. The first hypothesis is impossible to rule out given the limited sample size. For the second hypothesis, if AGP fathers were simply carrying greater risk, some of those additional risk alleles would be carried by the pseudo-controls and the heritability obtained from the contrast of probands and pseudo-controls should be substantially smaller than that observed from probands versus controls. Indeed the values are substantially smaller: 10.9% vs. 39.6% for SSC; 14.5% vs. 55.2% for all AGP; 0.0% vs. 49.8% for simplex AGP, and 27.1% vs. 65.5% for multiplex AGP. Finally, if (3) were true, then contrasting probands to pseudo-controls would produce substantial estimates of heritability because of the differentiation induced by protective alleles, but this is not observed.
Distribution of liability alleles in the genome
If the additive variation for liability to ASD conforms to the traditional polygenic or infinitesimal model, then liability variants should be distributed at random over the genome. The implication is that if heritability were estimated for each chromosome, the resulting estimates should be correlated with the lengths of the chromosomes. On the other hand, if the heritability traced to a relatively small number of variants, even a few dozen, such a correlation would be unlikely. In fact, we observe significant correlation between per-chromosome heritability and chromosome length (Figure 2), both for simplex (r = 0.46, P value = 0.028) and multiplex (r= 0.54, P value = 0.0075) families.
http://static-content.springer.com/image/art%3A10.1186%2F2040-2392-3-9/MediaObjects/13229_2012_Article_55_Fig2_HTML.jpg
Figure 2
Estimated heritability per chromosome for simplex and muliplex families. In this figure chromosome X is marked distinctly, but each chromosome is mapped by its length.
In Figure 2 the deviation from prediction for chromosome X is surprising. For both multiplex and simplex families, heritability estimated from X is less than that predicted by its size. This is noteworthy because chromosome X has been cited as a possible source of sex-differential liability for ASD [41]. Our results suggest that common variants affecting liability do not cluster on chromosome X.
Evaluating robustness of results
To evaluate the robustness of our results, we first contrasted the genotypes of SSC and AGP probands to a second large set of controls, 1,986 individuals from the Neurogenetics Research Consortium [32, 33]. These samples, genotyped on the Illumina Infinium® Human Omni2.5, were filtered and subjected to QC in an identical fashion to the HealthABC control set. There was excellent agreement of heritability estimates for ASD from the two control samples (Tables 2 and 3) despite differences in ascertainment of the controls and the different genotyping platforms.
Table 3
Heritability estimates and their standard errors (se) based on contrasts to HealthABC and NGRC controls using genotypes from 391,425 SNPs but separating the AGP data into multiplex and simplex families for estimation
AGP multiplex
AGP simplex
HealthABC
NGRC
HealthABC
NGRC
Estimate
se
Estimate
se
Estimate
se
Estimate
se
Probands
0.650
0.139
0.710
0.140
0.503
0.117
0.494
0.114
Mothers
0.369
0.141
0.387
0.136
0.311
0.119
0.268
0.117
Fathers
0.664
0.143
0.693
0.140
0.359
0.119
0.520
0.113
Pseudo controls
0.497
0.146
0.524
0.140
0.323
0.120
0.438
0.117
Next, the impact of different cohorts and genotyping platforms on estimates of heritability was explored by conducting a series of contrasts between SSC and AGP samples of the same relationship type: contrasting probands, mothers, fathers, and pseudo-controls. Note that most SSC samples were genotyped on the Illumina® 1Mv3 (duo) microarray (71.8%) while most AGP samples were genotyped on the Illumina Infinium® 1Mv1 microarray (98.7%). Contrasts between SSC and AGP samples of the same relationship type (Additional file 3: Table S2) produce estimates close to the difference between their control-based heritability. Indeed the estimates from direct contrasts were usually smaller than the difference of control-based heritability (for probands, 0.08 vs. 0.15 ≈ 0.552-0.396 from Table 1; for mothers, 0.11 vs. 0.17; for fathers, 0.19 vs. 0.17; and for pseudo-controls, 0.22 vs. 0.29). Thus these results are not consistent with effects attributable to genotyping platform or ascertainment beyond multiplex/simplex status. Implicit in these results is common genetic liability - SSC and AGP probands must share many liability variants despite their differences in ascertainment. Indeed when AGP multiplex probands are contrasted to SSC probands the resulting heritability is 0.23, quite similar to that expected by the difference in their estimated heritability (0.66 - 0.40 = 0.26); and when AGP simplex probands are contrasted to SSC probands, the resulting estimated heritability, 0.0, is below that of the difference in their estimated heritability (0.50 - 0.40 = 0.10). These results suggest that the difference between multiplex and simplex families is largely a matter of degree (see also [42]), namely the number of liability alleles carried by parents, rather than a fundamental difference in the genetic architecture [4, 43].
Given the remarkable similarities of heritability estimates obtained for either set of control samples (Tables 2 and 3), one might anticipate there would be little, if any, difference between these controls. When we contrasted these control samples, however, they produced a heritability of 26.5% (Additional file 3: Table S2). Mathematically, estimates of heritability arise from a high dimensional space of allele frequencies, phenotypes and their interrelationships. Therefore even if two controls groups evoke similar estimates of ASD heritability from the same sample of probands, the controls themselves need not be close in the multidimensional space of allele frequencies. What generates the differentiation between controls is unknown. It could arise from the different genotyping platforms or from differences in ascertainment. In light of this difference, the fact that both controls sets give rise to nearly identical estimates of heritability for all proband subsets is remarkable and suggests that the similarity amongst cases overwhelms differences between the controls.
Heritability of pseudo-controls
There remains an unexplained feature of the results: estimates of heritability for pseudo-controls tend to be elevated over their theoretical values (Figure 1). Several genetic forces could be at play. The simulations to derive the distribution of liability in families also produce estimates for pseudo-controls. Those results show (Figure 1) that while the expected heritability for simplex families is zero, multiplex status raises the expected value to 20%. It is not unreasonable to assume that the simplex collections analyzed here contain families with unrealized multiplex potential, and that might be especially true for AGP families that had ascertainment criteria less stringent than those for SSC families.
A factor that will elevate the expected heritability in pseudo-controls is positive assortative mating (henceforth assortative mating). Assortative mating on phenotypes related to ASD liability has been previously reported [39]. When parents are genetically similar at liability loci and they bear affected offspring, their gametes will tend to be highly enriched for risk alleles, even those that are not transmitted to affected offspring. Simple simulations mimicking assortative mating show that it can exert an impact similar to the difference between simplex and multiplex status. When simplex probands had heritability of 50% (that is, simulation a in Methods), the expected heritability of pseudo-controls was 11.3% – versus 0% without assortative mating. When multiplex probands had heritability of 75%, the expected heritability of pseudo-controls was 42.8% – versus 20.2% without assortative mating. These simple experiments were not intended to cover the range of plausible scenarios for assortative mating relevant to ASD, which would be impossible, but rather to demonstrate the effect of such mating on the nature of pseudo-controls. Thus assortative mating could be an important and salient source of enrichment. Whether these forces explain all of the elevated heritability for pseudo-controls will require further data and analyses.
Impact of genome coverage
Because the set of SNPs used for primary analyses constitute a small fraction of the SNPs in the human genome, estimates of heritability (Figure 1) could be biased downward. Still, due to linkage disequilibrium, the degree of bias is not trivial to estimate. Therefore we performed an experiment to evaluate the shortfall in genomic coverage and how it impacts estimates of heritability. Results from the experiment are shown in Additional file 4: Figure S2, in which estimated heritability was plotted against estimated coverage. These results suggest that heritability estimates from probands, as shown in Figure 1, are good approximations. They represent only slight underestimates of what would be obtained had the entire genome been sampled.
In total our results demonstrate that a substantial portion of ASD liability arises from inherited variation acting additively. This pattern holds both for simplex and multiplex families, with the burden of liability greater in multiplex families, consistent with theoretical and empirical [3840] results. The modeling reported here does not differentiate between additive effects due to common versus rare variation. Nonetheless it is reasonable to assume that most of the estimated heritability traces to common variants because linkage disequilibrium between the common variants analyzed and rare liability variants should, on average, be small [44]. Thus the additive contribution of rare variants to ASD liability is likely underestimated. Imperfect coverage must also have an impact, but our analyses suggest its impact is not large (Additional file 4: Figure S2).
Our analyses cannot address other features of the genetic architecture of ASD, including non-additive genetic effects, which add to ASD’s broad-sense heritability [45], and de novo mutations. In addition, because they underestimate the impact of rare inherited variation, they differ from family-based estimates, such as from twin studies, that do capture these effects. Still our findings of substantial heritability are consistent with the majority of twin studies [1, 2] and are richer in some ways because the analytic technique [17, 18] used here provides a direct estimate of the proportion of liability attributable to additive genetic effects, whereas twin studies obtain their estimates by relying on assumptions that are approximations. For example, Zuk et al. [45] point out that non-additive genetic effects are almost surely a component of the genetic architecture of any trait, but these effects cannot be captured by twin designs. Yet for autism and other psychiatric disorders non-additive genetic effects could be an integral component [4648]. Twin designs also fail to capture other features, such as maternal effects [49] and de novo mutations, which are an important component of ASD genetic architecture [411].
A recent ASD twin study [12] estimates 38% of ASD liability traces to additive genetic effects while 55% traces to common environment. Our point estimates would be close to theirs if ascertainment of their families was like that for SSC families, but not like that for AGP families. A substantial fraction of their dizygotic twins, however, are multiplex for ASD. Thus their point estimate for heritability from additive genetic effects is low relative to ours. If rare inherited variation contributes substantially to liability for ASD, this makes the 38% estimate seem lower still because twin studies should capture these effects whereas our estimates cannot.
Genomewide association studies [18, 5052] have detected only a handful of SNPs, all of small effect and none replicating reliably. Teaming this observation with our estimates of heritability (Figure 1) and the fact that these studies are underpowered to detect genetic variants of small effect size, but are otherwise well powered [15], we conclude there must be thousands of SNPs scattered across the genome with common liability alleles. Analyses of chromosome-specific heritability support this conclusion (Figure 2). Employing analyses like those proposed by Stahl et al. [53] could estimate this distribution of effects.
Because these loci have small effect, samples far larger than exist today will be required to identify a substantial fraction of them using standard genome-wide association methodology. Hence, for the immediate future, ample “missing heritability” for ASD will remain. Ingenious designs will be required in the near term [54] to identify SNPs affecting liability. In the longer term GWAS of a large number of ASD subjects, at least on the order of that performed for schizophrenia [5557], should be one of the priorities for the field of ASD genetics.
One way forward is to exploit shared liability across psychiatric disorders, taking advantage of larger samples [58] afforded by cross-disorder meta-analysis. There is now sound evidence for common variants affecting liability for schizophrenia [5557], including a study similar to ours [46]. Given the documented sharing of rare variants affecting risk for both disorders (for example [59]), it would not be surprising to find that some common variants affect liability to both schizophrenia and ASD.
The estimated heritability for schizophrenia using methods similar to ours is 23% [46]; for bipolar disorder and similar methods it is 40% [60]; and for major depression it is 32% [61]. None of these studies separate out simplex and multiplex families, so in that sense they are most comparable to the estimate obtained over all AGP families, 55%, although the representation of multiplex families in the AGP sample is likely larger than for the other samples. Regardless of the differences in simplex/multiplex representation, these estimates are stochastically similar, in view of their standard errors, emphasizing that common variants affect liability for most if not all psychiatric disorders. Moreover their impact appears to be similar in magnitude across disorders, as measured by heritability estimated from common variants.
That ASD shows the largest estimated heritability is notable and could reflect the fact that the sibling recurrence risk is, on average, higher for siblings of an ASD proband than for siblings of probands diagnosed with schizophrenia, bipolar disorder or major depression. Sibling recurrence risk is a ratio, defined as the probability of a sibling being affected, given that the proband is affected, divided by the prevalence of the disorder in the general population. Recent studies put this recurrence risk at almost 20 for ASD [62], whereas for schizophrenia it is 6 to 10 fold [63], for bipolar disorder it is 4 to 10 fold [64], and for major depression it is roughly twofold [64]. The larger heritability could also trace to differences among studies. It is possible that our estimates of heritability are inflated by unknown differences between our case and control samples, including ascertainment biases and genotype quality. Regarding the latter, we selected case and control samples genotyped on the same genotyping platform to minimize differences and we did not detect any large differences in allele frequencies, but we cannot rule out subtle differences in quality.
Regarding identification of common variants affecting liability, our results suggest that the contrast of case and pseudo-control genotypes, the “family-based” analysis, is not optimal. In many samples pseudo-controls carry a substantial burden of risk variants and their presence degrades the power of family-based analysis to detect risk SNPs (see also [30, 31]). Instead it appears that population-based controls contrasted with ASD cases would be a more powerful design [65], even after adjusting for ancestry [66]. In this regard it is intriguing that the earliest GWAS of ASD [50] used population-based controls to identify a single locus at 5p14.1, and this result has since garnered support from a functional study that reveals a plausible biological link to ASD liability [67].
The genetic architecture of ASD has numerous components: additive, non-additive and de novo genetic effects, as well as gene-gene and gene-environment interactions. The results shown here are relevant to only one of these components. Other components, such as de novo events, are also known to make a substantial contribution to liability [411], while others remain to be thoroughly investigated [45]. Already analyses of rare variation of major effect has revealed a substantial number of genes affecting liability [811, 6870]; it is reasonable to predict that common variants regulating expression of those ASD genes could also affect liability [71]. We hypothesize that the interplay of rare and common variants is critical not only to liability itself, but to the expression of ASD or other relevant psychiatric and developmental disorders. The dynamics of this interplay will likely be an important area for future autism research.
Conclusions
Common genetic polymorphisms exert substantial additive genetic effects on ASD liability and their impact differs by ascertainment strategies used to recruit families. For simplex families, who have only a single affected individual in multiple generations, approximately 40% of liability traces to additive effects whereas this narrow-sense heritability exceeds 60% for ASD individuals from multiplex families. Data for simplex ASD families follow the expectation for additive models closely. Data from multiplex families deviate somewhat from an additive model. This result is consistent with what would be expected from positive assortative mating, but our data do not prove such a pattern of mating occurred. In light of results from genome-wide association studies, there must be many common variants of very small effect affecting liability to ASD.
Availability of supporting data
The data sets supporting the results of this article are available in the repositories: Simons Foundation Autism Research Initiative, SFARI [http://sfari.org/sfari-initiatives/simons-simplex-collection]; and the National Institutes of Health database of Genotypes and Phenotypes, dbGaP [http://www.ncbi.nlm.nih.gov/gap].
Abbreviations
AGP:
Autism Genome Project
ASD:
Autism Spectrum Disorders
CNVs:
Copy Number Variants
GCTA:
Genome-Wide Complex Trait Analysis, Software used to estimate heritability, amongst others
GRM:
Genetic Relationship Matrices
HealthABC:
A sample of subjects used as controls and genotyped on the Illumina Infinium® 1Mv3 (duo) array
MAF:
Minor Allele Frequency
NGRC:
Neurogenetics Research Consortium, a sample of subjects used as controls and genotyped on the Illumina Infinium® Human Omni2.5 microarray
QC:
Quality Control
SNPs:
Single Nucleotide Polymorphisms
SSC:
Simons Simplex Collection.
Declarations
Acknowledgments
Research supported by grants from the Simons Foundation and MH057881.
SSC: We are grateful to all of the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC). This work was supported by a grant from the Simons Foundation. We wish to thank the SSC principal investigators A.L. Beaudet, R. Bernier, J. Constantino, E.H. Cook, Jr., E. Fombonne, D. Geschwind, D.E. Grice, A. Klin, D.H. Ledbetter, C. Lord, C.L. Martin, D.M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M.W. State, W. Stone, J.S. Sutcliffe, C.A. Walsh, and E. Wijsman; the coordinators and staff at the SSC sites; the SFARI staff, in particular M. Benedetti; Prometheus Research; the Yale Center of Genomic Analysis staff, in particular M. Mahajan, S. Umlauf, I. Tikhonova and A. Lopez; T. Brooks-Boone, N. Wright-Davis and M. Wojciechowski for their help in administering the project at Yale; I. Hart for support; and G.D. Fischbach, A. Packer, J. Spiro, M. Benedetti and M. Carlson for their helpful suggestions throughout. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org.
AGP: We used data from the Autism Genome Project (AGP) Consortium - Whole Genome Association and Copy Number Variation Study of over 1,500 Parent-Offspring Trios - Stage I (dbGaP Study Accession: phs000267.v1.p1). Funding for AGP was provided from National Institutes of Health (HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261); The Canadian Institutes for Health Research (CIHR); Assistance Publique - Hôpitaux de Paris, France; Autism Speaks UK; Canada Foundation for Innovation/Ontario Innovation Trust; Grant: Po 255/17-4. Deutsche Forschungsgemeinschaft, Germany; EC Sixth FP AUTISM MOLGEN; Fundação Calouste Gulbenkian, Portugal; Fondation de France; Fondation FondaMental, France; Fondation Orange, France; Fondation pour la Recherche Médicale, France; Fundação para a Ciência e Tecnologia, Portugal; The Hospital for Sick Children Foundation and University of Toronto, Canada; INSERM, France; Institut Pasteur, France; Convention 181 of 19.10.2001. Italian Ministry of Health; John P Hussman Foundation, USA; McLaughlin Centre, Canada; Rubicon 825.06.031. Netherlands Organization for Scientific Research; TMF/DA/5801. Royal Netherlands Academy of Arts and Sciences; Ontario Ministry of Research and Innovation, Canada; Seaver Foundation, USA; Swedish Science Council; The Centre for Applied Genomics, Canada; Utah Autism Foundation, USA; Core award 075491/Z/04. Wellcome Trust, UK. Genotype and phenotype data were obtained from dbGap, as provided by AGP Study Investigators.
HealthABC: These controls were obtained from Database for Genotypes and Phenotypes (dbGap) at http://www.ncbi.nlm.nih.gov/gap. Funding support for the “CIDR Visceral Adiposity Study” (Study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genome-wide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators.
NGRC: We also used the NINDS dbGaP database from the CIDR: NGRC Parkinson’s Disease Study (dbGap accession number phs000196.v2.p1). The genetic arm of the study has been funded by NIH since 1998 (R01 NS36960, Haydeh Payami, PI). In 2004, the consortium was formalized as a Michael J Fox Foundation Funded Global Genetic Consortium, and an epidemiologic arm was implemented. Genotype and phenotype data were obtained from dbGap, as provided by NGRC Parkinson’s Disease Study Investigators.
For both the HealthABC and NGRC studies, genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C and HHSN268201100011I.
Authors’ Affiliations
(1)
Department of Psychiatry, University of Pittsburgh School of Medicine
(2)
Program on Neurogenetics, Yale University School of Medicine
(3)
Child Study Center, Yale University School of Medicine
(4)
Department of Psychiatry, Yale University School of Medicine
(5)
Department of Genetics, Yale University School of Medicine
(6)
Department of Psychology, University of Michigan
(7)
Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles
(8)
Department of Human Genetics, Emory University School of Medicine
(9)
Division of Genetics, Children's Hospital Boston, Harvard Medical School
(10)
Department of Psychiatry, McGill University, Montreal Children's Hospital
(11)
Department of Psychiatry, Mount Sinai School of Medicine
(12)
Geisinger Health System
(13)
Center for Autism and the Developing Brain, Weill Cornell Medical College
(14)
Yale Center for Genome Analysis
(15)
Departments of Pediatrics and Human Genetics, The University of Michigan Medical Center
(16)
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University
(17)
Department of Psychiatry and Human Behavior, Brown University
(18)
Howard Hughes Medical Institute and Division of Genetics, Children's Hospital Boston, and Neurology and Pediatrics, Harvard Medical School Center for Life Sciences
(19)
Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University
(20)
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago
(21)
Department of Statistics, Carnegie Mellon University
References
1. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M: Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995, 25: 63-77.View ArticlePubMed
2. Devlin B, Scherer SW: Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012, 22: 229-237.View ArticlePubMed
3. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Petersen PB, Pingree C, McMahon W, Wong DL, Cavalli-Sforza LL, Kraemer HC: A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet. 1999, 65: 493-507.PubMed CentralView ArticlePubMed
4. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K: Strong association of de novo copy number mutations with autism. Science. 2007, 316: 445-449.PubMed CentralView ArticlePubMed
5. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R: Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008, 82: 477-488.PubMed CentralView ArticlePubMed
6. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M: Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011, 70: 886-897.View ArticlePubMed
7. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC: Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011, 70: 863-885.PubMed CentralView ArticlePubMed
8. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW: De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012, 485: 237-241.PubMed CentralView ArticlePubMed
9. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y: Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012, 485: 242-PubMed CentralView ArticlePubMed
10. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE: Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012, 485: 246-250.PubMed CentralView ArticlePubMed
11. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB: De novo gene disruptions in children on the autistic spectrum. Neuron. 2012, 74: 285-299.PubMed CentralView ArticlePubMed
12. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N: Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011, 68: 1095-1102.PubMed CentralView ArticlePubMed
13. Ronald A, Hoekstra RA: Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet. 2011, 156B: 255-274.View ArticlePubMed
14. Taniai H, Nishiyama T, Miyachi T, Imaeda M, Sumi S: Genetic influences on the broad spectrum of autism: study of proband-ascertained twins. Am J Med Genet B Neuropsychiatr Genet. 2008, 147B: 844-849.View ArticlePubMed
15. Devlin B, Melhem N, Roeder K: Do common variants play a role in risk for autism? Evidence and theoretical musings. Brain Res. 2011, 1380: 78-84.PubMed CentralView ArticlePubMed
16. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C: Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010, 466: 368-372.PubMed CentralView ArticlePubMed
17. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Madden PA, Heath AC, Martin NG, Montgomery GW, Goddard ME, Visscher PM: Common SNPs explain a large proportion of the heritability for human height. Nat Genet. 2010, 42: 565-569.PubMed CentralView ArticlePubMed
18. Lee SH, Wray NR, Goddard ME, Visscher PM: Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet. 2011, 88: 294-305.PubMed CentralView ArticlePubMed
19. Fischbach GD, Lord C: The Simons simplex collection: a resource for identification of autism genetic risk factors. Neuron. 2010, 68: 192-195.View ArticlePubMed
20. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A: A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet. 2010, 19: 4072-4082.PubMed CentralView ArticlePubMed
21. Falconer DS: Introduction to Quantitative Genetics. 1981, London: Longman
22. Lee AB, Luca D, Klei L, Devlin B, Roeder K: Discovering genetic ancestry using spectral graph theory. Genet Epidemiol. 2009, 34: 51-59.
23. Klei L, Kent BP, Melhem N, Devlin B, Roeder K: GemTools: a fast and efficient approach to estimating genetic ancestry. 2011,http://arxiv.org/pdf/1104.1162.pdf,
24. Hurley RS, Losh M, Parlier M, Reznick JS, Piven J: The broad autism phenotype questionnaire. J Autism Develop Dis. 2007, 37: 1679-1690.View Article
25. Constantino JN, Gruber CP: The Social Responsiveness Scale manual. 2005, Los Angeles, CA: Western Psychological Services
26. HealthABC data.http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000169.v1.p1,
27. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention: Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ. 2012, 61: 1-19.
28. Yang J, Lee SH, Goddard ME, Visscher PM: GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011, 88: 76-82.PubMed CentralView ArticlePubMed
29. http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1425&context=animalscifacpub
30. Risch N: Implications of multilocus inheritance for gene-disease association studies. Theor Popul Biol. 2001, 60: 215-220.View ArticlePubMed
31. Ferreira MA, Sham P, Daly MJ, Purcell S: Ascertainment through family history of disease often decreases the power of family-based association studies. Behav Genet. 2007, 37: 631-636.View ArticlePubMed
32. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H: Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. 2010, 42: 781-785.PubMed CentralView ArticlePubMed
33. Neurogenetics Research Consortium data.http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000196.v2.p1,
34. Clarke L, Zheng-Bradley X, Smith R, Kulesha E, Xiao C, Toneva I, Vaughan B, Preuss D, Leinonen R, Shumway M, Sherry S, Flicek P, 1000 Genomes Project Consortium: The 1000 Genomes Project: data management and community access. Nat Methods. 2012, 9: 459-462.PubMed CentralView ArticlePubMed
35. Rinaldo A, Bacanu SA, Devlin B, Sonpar V, Wasserman L, Roeder K: Characterization of multilocus linkage disequilibrium. Genet Epidemiol. 2005, 28: 193-206.View ArticlePubMed
36. Devlin B, Risch N: A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics. 1995, 29: 311-322.View ArticlePubMed
37. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81: 559-575.PubMed CentralView ArticlePubMed
38. Bernier R, Gerdts J, Munson J, Dawson G, Estes A: Evidence for broader autism phenotype characteristics in parents from multiple-incidence autism families. Autism Res. 2012, 5: 13-20.PubMed CentralView ArticlePubMed
39. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN: Familial aggregation of quantitative autistic traits in multiplex versus simplex autism. Am J Med Genet B Neuropsychiatr Genet. 2009, 150B: 328-334.PubMed CentralView ArticlePubMed
40. Szatmari P, MacLean JE, Jones MB, Bryson SE, Zwaigenbaum L, Bartolucci G, Mahoney WJ, Tuff L: The familial aggregation of the lesser variant in biological and nonbiological relatives of PDD probands: a family history study. J Child Psychol Psychiatry. 2000, 41: 579-586.View ArticlePubMed
41. Marco EJ, Skuse DH: Autism-lessons from the X chromosome. Soc Cogn Affect Neurosci. 2006, 1: 183-193.PubMed CentralView ArticlePubMed
42. Spiker D, Lotspeich LJ, Dimiceli S, Myers RM, Risch N: Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient. Am J Med Genet. 2002, 114: 129-136.View ArticlePubMed
43. Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, Law P, Qiu S, Lord C, Sebat J, Ye K, Wigler M: A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA. 2007, 104: 12831-12836.PubMed CentralView ArticlePubMed
44. Sun X, Namkung J, Zhu X, Elston RC: Capability of common SNPs to tag rare variants. BMC Proc. 2011, 5 (Suppl 9): S88-PubMed CentralView ArticlePubMed
45. Zuk O, Hechter E, Sunyaev SR, Lander ES: The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci USA. 2012, 109: 1193-1198.PubMed CentralView ArticlePubMed
46. Risch N: Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990, 46: 222-228.PubMed
47. Sanders AR, Duan J, Gejman PV: Complexities in psychiatric genetics. Int Rev Psychiatry. 2004, 16: 284-293.View ArticlePubMed
48. Slatkin M: Exchangeable models of complex inherited diseases. Genetics. 2008, 179: 2253-2261.PubMed CentralView ArticlePubMed
49. Devlin B, Daniels M, Roeder K: The heritability of IQ. Nature. 1997, 388: 468-471.View ArticlePubMed
50. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009, 459: 528-533.PubMed CentralView ArticlePubMed
51. Weiss LA, Arking DE, Daly MJ, Chakravarti A: A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009, 461: 802-808.PubMed CentralView ArticlePubMed
52. Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A: Individual common variants exert weak effects on risk for autism spectrum disorders. Hum Mol Genet. 2012, in press
53. Stahl EA, Wegmann D, Trynka G, Gutierrez-Achury J, Do R, Voight BF, Kraft P, Chen R, Kallberg HJ, Kurreeman FA, Kathiresan S, Wijmenga C, Gregersen PK, Alfredsson L, Siminovitch KA, Worthington J, de Bakker PI, Raychaudhuri S, Plenge RM, Diabetes Genetics Replication and Meta-analysis Consortium; Myocardial Infarction Genetics Consortium: Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat Genet. 2012, 44: 483-489.View ArticlePubMed
54. Melhem N, Devlin B: Shedding new light on genetic dark matter. Genome Med. 2010, 2: 79-PubMed CentralView ArticlePubMed
55. Lee SH, Decandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME, Keller MC, Visscher PM, Wray NR, Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), The International Schizophrenia Consortium (ISC), The Molecular Genetics of Schizophrenia Collaboration (MGS): Estimating the proportion of variation in susceptibility to Schizophrenia captured by common SNPs. Nat Genet. 2012, 44: 831-View Article
56. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P, International Schizophrenia Consortium: Common polygenic variation contributes to risk of Schizophrenia and bipolar disorder. Nature. 2009, 460: 748-PubMed
57. Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, Lin DY, Duan J, Ophoff RA, Andreassen OA, Scolnick E, Cichon S, St Clair D, Corvin A, Gurling H, Werge T, Rujescu D, Blackwood DH, Pato CN, Malhotra AK, Purcell S, Dudbridge F, Neale BM, Rossin L, Visscher PM, Posthuma D, Ruderfer DM, Fanous A, Stefansson H, Steinberg S: Genome-wide association study identifies five new Schizophrenia loci. Nat Genet. 2011, 43: 969-976.View Article
58. Sullivan PF: The psychiatric GWAS consortium: big science comes to psychiatry. Neuron. 2010, 68: 182-186.PubMed CentralView ArticlePubMed
59. Dolcetti A, Silversides CK, Marshall CR, Lionel AC, Stavropoulos DJ, Scherer SW, Bassett AS: 1q21.1 Microduplication expression in adults. Genet Med. 2012, in press
60. Lee SH, DeCandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME, Keller MC, Visscher PM, Wray NR, Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ); International Schizophrenia Consortium (ISC); Molecular Genetics of Schizophrenia Collaboration (MGS): Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet. 2012, 44: 247-250.PubMed CentralView ArticlePubMed
61. Lubke GH, Hottenga JJ, Walters R, Laurin C, de Geus EJ, Willemsen G, Smit JH, Middeldorp CM, Penninx BW, Vink JM, Boomsma DI: Estimating the genetic variance of major depressive disorder due to all single nucleotide polymorphisms. Biol Psychiatry. 2012, 72: 707-709.PubMed CentralView ArticlePubMed
62. Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson S, Carver LJ, Constantino JN, Dobkins K, Hutman T, Iverson JM, Landa R, Rogers SJ, Sigman M, Stone WL: Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011, 128: e488-e495.PubMed CentralPubMed
63. Kendler KS, Diehl SR: The genetics of schizophrenia: a current, genetic-epidemiologic perspective. Schizophr Bull. 1993, 19: 261-285.View ArticlePubMed
64. Smoller JW, Finn CT: Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet. 2003, 123C: 48-58.View ArticlePubMed
65. Bacanu S-A, Devlin B, Roeder K: The power of genomic control. Am J Hum Genet. 2000, 66: 933-944.View Article
66. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006, 38: 904-909.View ArticlePubMed
67. Kerin T, Ramanathan A, Rivas K, Grepo N, Coetzee GA, Campbell DB: A noncoding RNA antisense to moesin at 5p14.1 in autism. Sci Transl Med. 2012, 4: 128ra40-View ArticlePubMed
68. Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U, Endris V, Roberts W, Szatmari P, Pinto D, Bonin M, Riess A, Engels H, Sprengel R, Scherer SW, Rappold GA: Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet. 2010, 42: 489-491.View ArticlePubMed
69. Vaags AK, Lionel AC, Sato D, Goodenberger M, Stein QP, Curran S, Ogilvie C, Ahn JW, Drmic I, Senman L, Chrysler C, Thompson A, Russell C, Prasad A, Walker S, Pinto D, Marshall CR, Stavropoulos DJ, Zwaigenbaum L, Fernandez BA, Fombonne E, Bolton PF, Collier DA, Hodge JC, Roberts W, Szatmari P, Scherer SW: Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet. 2012, 90: 133-141.PubMed CentralView ArticlePubMed
70. Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, O'Connor I, Russell C, Drmic IE, Hamdan FF, Michaud JL, Endris V, Roeth R, Delorme R, Huguet G, Leboyer M, Rastam M, Gillberg C, Lathrop M, Stavropoulos DJ, Anagnostou E, Weksberg R, Fombonne E, Zwaigenbaum L, Fernandez BA, Roberts W, Rappold GA, Marshall CR, Bourgeron T, Szatmari P, Scherer SW: SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet. 2012, 90: 879-887.PubMed CentralView ArticlePubMed
71. Davis LK, Gamazon ER, Kistner-Griffin E, Badner JA, Liu C, Cook EH, Sutcliffe JS, Cox NJ: Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci. Mol Autism. 2012, 3: 3-PubMed CentralView ArticlePubMed
Copyright
© Klei et al.; licensee BioMed Central Ltd. 2012
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | {
"url": "http://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-3-9",
"source_domain": "molecularautism.biomedcentral.com",
"snapshot_id": "crawl=CC-MAIN-2016-07",
"warc_metadata": {
"Content-Length": "219420",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:7DXMCTDQWS2LC4LJ44WNVSPUCVZXTIQU",
"WARC-Concurrent-To": "<urn:uuid:6a687ba7-a9a6-4ae8-a038-9222ef7ebb1b>",
"WARC-Date": "2016-02-06T00:04:42",
"WARC-IP-Address": "23.235.39.250",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:HGKMFVXPL2C4UPFWGRJTZIEKXUVMOLET",
"WARC-Record-ID": "<urn:uuid:a0f36bb9-ee8a-42ad-97a7-e572fa51701c>",
"WARC-Target-URI": "http://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-3-9",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:22c3b664-8c10-4213-8e41-70a354581197>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-236-182-209.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2016-07\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for February 2016\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
82,
83,
104,
105,
125,
126,
161,
162,
184,
185,
212,
213,
237,
238,
262,
263,
289,
290,
320,
321,
349,
350,
383,
384,
414,
415,
455,
456,
488,
489,
522,
523,
557,
558,
595,
596,
632,
633,
674,
675,
713,
714,
757,
758,
798,
799,
846,
847,
889,
890,
936,
937,
981,
982,
1031,
1032,
1078,
1079,
1133,
1134,
1182,
1183,
1235,
1236,
1286,
1287,
1344,
1345,
1397,
1398,
1459,
1460,
1514,
1515,
1573,
1574,
1630,
1631,
1690,
1691,
1749,
1750,
1815,
1816,
1876,
1877,
1950,
1951,
2013,
2014,
2080,
2081,
2145,
2146,
2217,
2218,
2284,
2285,
2364,
2365,
2433,
2434,
2510,
2511,
2590,
2591,
2668,
2669,
2746,
2747,
2826,
2827,
2888,
2889,
2952,
2953,
3695,
3696,
3756,
3757,
4230,
4231,
4291,
4292,
5125,
5126,
5190,
5191,
5421,
5422,
5483,
5484,
5602,
5603,
5666,
5667,
6531,
6532,
7920,
7921,
9650,
9651,
9711,
9712,
9777,
9778,
10324,
10325,
11440,
11441,
11754,
11755,
11827,
11828,
13019,
13020,
13089,
13090,
13545,
13546,
13608,
13609,
14017,
14018,
14831,
14832,
14924,
14925,
15028,
15029,
15827,
15828,
15948,
15949,
16960,
16961,
17455,
17456,
17585,
17586,
18396,
18397,
20574,
20575,
20668,
20726,
20727,
20907,
20908,
20964,
21022,
21023,
21181,
21182,
21238,
21296,
21297,
21480,
21481,
21537,
21595,
21596,
21734,
21735,
21791,
21792,
22769,
22770,
23680,
23681,
23755,
23756,
24252,
24253,
24351,
24352,
24699,
24700,
24781,
24782,
25850,
25851,
27006,
27007,
27093,
27094,
27297,
27298,
27373,
27374,
27457,
27458,
28312,
28484,
28545,
28546,
29259,
29260,
29320,
29321,
29502,
29503,
29557,
29558,
29614,
29615,
29671,
29672,
29726,
29727,
29787,
29788,
29844,
29845,
29905,
29906,
29968,
29969,
30023,
30024,
30085,
30086,
30141,
30142,
30203,
30204,
30259,
30260,
30321,
30322,
30377,
30378,
30439,
30440,
30495,
30496,
30557,
30558,
30616,
30617,
30675,
30676,
30734,
30735,
30793,
30794,
30852,
30853,
30911,
30912,
30970,
30971,
31029,
31030,
31090,
31091,
31149,
31150,
31208,
31209,
31267,
31268,
31326,
31327,
31385,
31386,
31444,
31445,
31503,
31504,
31562,
31563,
31623,
31624,
31682,
31683,
31741,
31742,
31800,
31801,
31859,
31860,
31918,
31919,
31977,
31978,
32036,
32037,
32095,
32096,
32157,
32158,
32216,
32217,
32275,
32276,
32331,
32332,
32387,
32388,
32443,
32444,
32499,
32500,
32555,
32556,
32611,
32612,
32680,
32681,
32739,
32740,
32798,
32799,
32857,
32858,
32916,
32917,
32975,
32976,
33034,
33035,
33093,
33094,
33152,
33153,
33846,
33847,
35312,
35372,
35373,
35563,
35564,
35618,
35619,
35675,
35676,
35732,
35733,
35787,
35788,
35850,
35851,
35908,
35909,
35971,
35972,
36029,
36030,
36084,
36085,
36146,
36147,
36202,
36203,
36264,
36265,
36320,
36321,
36382,
36383,
36438,
36439,
36500,
36501,
36556,
36557,
36618,
36619,
36677,
36678,
36736,
36737,
36795,
36796,
36854,
36855,
36913,
36914,
36972,
36973,
37031,
37032,
37090,
37091,
37151,
37152,
37210,
37211,
37269,
37270,
37328,
37329,
37387,
37388,
37446,
37447,
37505,
37506,
37564,
37565,
37623,
37624,
37684,
37685,
37743,
37744,
37802,
37803,
37861,
37862,
37920,
37921,
37979,
37980,
38038,
38039,
38097,
38098,
38156,
38157,
38218,
38219,
38277,
38278,
38336,
38337,
38395,
38396,
38454,
38455,
38510,
38511,
38566,
38567,
38622,
38623,
38678,
38679,
38747,
38748,
38806,
38807,
38865,
38866,
38924,
38925,
38983,
38984,
39042,
39043,
39101,
39102,
39160,
39161,
39219,
39220,
40194,
40195,
41121,
41122,
41222,
41223,
41970,
42142,
42203,
42204,
42424,
42425,
42876,
42877,
42962,
42963,
43579,
43639,
43640,
43909,
43910,
43964,
43965,
44031,
44032,
44096,
44097,
44151,
44152,
44214,
44215,
44272,
44273,
44335,
44336,
44393,
44394,
44448,
44449,
44510,
44511,
44566,
44567,
44628,
44629,
44684,
44685,
44746,
44747,
44802,
44803,
44864,
44865,
44920,
44921,
44982,
44983,
45041,
45042,
45100,
45101,
45159,
45160,
45218,
45219,
45277,
45278,
45336,
45337,
45395,
45396,
45454,
45455,
45515,
45516,
45574,
45575,
45633,
45634,
45692,
45693,
45751,
45752,
45810,
45811,
45869,
45870,
45928,
45929,
45987,
45988,
46048,
46049,
46107,
46108,
46166,
46167,
46225,
46226,
46284,
46285,
46343,
46344,
46402,
46403,
46461,
46462,
46520,
46521,
46589,
46590,
46648,
46649,
46707,
46708,
46766,
46767,
46825,
46826,
46884,
46885,
46943,
46944,
47002,
47003,
47061,
47062,
48953,
48954,
50092,
50093,
50177,
50178,
50949,
50950,
52352,
52353,
52431,
52432,
53231,
53232,
54155,
54156,
55440,
55441,
56156,
56157,
56835,
56836,
57440,
57441,
57995,
57996,
58882,
58883,
60116,
60117,
60956,
60957,
61946,
61947,
62011,
62012,
62919,
62920,
63004,
63005,
63388,
63389,
63455,
63456,
63514,
63515,
63589,
63590,
63648,
63649,
63727,
63728,
63787,
63788,
63861,
63862,
63921,
63922,
64065,
64066,
64124,
64125,
64207,
64208,
64272,
64273,
64420,
64421,
64479,
64480,
64555,
64556,
64615,
64616,
64806,
64807,
64864,
64865,
64933,
64934,
64993,
64994,
65078,
65079,
65137,
65138,
65217,
65218,
65283,
65284,
65352,
65353,
65475,
65476,
66658,
66659,
68301,
68302,
69037,
69038,
69579,
69580,
69931,
69932,
70006,
70007,
70063,
70185,
70241,
70354,
70410,
70517,
70573,
70686,
70742,
70853,
70909,
71010,
71066,
71298,
71354,
71472,
71528,
71653,
71710,
71836,
71893,
72002,
72059,
72135,
72192,
72318,
72375,
72459,
72516,
72656,
72713,
72846,
72903,
73017,
73074,
73290,
73347,
73505,
73562,
73707,
73764,
73869,
73870,
73933,
73934,
74190,
74375,
74892,
75401,
75928,
76271,
76866,
77410,
77897,
78342,
78832,
79223,
79457,
79731,
79964,
80493,
80824,
81071,
81287,
81805,
81935,
82127,
82349,
82553,
82730,
82901,
83272,
83487,
83630,
83827,
84085,
84508,
84703,
85048,
85278,
85472,
85799,
86071,
86366,
86711,
86901,
87173,
87484,
87690,
87952,
88131,
88313,
88495,
88652,
89185,
89420,
89918,
90446,
90622,
91100,
91392,
91899,
92093,
92314,
92808,
93163,
93543,
93751,
93955,
94120,
94388,
94619,
94988,
95485,
96022,
96417,
96418,
96480,
96481,
96582,
96583
],
"line_end_idx": [
82,
83,
104,
105,
125,
126,
161,
162,
184,
185,
212,
213,
237,
238,
262,
263,
289,
290,
320,
321,
349,
350,
383,
384,
414,
415,
455,
456,
488,
489,
522,
523,
557,
558,
595,
596,
632,
633,
674,
675,
713,
714,
757,
758,
798,
799,
846,
847,
889,
890,
936,
937,
981,
982,
1031,
1032,
1078,
1079,
1133,
1134,
1182,
1183,
1235,
1236,
1286,
1287,
1344,
1345,
1397,
1398,
1459,
1460,
1514,
1515,
1573,
1574,
1630,
1631,
1690,
1691,
1749,
1750,
1815,
1816,
1876,
1877,
1950,
1951,
2013,
2014,
2080,
2081,
2145,
2146,
2217,
2218,
2284,
2285,
2364,
2365,
2433,
2434,
2510,
2511,
2590,
2591,
2668,
2669,
2746,
2747,
2826,
2827,
2888,
2889,
2952,
2953,
3695,
3696,
3756,
3757,
4230,
4231,
4291,
4292,
5125,
5126,
5190,
5191,
5421,
5422,
5483,
5484,
5602,
5603,
5666,
5667,
6531,
6532,
7920,
7921,
9650,
9651,
9711,
9712,
9777,
9778,
10324,
10325,
11440,
11441,
11754,
11755,
11827,
11828,
13019,
13020,
13089,
13090,
13545,
13546,
13608,
13609,
14017,
14018,
14831,
14832,
14924,
14925,
15028,
15029,
15827,
15828,
15948,
15949,
16960,
16961,
17455,
17456,
17585,
17586,
18396,
18397,
20574,
20575,
20668,
20726,
20727,
20907,
20908,
20964,
21022,
21023,
21181,
21182,
21238,
21296,
21297,
21480,
21481,
21537,
21595,
21596,
21734,
21735,
21791,
21792,
22769,
22770,
23680,
23681,
23755,
23756,
24252,
24253,
24351,
24352,
24699,
24700,
24781,
24782,
25850,
25851,
27006,
27007,
27093,
27094,
27297,
27298,
27373,
27374,
27457,
27458,
28312,
28484,
28545,
28546,
29259,
29260,
29320,
29321,
29502,
29503,
29557,
29558,
29614,
29615,
29671,
29672,
29726,
29727,
29787,
29788,
29844,
29845,
29905,
29906,
29968,
29969,
30023,
30024,
30085,
30086,
30141,
30142,
30203,
30204,
30259,
30260,
30321,
30322,
30377,
30378,
30439,
30440,
30495,
30496,
30557,
30558,
30616,
30617,
30675,
30676,
30734,
30735,
30793,
30794,
30852,
30853,
30911,
30912,
30970,
30971,
31029,
31030,
31090,
31091,
31149,
31150,
31208,
31209,
31267,
31268,
31326,
31327,
31385,
31386,
31444,
31445,
31503,
31504,
31562,
31563,
31623,
31624,
31682,
31683,
31741,
31742,
31800,
31801,
31859,
31860,
31918,
31919,
31977,
31978,
32036,
32037,
32095,
32096,
32157,
32158,
32216,
32217,
32275,
32276,
32331,
32332,
32387,
32388,
32443,
32444,
32499,
32500,
32555,
32556,
32611,
32612,
32680,
32681,
32739,
32740,
32798,
32799,
32857,
32858,
32916,
32917,
32975,
32976,
33034,
33035,
33093,
33094,
33152,
33153,
33846,
33847,
35312,
35372,
35373,
35563,
35564,
35618,
35619,
35675,
35676,
35732,
35733,
35787,
35788,
35850,
35851,
35908,
35909,
35971,
35972,
36029,
36030,
36084,
36085,
36146,
36147,
36202,
36203,
36264,
36265,
36320,
36321,
36382,
36383,
36438,
36439,
36500,
36501,
36556,
36557,
36618,
36619,
36677,
36678,
36736,
36737,
36795,
36796,
36854,
36855,
36913,
36914,
36972,
36973,
37031,
37032,
37090,
37091,
37151,
37152,
37210,
37211,
37269,
37270,
37328,
37329,
37387,
37388,
37446,
37447,
37505,
37506,
37564,
37565,
37623,
37624,
37684,
37685,
37743,
37744,
37802,
37803,
37861,
37862,
37920,
37921,
37979,
37980,
38038,
38039,
38097,
38098,
38156,
38157,
38218,
38219,
38277,
38278,
38336,
38337,
38395,
38396,
38454,
38455,
38510,
38511,
38566,
38567,
38622,
38623,
38678,
38679,
38747,
38748,
38806,
38807,
38865,
38866,
38924,
38925,
38983,
38984,
39042,
39043,
39101,
39102,
39160,
39161,
39219,
39220,
40194,
40195,
41121,
41122,
41222,
41223,
41970,
42142,
42203,
42204,
42424,
42425,
42876,
42877,
42962,
42963,
43579,
43639,
43640,
43909,
43910,
43964,
43965,
44031,
44032,
44096,
44097,
44151,
44152,
44214,
44215,
44272,
44273,
44335,
44336,
44393,
44394,
44448,
44449,
44510,
44511,
44566,
44567,
44628,
44629,
44684,
44685,
44746,
44747,
44802,
44803,
44864,
44865,
44920,
44921,
44982,
44983,
45041,
45042,
45100,
45101,
45159,
45160,
45218,
45219,
45277,
45278,
45336,
45337,
45395,
45396,
45454,
45455,
45515,
45516,
45574,
45575,
45633,
45634,
45692,
45693,
45751,
45752,
45810,
45811,
45869,
45870,
45928,
45929,
45987,
45988,
46048,
46049,
46107,
46108,
46166,
46167,
46225,
46226,
46284,
46285,
46343,
46344,
46402,
46403,
46461,
46462,
46520,
46521,
46589,
46590,
46648,
46649,
46707,
46708,
46766,
46767,
46825,
46826,
46884,
46885,
46943,
46944,
47002,
47003,
47061,
47062,
48953,
48954,
50092,
50093,
50177,
50178,
50949,
50950,
52352,
52353,
52431,
52432,
53231,
53232,
54155,
54156,
55440,
55441,
56156,
56157,
56835,
56836,
57440,
57441,
57995,
57996,
58882,
58883,
60116,
60117,
60956,
60957,
61946,
61947,
62011,
62012,
62919,
62920,
63004,
63005,
63388,
63389,
63455,
63456,
63514,
63515,
63589,
63590,
63648,
63649,
63727,
63728,
63787,
63788,
63861,
63862,
63921,
63922,
64065,
64066,
64124,
64125,
64207,
64208,
64272,
64273,
64420,
64421,
64479,
64480,
64555,
64556,
64615,
64616,
64806,
64807,
64864,
64865,
64933,
64934,
64993,
64994,
65078,
65079,
65137,
65138,
65217,
65218,
65283,
65284,
65352,
65353,
65475,
65476,
66658,
66659,
68301,
68302,
69037,
69038,
69579,
69580,
69931,
69932,
70006,
70007,
70063,
70185,
70241,
70354,
70410,
70517,
70573,
70686,
70742,
70853,
70909,
71010,
71066,
71298,
71354,
71472,
71528,
71653,
71710,
71836,
71893,
72002,
72059,
72135,
72192,
72318,
72375,
72459,
72516,
72656,
72713,
72846,
72903,
73017,
73074,
73290,
73347,
73505,
73562,
73707,
73764,
73869,
73870,
73933,
73934,
74190,
74375,
74892,
75401,
75928,
76271,
76866,
77410,
77897,
78342,
78832,
79223,
79457,
79731,
79964,
80493,
80824,
81071,
81287,
81805,
81935,
82127,
82349,
82553,
82730,
82901,
83272,
83487,
83630,
83827,
84085,
84508,
84703,
85048,
85278,
85472,
85799,
86071,
86366,
86711,
86901,
87173,
87484,
87690,
87952,
88131,
88313,
88495,
88652,
89185,
89420,
89918,
90446,
90622,
91100,
91392,
91899,
92093,
92314,
92808,
93163,
93543,
93751,
93955,
94120,
94388,
94619,
94988,
95485,
96022,
96417,
96418,
96480,
96481,
96582,
96583,
96976
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 96976,
"ccnet_original_nlines": 851,
"rps_doc_curly_bracket": 0.00003093999839620665,
"rps_doc_ldnoobw_words": 1,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.22569704055786133,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.08377993106842041,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.28824368119239807,
"rps_doc_frac_unique_words": 0.2462611198425293,
"rps_doc_mean_word_length": 5.343517780303955,
"rps_doc_num_sentences": 853,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 6.661699295043945,
"rps_doc_word_count": 10899,
"rps_doc_frac_chars_dupe_10grams": 0.04915950074791908,
"rps_doc_frac_chars_dupe_5grams": 0.1122443675994873,
"rps_doc_frac_chars_dupe_6grams": 0.0849945917725563,
"rps_doc_frac_chars_dupe_7grams": 0.06444135308265686,
"rps_doc_frac_chars_dupe_8grams": 0.059066951274871826,
"rps_doc_frac_chars_dupe_9grams": 0.051323000341653824,
"rps_doc_frac_chars_top_2gram": 0.004636070225387812,
"rps_doc_frac_chars_top_3gram": 0.00618141982704401,
"rps_doc_frac_chars_top_4gram": 0.003090709913522005,
"rps_doc_books_importance": -7319.2265625,
"rps_doc_books_importance_length_correction": -7319.2265625,
"rps_doc_openwebtext_importance": -4068.29443359375,
"rps_doc_openwebtext_importance_length_correction": -4068.29443359375,
"rps_doc_wikipedia_importance": -3118.27587890625,
"rps_doc_wikipedia_importance_length_correction": -3118.27587890625
},
"fasttext": {
"dclm": 0.03667771816253662,
"english": 0.8678808808326721,
"fineweb_edu_approx": 2.463306427001953,
"eai_general_math": 0.7217530608177185,
"eai_open_web_math": 0.5024020671844482,
"eai_web_code": 0.06155925989151001
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.858",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "576.5",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Biology and Anthropology",
"level_3": "Microbiology"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
7,490,856,474,268,100,000 | Email updates
Keep up to date with the latest news and content from BMC Microbiology and BioMed Central.
Open Access Open Badges Research article
Identification of two Mycobacterium tuberculosis H37Rv ORFs involved in resistance to killing by human macrophages
Barbara H Miller12 and Thomas M Shinnick1*
Author Affiliations
1 Department of Microbiology and Immunology, Emory University School of Medicine and Division of AIDS, STD, and TB Laboratory Research, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
2 Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI
For all author emails, please log on.
BMC Microbiology 2001, 1:26 doi:10.1186/1471-2180-1-26
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2180/1/26
Received:6 September 2001
Accepted:17 October 2001
Published:17 October 2001
© 2001 Miller and Shinnick; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Abstract
Background
The ability of Mycobacterium tuberculosis to survive and replicate in macrophages is crucial for the mycobacterium's ability to infect the host and cause tuberculosis. To identify Mycobacterium tuberculosis genes involved in survival in macrophages, a library of non-pathogenic Mycobacterium smegmatis bacteria, each carrying an individual integrated cosmid containing M. tuberculosis H37Rv genomic DNA, was passed through THP-1 human macrophages three times.
Results
Two of the clones recovered from this enrichment process, sur2 and sur3, exhibited significantly increased survival relative to wild-type bacteria. In coinfection experiments, the ratio of sur2 colonies to wild-type colonies was 1:1 at 0 hours but increased to 20:1 at 24 hours post phagocytosis. The ratio of sur3 colonies to wild-type colonies was 1:1 at 0 hours and 5:1 at 24 hours. The M. tuberculosis ORFs responsible for increased survival were shown to be Rv0365c for the sur2 clone and Rv2235 for the sur3 clone. These ORFs encode proteins with as-of-yet unknown functions.
Conclusions
We identified two M. tuberculosis ORFs which may be involved in the ability of tubercle bacilli to survive in macrophages.
Background
Today, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis [1,2], and tuberculosis causes about 2 million deaths annually [1,2]. Many aspects of the interactions between M. tuberculosis and its human host remain unclear. Not only is this bacterium able to evade the defenses of the host's immune system, it is also able to persist in the body for years and may reactivate to cause disease decades after the initial infection. A better understanding of the interaction between M. tuberculosis and its human host is critical to developing new strategies to control the tuberculosis epidemic.
A key feature of the pathogenicity of M. tuberculosis is its ability to evade the antimicrobial processes of the macrophage and replicate intracellularly. Mycobacteria enter macrophages primarily by conventional receptor-mediated phagocytic pathways [3]. Following phagocytosis, phagosomes containing viable tubercle bacilli fail to acidify, apparently because of failure to insert a proton-ATPase pump into the phagosomal membrane [4-6]. This leads to altered vacuolar maturation such that phagosome-lysosome fusion is blocked and the mycobacteria-containing vacuoles end up with an internal pH of about 6 and markers of phagosomes and early and late endosomes [7-11]. The mycobacterial genes responsible for these processes are largely unknown.
One method for identifying bacterial genes involved in pathogenesis is to express these genes in a nonpathogenic host and isolate bacteria with increased virulence. This technique was first used to identify a gene that enables Yersinia pseudotuberculosis to invade HEp-2 cells [12]. In these studies, Escherichia coli bacteria expressing Y. pseudotuberculosis genes were used to infect HEp-2 cells. Only E. coli bacteria expressing the Y. pseudotuberculosis inv gene were able to invade the animal cells [12]. Using a similar approach, Arruda et al.[13] identified an M tuberculosis gene responsible for invasion of HeLa cells. We have previously used a similar technique to identify M. leprae genes involved in intracellular survival [14]. That is, by expressing M. leprae genes in E. coli, we were able to isolate recombinant bacteria that exhibited increased resistance to killing by murine bone-marrow derived macrophages [14].
A similar approach was used by Wei et al [15] to isolate 21 Mycobacterium smegmatis recombinant clones that displayed a greater than 2-fold enhancement in survival after 48 hours. M. smegmatis is a fast-growing, nonpathogenic species of Mycobacterium in which M. tuberculosis genes can be efficiently expressed [16-18]. An in depth analysis of one recombinant clone revealed that M. smegmatis recipients carrying the M. tuberculosis eis gene on an extrachromosomal multicopy plasmid displayed 2.4- to 5.3-fold greater survival in U937 macrophages than wild-type M. smegmatis bacteria at 24 to 48 hours post-infection [15]. The 42-kDa eis gene product has been shown to be associated with the mycobacterial cell surface and is released into extracellular medium, but its precise function is not yet known [19].
In the studies reported here, we used a similar enrichment scheme to identify two additional recombinant M. smegmatis clones, sur2 and sur3, that demonstrated enhanced survival during infections of THP-1 human monocyte-derived macrophages. The M. tuberculosis ORFs responsible for increased survival were shown to be Rv0365c for the sur2 clone and Rv2235 for the sur3 clone. These ORFs encode proteins with as-of-yet unknown functions.
Results
Cosmids carrying M. tuberculosis genes [20] were electroporated into M. smegmatis LR222 to create a library of M. smegmatis transformants, each of which carries a pYUB178::H37Rv cosmid integrated into its chromosome. The library was generated from about 4000 independent transformants. This represents about 20 M. tuberculosis genome-equivalents given that ~225 cosmids contain one genome-equivalent of M. tuberculosis[20].
To enrich for clones with increased survival in human macrophages, the library was passed through THP-1 macrophages as shown schematically in Figure 1. THP-1 is a human monocyte-derived macrophage cell line [21] and wild-type M. smegmatis bacteria are rapidly killed by THP-1 macrophages [22]. After three rounds of enrichment, the resulting clones were analyzed individually by Southern blot to evaluate the number of different clones present as previously described [20]. Out of the 3000 colonies recovered, genomic DNAs from the bacteria of 90 randomly chosen colonies were digested with PstI and hybridized with the pYUB178 vector. Strains carrying different cosmids should exhibit a different pattern of hybridizing bands because of the presence of different M. tuberculosis H37Rv inserts. Two clones, designated sur2 and sur3, were each present three times and were chosen for further study. The remaining 84 clones each displayed unique patterns.
thumbnailFigure 1. Enrichment procedure.
As a first step in the analysis of the sur2 clone, the time course of its survival in THP-1 macrophages was determined by infecting THP-1 macrophages, lysing the infected macrophages at various times after phagocytosis, and enumerating viable intracellular bacteria by plating on solid medium. Both parental and the sur2 bacteria were rapidly killed during the first few hours after phagocytosis (Figure 2). The sur2 bacteria appeared to survive slightly better at the 9 hour time point, but the difference was not statistically significant.
thumbnailFigure 2. Survival of sur2. THP-1 macrophages were infected with bacteria containing pYUB178 (hatched) or sur2 bacteria (horizontal stripe). Time zero is defined as immediately after the phagocytosis interval. Percent survival at time × was calculated by dividing the number of CFUs recovered at time × by the number of CFU recovered at time zero and multiplying by 100.
To compare directly the relative ability of the sur2 and wild-type bacteria to survive in macrophages, THP-1 macrophages were infected with a mixture of a genetically marked control strain and the sur2 strain and the survival of each strain was followed independently as previously described [22]. The wild-type strain expresses the xylE gene product, catechol 2,3-dioxygenase, such that when its colonies are sprayed with catechol, they turn bright yellow, while wild-type colonies remain white. In essence, each well of the experiment contains an internal standard (the wild-type bacteria) to which to compare the survival of the recombinant bacteria. In experiments in which THP-1 cells were infected at a MOI of 50:1 (results in ~1 phagocytosed M. smegmatis bacterium per macrophage) with a mixture containing equal numbers of bacteria of the xylE-expressing control strain and a strain carrying the cosmid vector pYUB178, the ratio of recovered white colonies to yellow colonies was 1:1 at all time points (data not shown). This indicates that the survival of the xylE-expressing strain was the same as that of the wild-type and could be used an internal reference by which to measure the survival of other clones.
In coinfection experiments with xylE-expressing bacteria, both sur2 and sur3 bacteria exhibited increased survival (Figure 3). Immediately after the 2 hour phagocytosis period (0 hr time point) the ratio of sur2 colonies to xylE-expressing colonies was 1:1 and by 12 hours it was about 7:1. By 24 hours, the ratio was approximately 20:1. The differences between the ratios at the zero time point and the subsequent time points were statistically significant (p < 0.005) for the 9, 12, and 24 hr time points. The ratio of sur3 colonies to control colonies increased from 1:1 at time 0 to 4:1 at 12 hours and to 5:1 at 24 hours (p < 0.005).
thumbnailFigure 3. Survival of recombinants relative to wild-type M. smegmatis. THP-1 macrophages were infected with an equal mixture of xylE-expressing bacteria and sur2 bacteria (hatched) or sur3 bacteria (horizontal stripe). The ratio of the recovered white-to-yellow colonies is shown for -2 hours (initial inoculum), 0 hours (immediately after phagocytosis interval), and at 3, 6, 9, 12, and 24 hours after phagocytosis. The ratios represent the average of the results of three independent experiments. Error bars represent the standard deviation in the ratio of white-to-yellow colonies between experiments.
Because the recombinant clones contain integrated pYUB178::H37Rv cosmids, the following strategy was used to isolate cosmids corresponding to those in the sur2 and sur3 clones. First, genomic DNA from the sur2 clone was digested with PstI, and genomic DNA from the sur3 clone was digested with BamHI to generate fragments of each integrated cosmid carrying oriE, aph, and a portion of the M. tuberculosis genomic DNA insert. The presence of oriE allows the recombinant to replicate as a plasmid in E. coli. The digestion products were treated with T4 DNA ligase and transformed into E. coli XL 1-Blue. Plasmid DNA from the resulting kanamycin-resistant colonies were analyzed by restriction site mapping and partial sequencing of the M. tuberculosis genomic DNA insert as described in Materials and Methods. For the sur2 recombinant, PCR primers were designed to amplify a 0.8 kb region of the M. tuberculosis insert from M. tuberculosis genomic DNA for use as a probe in colony blot experiments. Probing colony blots of the E. coli (pYUB178::H37Rv) library with the 0.8 kb PCR fragment led to the isolation of a 4 kb plasmid. This plasmid contained an intact oriE and aph gene, a portion of the integrase gene, and 1.1 kb of M. tuberculosis genomic DNA (Figure 4). PCR, DNA sequence, and Southern blot data indicated that the recovered plasmid was the same as the cosmid integrated in the sur2 genome (data not shown). For example, sequencing of PCR amplicons of the junctions between the mycobacterial sequences and vector sequences revealed that the junctions in the recovered plasmid were identical to those in the sur2 genomic DNA.
thumbnailFigure 4. Map of the M. tuberculosis H37Rv DNA integrated in the sur2 genome. The integrated 4 kb cosmid is between the two attachment sites, attL and attR. The 4.4 kb PstI fragment of sur2 is indicated by the two PstI sites. The 1,106 bp M. tuberculosis H37Rv genomic DNA insert contains two ORFs designated Rv0365c and Rv0366c [Reference 23]. The arrows indicate the direction of transcription. Arrows are color coded according to annotations found on the TubercuList server http://genolist.Pasteur.fr/TubercuList/ webcite: light green (unknown), brown (conserved), yellow (intermediary metabolism), light blue (regulatory), gray (virulence), red (information pathway), dark green (cell wall process), black (lipid metabolism), and dark blue (stable RNA).
Comparison of the sequence of the cloned 1.1 kb fragment with the M. tuberculosis H37Rv genome sequence [23] revealed that it contains portions of the Rv0366c and Rv0365c genes (Figure 4). In the sur2 clone, the amino-terminal 970 bp of the 1128 bp Rv0365c ORF is fused to 14 bp from the pYUB178 vector to generate an ORF encoding 328 amino acids (aa), compared to 376 aa encoded by the full-length Rv0365c ORF. The insert also contains 104 bp of the Rv0366c ORF fused to 220 bp of the L5 integrase ORF. This ORF could encode a 108 aa protein which contains the 73 amino-terminal amino acids of the 344 aa L5 integrase protein fused to the 34 carboxyl-terminal amino acids of the Rv0366c ORF.
To determine if the Rv0365c gene was responsible for the increased survival of sur2 bacteria, the full-length M. tuberculosis Rv0365c ORF as well as a truncated ORF similar to that present in the insert in the sur2 clone were subcloned into the pHIP vector downstream of the M. tuberculosis hsp65 promoter. The truncated ORF contained the 969 bp of Rv0365c present in the sur2 insert followed by a stop codon but did not contain the 5 amino acids corresponding to the vector contribution to the ORF. In coinfection experiments, the ratio of M. smegmatis bacteria expressing the full-length Rv0365c ORF to xylE-expressing wild-type bacteria was 1:1 at time zero and increased to approximately 10:1 at 12 hours and to 11:1 at 24 hours (Figure 5). The clone expressing the truncated Rv0365c ORF exhibited slightly less, but not statistically significantly different, increased survival (1:1 at time zero, 8.6:1 at 24 hrs).
thumbnailFigure 5. Survival of bacteria expressing ORF Rv0365c. THP-1 macrophages were infected with an equal mixture of xylE-expressing bacteria and bacteria expressing the full length Rv0365c ORF under the control of the hsp65 promoter (hatched) or sur2 bacteria (horizontal stripes). The ratios of white-to-yellow colonies represent the average of at least three independent experiments. Error bars represent the standard deviation in the ratio of white-to-yellow colonies between experiments.
To investigate the difference in survival at 24 hours of the full-length Rv0365c ORF expressing bacteria and sur2 bacteria, a strain expressing Rv0365c and xylE was constructed and used in THP-1 coinfections with the original sur2 clone. In this coinfection, the ratio of white (sur2) to yellow (xylE and Rv0365c expressing) colonies remained 1:1 through 12 hours and then increased to ~3:1 at 24 hrs, consistent with the above-described observations.
A cosmid corresponding to the one in the sur3 clone was isolated from the E. coli (pYUB178::H37Rv) library by probing colony blots with the 4.5 kb BamHI/EcoRl fragment of the M. tuberculosis genomic DNA insert in the plasmid recovered from the sur3 clone. PCR, DNA sequence, and Southern blot data indicated that the recovered cosmid was the same as the cosmid integrated in the sur3 genome (data not shown). The ~10.7 kb cosmid in the sur3 chromosome contains a 5.76 kb fragment of M. tuberculosis H37Rv genomic DNA (Figure 6) [23]. This region encodes eight potential ORFs designated Rv2233-Rv2240c as well as the tRNA for valine.
thumbnailFigure 6. Map of the M. tuberculosis H37Rv DNA integrated in the sur3 genome. The integrated 10.7 kb cosmid is between the two attachment sites, attL and attR. The ~7.4 kb BamHl and ~4.5 kb BamHI/EcoRI fragments are indicated by the BamHI and EcoRI sites. The 5.76 kb fragment of M. tuberculosis H37Rv genomic DNA contains the 34 bp of DNA upstream of Rv2233, Rv2233-Rv2240c, and the tRNA for valine [Reference 23]. The arrows indicate the direction of transcription. Arrows are color coded according to annotations found on the TubercuList server http://genolist-Pasteur.fr/TubercuList/ webcite: light green (unknown), brown (conserved), yellow (intermediary metabolism), light blue (regulatory), gray (virulence), red (information pathway). dark green (cell wall process), black (lipid metabolism), and dark blue (stable RNA).
To determine which ORF(s) was responsible for the increased survival exhibited by sur3 bacteria, each ORF was subcloned individually into the expression vector pHIP. The two potential operons, Rv2233-Rv2235 and Rv2238c-Rv2240c, were also subcloned into pHIP. The recombinant bacteria were examined for survival in the macrophage in coinfection experiments at 0, 6, and 12 hours post phagocytosis (Figure 7). Each of the recombinants tested exhibited a 1:1 ratio of white-to-yellow colonies at 0 hours. Two of the recombinants demonstrated an increase in the ratio of white-to-yellow colonies over time, while the ratio remained at 1:1 for the other eight recombinants. One of the two recombinants contained the potential operon of Rv2233-Rv2235, and the other contained Rv2235 only. The ratio of white-to-yellow colonies for bacteria expressing ORFs Rv2233-Rv2235 was ~2:1 at 6 hours and ~6:1 at 12 hours. For bacteria expressing Rv2235, the ratio of white-to-yellow colonies was ~2:1 at 6 hours and >3:1 at 12 hours. The survival of recombinant bacteria expressing the Rv2235 ORF relative to wild-type was more directly compared to the relative survival of sur3 by doing the coinfections in parallel. The ratios of white-to-yellow for both recombinant bacteria and sur3 bacteria were 1:1 at 0 hours, ~5:1 at 12 hours, and >5:1 at 24 hours. The differences in the relative survival of the three strains were not statistically significant.
thumbnailFigure 7. Survival of M. smegmatis LR222 bacteria expressing ORFs in the sur3 insert. THP-1 macrophages were infected with an equal mixture of xylE-expressing bacteria and bacteria expressing one or more of the sur3 ORFs. The ratio of the recovered white-to-yellow colonies is shown for -2 hours (initial inoculum), 0 hours (immediately after phagocytosis interval), and at 6 and 12 hours after phagocytosis. THP-1 macrophages were infected with an equal mixture of xylE-expressing bacteria and bacteria expressing Rv2233 (first open column), Rv2234 (first /// lines), Rv2235 (first \\\ lines), Rv2236c (hatched), Rv2237 (horizontal stripes), Rv2238c (vertical stripes), Rv2239c (box pattern), Rv2240c (second open column), Rv2233-Rv2235 (second /// lines), or Rv2238c-Rv2240c (second \\\ lines). Error bars represent the standard deviation in the ratio of white-to-yellow colonies between experiments.
A PCR fragment containing the M. tuberculosis ORFs Rv2233, Rv2234, and Rv2235 without the upstream promoter region, was cloned into the pBPhin vector, which does not contain a promoter to express the inserted DNA. In coinfections with the xylE-expressing bacteria, the recombinant bacteria containing Rv2233, Rv2234, and Rv2235 did not exhibit the same increase in macrophage survival as the sur3 clone (data not shown), suggesting that the Rv2235 ORF is expressed using signals upstream of the Rv2233 ORF.
Southern blots of genomic DNA from M. tuberculosis, M. smegmatis, Mycobacterium leprae, and Mycobacterium avium were probed with Rv0365c and Rv2235. Rv0365c hybridized to bands in M. tuberculosis, M. avium, and M. smegmatis under high stringency conditions (data not shown). Rv2235 hybridized to a band in M. tuberculosis, and under low stringency conditions recognized a band in M. leprae (data not shown).
Database searches revealed that Rv0365c encodes an ~41-kDa protein which displays significant homology only to a truncated Corynebacterium glutamicum hypothetical protein of unknown function (42% identity in a 296 aa overlap) located upstream of a gene encoding a fructose-bisphosphate aldolase. Rv2235 encodes a conserved hypothetical membrane protein of about 30-kDa and shares a motif with the SURF-1 family of proteins. The other two ORFs in the putative Rv2233-Rv2235 operon, Rv2233 and Rv2234, share homology with several proteins in data base searches. Rv2233 may encode a putative phosphatase, and Rv2234 may encode a low molecular weight protein tyrosine phosphatase [23].
Discussion
There are several potential limitations of isolating M. tuberculosis genes involved in intracellular survival using an enrichment procedure. One limitation is that this protocol is biased towards the recovery of clones with the greatest increase in survival relative to wild-type [14]. Thus, the recovered clones are not a random collection of genes involved in intracellular survival and hence the number of genes involved for survival cannot be calculated. This approach is also biased towards identifying genes expressing proteins that directly interfere with the antimicrobial processes of the macrophage. Some types of genes involved in resistance to killing, such as genes that are part of a multi-enzyme pathway, may not be isolated. Also, genes necessary for intracellular survival as opposed to resistance to killing are not likely to be isolated.
Two general classes of clones might be recovered following enrichment of the M. smegmatis recombinant library for clones with increased intracellular survival. One type might be clones that carry M. tuberculosis genes that confer enhanced resistance to the antimicrobial processes of the macrophage. Another type might be clones whose M. tuberculosis gene products are involved in attachment or invasion or increase phagocytosis. The two genes that were isolated in the studies reported here confer enhanced resistance rather than increased uptake. That is, the ratios of bacteria expressing either Rv0365c or Rv2235 to wild-type bacteria were 1:1 in both the initial mixture and inside the macrophages at the end of the phagocytosis period. Differences in survival compared to wild-type did not become apparent until about 9 hours post-phagocytosis for bacteria expressing Rv0365c and about 6 hours post-phagocytosis for those expressing Rv2235.
In this study, the enrichment process resulted in the isolation of two strains containing small, integrated plasmids rather than the expected 30–50 kb cosmids [20]. Small plasmids corresponding to the integrated ones were present in the original E. coli (pYUB178:H37Rv) cosmid library. PCR, sequencing, and Southern blot analysis demonstrated that the plasmid integrated in the sur2 clone was approximately 4 kb containing 1.1 kb of M. tuberculosis DNA and the plasmid integrated in the sur3 clone was approximately 10.7 kb containing about 5.7 kb of M. tuberculosis DNA. Cosmid libraries frequently contain clones without DNA inserts [24], so it is not too surprising that clones with small DNA fragments were present in the E. coli library after infection with λ phage. The small plasmids may have a growth or replication advantage causing them to be over-represented in the library following the various amplification steps.
The ~2 kb deletion of vector DNA in the sur2 clone results in a fusion of the ORF of the L5 integrase with that of the M. tuberculosis insert such that the fused ORF encodes a protein that contains only the amino-terminal 73 aa of the 344 aa L5 integrase. The observation that the sur2 clone contains an integrated plasmid corresponding to the plasmid isolated from the cosmid library suggests that either a) the hybrid protein retains integrase activity, b) the plasmid inserted into the attachment site by homologous recombination between attP and attB, or c) a functional integrase was provided in trans by a second cosmid transiently present in the original transformant or by a gene present in the M. smegmatis LR222 genome. However, repeated attempts to electroporate the 4 kb plasmid into M. smegmatis LR222 did not generate any stable kanamycin-resistant transformants (data not shown). These results suggests that the hybrid protein does not retain integrase activity, that integration by homologous recombination into attP is unlikely, and that provision of integrase activity by an M. smegmatis gene chromosomal does not occur. The simplest explanation is that integrase was provided in trans by a second cosmid transiently present in the original transformant, and indeed, M. smegmatis bacteria carrying an integrated copy of the 4-kb plasmid can be readily isolated following electroporation of a mixture of the 4-kb plasmid and a plasmid that expresses integrase (unpublished results).
Data base searches did not reveal any homologies that could be used to predict functions for the gene products of ORFs Rv0365c or Rv2235. Rv0365c encodes a hypothetical protein of 376 amino acids which displays significant homology only to a Corynebacterium glutamicum hypothetical protein of unknown function (42% identity in a 296 aa overlap) [23]. Rv2235 encodes a hypothetical protein of 271 aa with three putative transmembrane domains and which displays significant homology only to hypothetical protein MLCB1243.32c in M. leprae, to which it is 74% identical [23,25]. This M. leprae homologue was evident in Southern blot experiments done under low stringency conditions. Rv2235 also contains the SURF-1 signature sequence [26] and modest homology to members of the SURF-1 family such as the SURF-1 protein of Caulobacter crescentus (25% identity; 40% similarity) [27]. SURF-1 proteins are ~33-kDa, integral membrane proteins whose precise function is not known. In eukaryotic cells, SURF-1 proteins are involved in the assembly and maintenance of mitochondrial respiratory chain complexes including cytochrome oxidase [26,28]. The homology to SURF-1 proteins raises the possibility that Rv2235 could play a role in resisting the antimicrobial activities of macrophages by helping to maintain the stability or function of an important cellular process, akin to the stabilizing role of chaperonins during a heat shock.
In addition to the genes described in this report, other studies with M. smegmatis recombinants and/or mutants have implicated 11 other M. tuberculosis genes in intracellular survival. Genes identified using enrichment or screening protocols include Rv2962c and Rv2958c (probable glucuronsyl transferases), Rv2220 (glutamine synthetase A1), Rv3913-Rv3914 (thioredoxin, thioredoxin reductase) and Rv2416c (eis, unknown function) [14,15,22,29]. By screening insertional mutants of M. smegmatis, Lagier et al [30] isolated 8 mutants with impaired ability to survive in human peripheral blood monocyte-derived macrophages and identified the M. tuberculosis gene corresponding the mutated M. smegmatis gene for five of them. The genes included: Rv3052c (probable nrdI) which is postulated to be involved in deoxynucleotide production under stressed conditions; Rv0101 which is a nonribosomal peptide synthetase that displays strong homology with a Pseudomonas nonribosomal peptide synthetase required for the synthesis of the pyoveridine, a siderophore involved in iron uptake; Rv3420c which displays homology with the S18 ribosomal protein acetyltransferase which behaves as a heat shock protein in Chlamydia trachomatis; and Rv0497 and Rv3604c which are hypothetical conserved membrane proteins of unknown function.
It should be noted that these M. tuberculosis genes generally confer only a limited enhancement of the survival of M. smegmatis bacteria in the human macrophages. That is, usually only a few per cent of the recipients are viable 24 to 48 hours post-infection. This reinforces the concept that the intracellular survival of a pathogenic mycobacteria is a complex multifactoral process. The precise role(s) of any of the identified genes in the intracellular survival of mycobacteria is not yet known, although several of the identified genes have features of stress response genes. This is not unexpected given the relatively small enhancements of the survival of the M. smegmatis recombinants and the numerous environmental stresses encountered in the macrophage. Additional studies, such as the construction and characterization of targeted knock-out mutants, will be needed to determine the roles of the proteins encoded by these genes in the survival of M. tuberculosis in human macrophages.
Conclusions
Using an enrichment and screening procedure, two M. tuberculosis genes, Rv0365c and Rv2235, were identified that could confer an enhanced ability to survive in human macrophages to normally susceptible M. smegmatis recipients. The functions of these two proteins are not known. This study brings the number of M. tuberculosis genetic loci that have been implicated in enhancing the intracellular survival of M. smegmatis cells to 13. The precise role(s) of any of the identified genes in the intracellular survival of mycobacteria remain to be elucidated.
Materials and methods
Bacterial strains, plasmids, and growth conditions
The bacterial strains and plasmids used in this study are listed in Table 1. The E. coli strain XL 1-Blue was obtained from Stratagene (La Jolla, Calif). The M. smegmatis strain LR222 was obtained from Dr. Jack Crawford, Tuberculosis and Mycobacteriology Branch, Centers for Disease Control and Prevention (CDC), Atlanta, GA. The pYUB178 plasmid and the λ phage library of pYUB178::H37Rv cosmids were generously provided by Dr. William Jacobs, Albert Einstein University, New York, NY [20]. The cosmid library contains 30–50 kb fragments of M. tuberculosis genomic DNA generated by partial Sau3A digestion cloned into BclI-digested pYUB178. In the λ phage library, ~225 cosmids represent one genome-equivalent of M. tuberculosis[20]. An E. coli (pYUB178::H37Rv) library was created by infecting E. coli XL1-Blue with the λ phage library. Bacteria from ~4000 colonies were recovered and pooled, and cosmid DNA was isolated. The pooled pYUB178::H37Rv cosmid DNAs were electroporated into M. smegmatis LR222, and kanamycin-resistant colonies were isolated. Bacteria from ~4,000 colonies (representing ~20 genome equivalents) were recovered and pooled to generate the M. smegmatis (pYUB178::H37Rv) library. Because the cosmids integrate into the mycobacteriophage L5 attachment site in the M. smegmatis genome, a single copy of the M. tuberculosis DNA is maintained in the M. smegmatis transformants [20].
Table 1. Bacterial strains and plasmids used in this study.
The E. coli (pYUB178::H37Rv) library was grown in Luria broth (LB) (Difco Laboratories, Detroit, Mich.) containing 50 μg kanamycin/mL (Sigma Chemical Company, St. Louis, Mo.). The M. smegmatis (pYUB178::H37Rv) library was grown in Middlebrook 7H9 media (Difco) containing 10 μg kanamycin/mL and 0.05% (v/v) Tween 80 (Sigma) or on tryptic soy agar (TSA) (Difco) containing 10 μg kanamycin/mL. E. coli bacteria containing pHIP-based plasmids were grown in LB containing 200 μg hygromycin/mL (Boehringer Mannheim Biochemicals, Indianapolis, Ind.). M. smegmatis bacteria containing pHIP-based plasmids were grown on TSA containing 50 μg hygromycin/mL or in Middlebrook 7H9 media containing 50 μg hygromycin/mL and 0.05% (v/v) Tween 80.
An amplicon containing the hsp65 promoter was generated by PCR from the M. tuberculosis H37Rv genome. This PCR fragment was cloned into the BamHI site of pBPhin [31] to generate pHIP. An amplicon carrying the complete xylE ORF without the xylE promoter was generated by PCR of pTKmx [32], cleaved with BamHI, and cloned into the BamHI site of pHIP downstream from the hsp65 promoter to generate pHIP1.
DNA manipulations
All enzyme reactions were performed as recommended by the manufacturers (GIBCO Bethesda Research Laboratories, Inc., Gaithersburg, Md., New England Biolabs, Beverly, Mass.). Cosmid DNA from E. coli was prepared using the Qiagen Plasmid Maxi Kit (Qiagen, Valencia, Calif.) according to manufacturer's instructions for low-copy number plasmids. Wizard Plus Minipreps Kits (Promega, Madison, Wis.) were used to isolate plasmid DNA from E. coli strains. Mycobacterial genomic DNA was isolated as previously described [33].
PCR
The primers used in this study and their sequences are listed in Table 2. Primers were synthesized on a 381A DNA synthesizer (Applied Biosystems, Foster City, Calif.) at the Biotechnology Core Facility, National Center for Infectious Diseases, CDC. Amplifications were done using either a Perkin-Elmer Amp PCR System 2400 or Model 480 DNA Thermal Cycler (Perkin-Elmer Cetus, Norwalk, Conn). Each 100 μl PCR contained 3–5 μl of template DNA, 5 μl of dimethyl sulfoxide (DMSO), and 90–92 μl of a reaction mixture (200 μM (each) deoxynucleotide triphosphates, 1.0 μM (each) primer, 1.25 U of AmpliTaq DNA Polymerase (Perkin-Elmer Cetus), 10 mM Tris hydrochloride pH 8.3, 50 mM KCl, 1.5 mM MgCl2, and 0.01% (w/v) gelatin). Each sample was amplified for 30 cycles of denaturation at 94°C for 1.5 minutes, annealing at 60°C for 1.75 minutes, and extension at 72°C for 2.5 minutes.
Table 2. PCR and sequencing primers used in this study. Underlined bases are restriction enzyme sites used in cloning. Bold bases represent either the start codon or stop codon of the gene being cloned.
THP-1 human macrophages
The THP-1 cell line was obtained through the Biological Products Branch of the National Center for Infectious Diseases, CDC. THP-1 cells were grown in RPMI 1640 media (GIBCO BRL) containing 10% fetal calf serum (FCS) (GIBCO BRL) at 37°C in 5% CO2[21]. To differentiate the THP-1 cells into macrophage-like cells, the cells were treated with 10 μM phorbol myristate acetate (PMA) (Sigma) as follows [21]. All PMA manipulations were done under low light conditions. THP-1 cells were harvested by centrifugation for 10 minutes at 228 × g, and the pellet was resuspended in RPMI 1640/10% FCS/10 μM PMA to give a cell density of approximately 1 × 106 THP-1 cells/mL. Three milliliters of the suspension was added to each well of a six-well tissue culture plate (Costar, Corning, NY). The plates were incubated for 48 hours at 37°C in 5% CO2. The medium was removed from each well, the attached cells were washed once with RPMI 1640/10% FCS, and 3 ml of fresh RPMI 1640/10% FCS was added. The cultures were incubated at 37°C in 5% CO2 for an additional 48 hours. Immediately prior to infection, cells in each well were washed once with fresh RPMI 1640/10% FCS.
Enrichment protocol
About 106 bacteria of the M. smegmatis (pYUB178::H37Rv) library were inoculated into Middlebrook 7H9 media containing 10 μg kanamycin/mL and then were grown to midlog phase (OD600 ~ 0.3). The bacteria were harvested by centrifugation for 1 minute at 16,000 × g and washed twice with RPMI 1640/10% FCS. The bacteria were suspended in RPMI 1640/10% FCS at 5 × 108 bacteria/mL. The enrichment process was as follows (Figure 1): differentiated THP-1 macrophages were infected by adding 3 mL of the bacterial suspension to each well of a six-well plate. The multiplicity of infection (MOI) was ~500 bacteria per THP-1 cell. The culture was left at 37°C in 5% CO2 for 2 hours, which resulted in the phagocytosis of about 10 bacteria per macrophage. After the phagocytosis period, each well was washed twice with RPMI 1640/10% FCS to remove free bacteria. To kill any remaining extracellular bacteria, 3 mL of fresh RPMI 1640/10% FCS/200 μg amikacin/mL (Sigma) was added to each well. The infected THP-1 cultures were incubated at 37°C for an additional 5 hours. Each well was then washed twice with 3 mL of RPMI 1640/10% FCS, and then 1 mL of 0.1% (v/v) Triton X-100 (Sigma) was added to each well to lyse the macrophages. The wells were scraped with a rubber policeman, and the lysates were removed and diluted for plating on TSA containing 10 μg kanamycin/mL. After 3 days of incubation at 37°C, bacteria from the resulting colonies were harvested, suspended in Middlebrook 7H9 media containing 10 μg kanamycin/mL and 0.05% (v/v) Tween 80, and pooled for reinfection of THP-1 macrophages. The enrichment process was done for a total of three cycles. After the third round of enrichment, individual clones were isolated and analyzed.
Southern blots
PstI-digested genomic DNA was electrophoresed through a 1.0% agarose gel, denatured, neutralized, and transferred by capillary blotting to a Hybond -N+ membrane (Amersham, Arlington Heights, IL). The blots were hybridized to pYUB178 plasmid DNA labeled using the ECL Direct Nucleic Acid Labeling and Detection System (Amersham). All hybridization and washing steps were done at 42°C under either stringent (0.1 M NaCl) or non-stringent conditions (0.5 M NaCl) according to kit instructions.
Coinfection assay to measure survival
Coinfection assays were done as previously described [22]. Briefly, separate cultures of recombinant and of xylE-expressing bacteria were grown to midlog phase (OD600 = ~0.3). The bacteria from each culture were harvested by centrifugation for 1 minute at 16,000 × g, washed twice with RPMI 1640/10% FCS, and resuspended in RPMI 1640/10% FCS at a concentration of 1.5 × 108 bacteria/mL. Equal volumes of the two bacterial suspensions were mixed to produce a suspension containing a 1:1 ratio of recombinant-to-control bacteria. A portion of the combined mixture was plated onto TSA plates to determine the number of colony forming units (CFUs) of each strain in the initial inoculum (the -2 hour time point in figures). The bacterial suspension was diluted with RPMI 1640/10% FCS to give approximately 5 × 107 bacteria/mL, and 3 mL was added to each well containing 1 × 106 THP-1 macrophages (MOI of 50 bacteria/macrophage). The cultures were incubated for 2 hours at 37°C in 5% CO2 to allow phagocytosis to occur, and then each well was washed twice with RPMI 1640/10% FCS to remove unphagocytosed bacteria. Typically, this results in one phagocytosed bacterium per macrophage. To kill extracellular bacteria, 3 mL of RPMI 1640/10% FCS containing 200 μg amikacin/mL was added to each well. Cultures were incubated at 37°C in 5% CO2. At various times, the medium was removed from each of three wells, and 1 mL of 0.1% (v/v) Triton X-100 in H20 was added to each well to lyse the macrophages. Each lysate was diluted as necessary, and portions were plated on TSA plates. The cultures which were assayed immediately after the addition of the media with amikacin serve to measure of the number of phagocytosed viable bacteria; the time at which these cultures were assayed was considered time zero (t0).
After a 3-day incubation at 37°C, the TSA plates from each time point were stored overnight at 4°C. The following day, the plates were sprayed with 0.5 M catechol (Sigma) in 50 mM potassium phosphate (pH 7.5) to distinguish the xylE-expressing colonies (yellow) from the recombinant colonies (white). Storing the plates overnight at 4°C results in a stronger yellow color. To determine the percent survival of a particular clone at time point X, the number of CFUs at time × was divided by the number of CFUs at to and multiplied by 100.
Recovery of the cloned M. tuberculosis genomic DNA fragment
One μg of sur2 genomic DNA was digested with the restriction enzyme PstI then ethanol precipitated. The precipitated DNA was resuspended in 20 μL T4 ligase buffer (GIBCO BRL) and then ligated for 2 hours at room temperature with 0.5 units of T4 ligase (GIBCO BRL). The ligation mixture was electroporated into electrocompetent E. coli, and kanamycin-resistant transformants were isolated. After sequencing the M. tuberculosis H37Rv insert in the recovered plasmid, PCR primers were designed to amplify a product containing a portion of the cloned M. tuberculosis H37Rv genomic DNA. The PCR product was used as a probe for colony blots to find cosmids in the E. coli (pYUB178::H37Rv) library carrying at least a portion of the cosmid integrated in the sur2 clone.
A plasmid carrying a portion of the M. tuberculosis H37Rv insert in the sur3 clone was isolated in a similar manner from a BamHI digest of sur3 genomic DNA. The BamHI/EcoRI fragment of the M. tuberculosis H37Rv insert of the recovered plasmid was used as a probe in colony blots to find cosmids in the E. coli (pYUB178::H37Rv) library.
Colony blots
Portions of the E. coli (pYUB178::H37Rv) cosmid library were plated on LB agar containing 50 μg kanamycin/mL, and colony blots were performed with the ECL Direct Nucleic Acid Labeling & Detection System (Amersham) according to manufacturer's instructions. Colonies hybridizing with the probe of interest were removed as plugs and incubated in LB containing 50 μg kanamycin/mL for approximately 30 minutes at 37°C. Dilutions of this culture were plated on LB agar containing 50 μg kanamycin/mL to give well-separated colonies. Colony blots were performed and positive clones were selected for further study.
Subcloning ORFs into pHIP and pBPhin
Unless otherwise stated, all M. tuberculosis open-reading frames (ORFs) were generated by PCR from M. tuberculosis H37Rv genomic DNA as full-length ORFs without their natural promoters. The PCR primers (Table 2) were designed to contain restriction enzyme sites for cloning of the amplicon into the pHIP vector downstream of the hsp65 promoter as well as the eight basepairs (bp) upstream of the start codon of the gene being cloned. Because the hsp65 promoter in pHIP contains a ribosome binding site (rbs), the spacing between the rbs and the start codon of the cloned gene is about the same in these constructs as the spacing between the rbs and the start codon of the hsp65 gene in wild-type M. tuberculosis.
A truncated form of the Rv0365c gene was generated by PCR to contain 969 bp of the 970 bp of the truncated ORF present in the sur2 clone followed immediately by a stop codon. This fragment was BamHI-digested and ligated to BamHI-digested pHIP to form pHIP3. An amplicon containing the hsp65 promoter and full-length Rv0365c gene was generated by PCR amplification of the pHIP2 plasmid. This amplicon was NotI-digested and cloned into the NotI site of the pHIP1 plasmid containing the xylE gene to generate pHIP4. Plasmid pBPhin1 was constructed by ligating a BamHI-digested PCR fragment containing the Rv0365c gene plus 24 bp located upstream of it to BamHI-digested pBPhin. Plasmid pHIP13 was created by cloning a BglII-digested PCR fragment containing Rv2233,Rv2234, and Rv2235 into the BamHI site downstream of the hsp65 promoter of pHIP. Plasmid pHIP14 was created by cloning a BamHI-digested PCR fragment containing Rv2238c, Rv2239c, and Rv2240c into the BamHI site downstream of the hsp65 promoter of pHIP such that Rv2240c was proximal to the hsp65 promoter. Plasmid pBPhin2 was created by ligating the BglII-digested Rv2233-Rv2235 fragment into the BamHI site of pBPhin.
Electroporation
All electroporations were conducted using a Bio-Rad Pulse Controller (Bio-Rad, Hercules, Calif). Preparation and electroporation of competent E. coli XL 1-Blue cells were done according to Bio-Rad instructions. Competent M. smegmatis LR222 cells were prepared and electroporated as described by Jacobs et al.[34].
DNA sequencing
All sequencing reactions were prepared with the Applied Biosystems, Inc. (ABI) PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems) according to the manufacturer. All sequencing was conducted using an ABI 373 DNA Sequencing System (Applied Biosystems).
Statistical analysis
Results were analyzed by the two-sample T test.
DNA and protein homology analyses
DNA and protein database searches were performed using the BLAST services (blastn, blastp, and psi-blast) at the National Center for Biotechnology Information (NCBI) [35,36] and the genomes site at The Institute for Genomic Research http://www.tigr.org webcite. Protein domain/motif searches were performed using PSI-BLAST [37], and CD-Search (RPS-BLAST) [36] at NCBI and the SMART utility at the European Molecular Biology Laboratories [38,39].
Acknowledgements
We thank Dr. William Jacobs for generously providing the pYUB178::H37Rv cosmid library and Dr Jack Crawford for providing strain LR222.
References
1. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC: Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project.
JAMA 1999, 282:677-686. PubMed Abstract | Publisher Full Text OpenURL
2. Murray CJ, Salomon JA: Modeling the impact of global tuberculosis control strategies.
Proc Natl Acad Sci USA 1998, 95:13881-13886. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
3. Schlesinger LS: Entry of Mycobacterium tuberculosis into Mononuclear Phagocytes.
In: Tuberculosis Edited by Shinnick TM, vol. 215. pp. 71–96. Berlin: Springer-Verlag; 1996, 71-96. OpenURL
4. Crowle AJ, Dahl R, Ross E, May MH: Evidence that vesicles containing living, virulent Mycobacterium tuberculosis or Mycobacterium avium in cultured human macrophages are not acidic.
Infect Immun 1991, 59:1823-1831. PubMed Abstract OpenURL
5. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, Haddix PL, Collins HL, Fok AK, Allen RD, Gluck SL, Heuser J, Russell DG: Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.
Science 1994, 263:678-681. PubMed Abstract OpenURL
6. Oh YK, Straubinger RM: Intracellular fate of Mycobacterium avium: use of dual-label spectrofluorometry to investigate the influence of bacterial viability and opsonization on phagosomal pH and phagosome-lysosome interaction.
Infect Immun 1996, 64:319-325. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
7. Armstrong JA, D'Arcy Hart P: Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes.
J Exp Med 1971, 134:713-740. OpenURL
8. Sturgill-Koszycki S, Schaible UE, Russell DG: Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis.
Embo J 1996, 15:6960-8. PubMed Abstract OpenURL
9. Clemens DL, Horwitz MA: Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited.
J Exp Med 1995, 181:257-270. PubMed Abstract OpenURL
10. Clemens DL, Lee BY, Horwitz MA: Deviant expression of Rab5 on phagosomes containing the intracellular pathogens Mycobacterium tuberculosis and Legionella pneumophila is associated with altered phagosomal fate.
Infect Immun 2000, 68:2671-2684. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
11. Deretic V, Via LE, Fratti RA, Deretic D: Mycobacterial phagosome maturation, rab proteins, and intracellular trafficking.
Electrophoresis 1997, 18:2542-2547. PubMed Abstract OpenURL
12. Isberg RR, Falkow S: A single genetic locus encoded by Yersinia pseudotuberculosis permits invasion of cultured animal cells by Escherichia coli K-12.
Nature 1985, 317:262-264. PubMed Abstract OpenURL
13. Arruda S, Bomfim G, Knights R, Huima-Byron T, Riley LW: Cloning of an M. tuberculosis DNA fragment associated with entry and survival inside cells.
Science 1993, 261:1454-1457. PubMed Abstract OpenURL
14. Mundayoor S, Shinnick TM: Identification of genes involved in the resistance of mycobacteria to killing by macrophages.
Annals NY Acad Sci 1994, 730:26-36. OpenURL
15. Wei J, Dahl JL, Moulder JW, Roberts EA, O'Gaora P, Young DB, Friedman RL: Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages.
J Bacteriol 2000, 182:377-384. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
16. Zhang Y, Heym B, Allen B, Young D, Cole S: The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis.
Nature 1992, 358:591-593. PubMed Abstract | Publisher Full Text OpenURL
17. Garbe T, Harris D, Vordermeier M, Lathigra R, Ivanyi J, Young D: Expression of the Mycobacterium tuberculosis 19-kilodalton antigen in Mycobacterium smegmatis. immunological analysis and evidence of glycosylation.
Infect Immun 1993, 61:260-267. PubMed Abstract OpenURL
18. Harth G, Horwitz MA: Expression and efficient export of enzymatically active Mycobacterium tuberculosis glutamine synthetase in Mycobacterium smegmatis and evidence that the information for export is contained within the protein.
J Biol Chem 1997, 272:22728-22735. PubMed Abstract | Publisher Full Text OpenURL
19. Dahl JL, Wei J, Moulder JW, Laal S, Friedman RL: Subcellular localization of the intracellular survival-enhancing Eis protein of Mycobacterium tuberculosis.
Infect Immun 2001, 69:4295-4302. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
20. Pascopella L, Collins FM, Martin JM, Lee MH, Hatfull GF, Stover CK, Bloom BR, Jacobs WR Jr: Use of in vivo complementation in Mycobacterium tuberculosis to identify a genomic fragment associated with virulence.
Infect Immun 1994, 62:1313-1319. PubMed Abstract OpenURL
21. Asseffa A, Dickson LA, Mohla S, Bremner TA: Phorbol myristate acetate-differentiated THP-1 cells display increased levels of MHC class I and class II mRNA and interferon-gamma-inducible tumoricidal activity.
Oncology Res 1993, 5:11-18. PubMed Abstract OpenURL
22. Miller BH, Shinnick TM: Evaluation of Mycobacterium tuberculosis genes involved in resistance to killing by human macrophages.
Infect Immun 2000, 68:387-390. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
23. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Barrell BG, et al.: Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.
Nature 1998, 393:537-544. PubMed Abstract | Publisher Full Text OpenURL
24. Sambrook J, Fritsch EF, Maniatis T:
Molecular Cloning: A Laboratory Manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press;. 1989. OpenURL
25. Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, Honore N, Garnier T, Churcher C, Harris D, Mungall K, Basham D, Brown D, Chillingworth T, Connor R, Davies RM, Devlin K, Duthoy S, Feltwell T, Fraser A, Hamlin N, Holroyd S, Hornsby T, Jagels K, Lacroix C, Maclean J, Moule S, Murphy L, Oliver K, Quail MA, Rajandream MA, Rutherford KM, Rutter S, Seeger K, Simon S, Simmonds M, Skelton J, Squares R, Squares S, Stevens K, Taylor K, Whitehead S, Woodward JR, Barrell BG: Massive gene decay in the leprosy bacillus.
Nature 2001, 409:1007-1011. PubMed Abstract | Publisher Full Text OpenURL
26. Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C, Cuthbert AP, Newbold RF, Wang J, Chevrette M, Brown GK, Brown RM, Shoubridge EA: SURFl, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.
Nat Genet 1998, 20:337-343. PubMed Abstract | Publisher Full Text OpenURL
27. Nierman WC, Feldblyum TV, Laub MT, Paulsen IT, Nelson KE, Eisen J, Heidelberg JF, Alley MR, Ohta N, Maddock JR, Potocka I, Nelson WC, Newton A, Stephens C, Phadke ND, Ely B, DeBoy RT, Dodson RJ, Durkin AS, Gwinn ML, Haft DH, Kolonay JF, Smit J, Craven MB, Khouri H, Shetty J, Berry K, Utterback T, Tran K, Wolf A, Vamathevan J, Ermolaeva M, White 0, Salzberg SL, Venter JC, Shapiro L, Fraser CM: Complete genome sequence of Caulobacter crescentus.
Proc Natl Acad Sci USA 2001, 98:4136-4141. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
28. Nijtmans LG, Artal Sanz M, Bucko M, Farhoud MH, Feenstra M, Hakkaart GA, Zeviani M, Grivell LA: Shy1p occurs in a high molecular weight complex and is required for efficient assembly of cytochrome c oxidase in yeast.
FEBS Lett 2001, 498:46-51. PubMed Abstract | Publisher Full Text OpenURL
29. Wieles B, Ottenhoff TH, Steenwijk TM, Franken KL, de Vries RR, Langermans JA: Increased intracellular survival of Mycobacterium smegmatiscontaining the Mycobacterium leprae thioredoxin-thioredoxin reductase gene.
Infect Immun 1997, 65:2537-2541. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
30. Lagier B, Pelicic V, Lecossier D, Prod'hom G, Rauzier J, Guilhot C, Gicquel B, Hance AJ: Identification of genetic loci implicated in the survival of Mycobacterium smegmatis in human mononuclear phagocytes.
Mol Microbiol 1998, 29:465-475. PubMed Abstract | Publisher Full Text OpenURL
31. Plikaytis BB, Crawford JT, Shinnick TM: IS1549 from Mycobacterium smegmatis forms long direct repeats upon insertion.
J Bacteriol 1998, 180:1037-1043. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
32. Kenney TJ, Churchward G: Genetic analysis of the Mycobacterium smegmatis rpsL promoter.
J Bacteriol 1996, 178:3564-3571. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
33. Wilson K: Preparation of genomic DNA from bacteria.
In: Current Protocols in Molecular Biology Edited by Ausubel F, Brent R, Kinston R, Moore D, Seidman I, Smith J, Struhl K, vol. 1. pp. 2.4.1–2.4.2. New York: Wiley Interscience; 1990, 2.4.1-2.4.2. OpenURL
34. Jacobs WR Jr, Kalpana GV, Cirillo JD, Pascopella L, Snapper SB, Udani RA, Jones W, Barletta RG, Bloom BR: Genetic systems for mycobacteria.
Methods Enzymol 1991, 204:537-555. PubMed Abstract OpenURL
35. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ: Basic local alignment search tool.
J Mol Biol 1990, 215:403-410. PubMed Abstract | Publisher Full Text OpenURL
36. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
Nucleic Acids Res 1997, 25:3389-3402. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
37. Schaffer AA, Aravind L, Madden TL, Shavirin S, Spouge JL, Wolf YI, Koonin EV, Altschul SF: Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements.
Nucleic Acids Res 2001, 29:2994-3005. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
38. Schultz J, Milpetz F, Bork P, Ponting CP: SMART, a simple modular architecture research tool: identification of signaling domains.
Proc Natl Acad Sci USA 1998, 95:5857-5864. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
39. Schultz J, Copley RR, Doerks T, Ponting CP, Bork P: SMART: a web-based tool for the study of genetically mobile domains.
Nucleic Acids Res 2000, 28:231-234. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
40. Miller LP, Crawford JT, Shinnick TM: The rpo B Gene of Mycobacterium tuberculosis.
Antimicrob Agents Chemoth 1994, 38:805-811. PubMed Abstract OpenURL | {
"url": "http://www.biomedcentral.com/1471-2180/1/26",
"source_domain": "www.biomedcentral.com",
"snapshot_id": "crawl=CC-MAIN-2015-40",
"warc_metadata": {
"Content-Length": "156767",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JGUAYRCPTSNOVBNBQ5IMBGMIYQ6TEDYG",
"WARC-Concurrent-To": "<urn:uuid:ca36984a-9826-4e8c-bb61-6ea0f4936910>",
"WARC-Date": "2015-10-10T17:28:27",
"WARC-IP-Address": "23.235.39.250",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:CBAEUITZPZGTBWLOPXJYN7NFZHDXSR3X",
"WARC-Record-ID": "<urn:uuid:e91687d4-3af9-4e50-aa56-2cc77c04d8fa>",
"WARC-Target-URI": "http://www.biomedcentral.com/1471-2180/1/26",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:78aa8888-c1fe-4505-955e-158ed636aa5e>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-137-6-227.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2015-40\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for September 2015\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
14,
15,
106,
107,
148,
149,
264,
265,
308,
309,
329,
330,
532,
533,
625,
626,
664,
665,
721,
722,
853,
854,
855,
881,
906,
932,
933,
1191,
1192,
1201,
1202,
1213,
1214,
1674,
1675,
1683,
1684,
2266,
2267,
2279,
2280,
2403,
2404,
2415,
2416,
3084,
3085,
3832,
3833,
4765,
4766,
5576,
5577,
6013,
6014,
6022,
6023,
6447,
6448,
7402,
7403,
7444,
7445,
7987,
7988,
8368,
8369,
9589,
9590,
10229,
10230,
10844,
10845,
12482,
12483,
13250,
13251,
13944,
13945,
14865,
14866,
15363,
15364,
15816,
15817,
16450,
16451,
17289,
17290,
18729,
18730,
19642,
19643,
20150,
20151,
20559,
20560,
21242,
21243,
21254,
21255,
22112,
22113,
23060,
23061,
23989,
23990,
25490,
25491,
26916,
26917,
28230,
28231,
29226,
29227,
29239,
29240,
29796,
29797,
29819,
29820,
29871,
29872,
31274,
31275,
31335,
31336,
32068,
32069,
32471,
32472,
32490,
32491,
33010,
33011,
33015,
33016,
33891,
33892,
34095,
34096,
34120,
34121,
35276,
35277,
35297,
35298,
37027,
37028,
37043,
37044,
37535,
37536,
37574,
37575,
39376,
39377,
39915,
39916,
39976,
39977,
40740,
40741,
41077,
41078,
41091,
41092,
41699,
41700,
41737,
41738,
42451,
42452,
43631,
43632,
43648,
43649,
43963,
43964,
43979,
43980,
44258,
44259,
44280,
44281,
44329,
44330,
44364,
44365,
44811,
44812,
44829,
44830,
44966,
44967,
44978,
44979,
45197,
45198,
45272,
45273,
45364,
45365,
45487,
45488,
45574,
45575,
45686,
45687,
45874,
45875,
45936,
45937,
46171,
46172,
46227,
46228,
46458,
46459,
46567,
46568,
46724,
46725,
46766,
46767,
46953,
46954,
47006,
47007,
47151,
47152,
47209,
47210,
47426,
47427,
47537,
47538,
47666,
47667,
47731,
47732,
47889,
47890,
47944,
47945,
48099,
48100,
48157,
48158,
48284,
48285,
48333,
48334,
48519,
48520,
48628,
48629,
48763,
48764,
48840,
48841,
49061,
49062,
49121,
49122,
49358,
49359,
49444,
49445,
49608,
49609,
49719,
49720,
49937,
49938,
49999,
50000,
50214,
50215,
50271,
50272,
50405,
50406,
50514,
50515,
50891,
50892,
50968,
50969,
51011,
51012,
51128,
51129,
51666,
51667,
51745,
51746,
51992,
51993,
52071,
52072,
52526,
52527,
52647,
52648,
52871,
52872,
52949,
52950,
53169,
53170,
53280,
53281,
53494,
53495,
53577,
53578,
53702,
53703,
53813,
53814,
53908,
53909,
54019,
54020,
54078,
54079,
54288,
54289,
54435,
54436,
54499,
54500,
54593,
54594,
54674,
54675,
54839,
54840,
54955,
54956,
55172,
55173,
55288,
55289,
55426,
55427,
55547,
55548,
55675,
55676,
55789,
55790,
55879,
55880
],
"line_end_idx": [
14,
15,
106,
107,
148,
149,
264,
265,
308,
309,
329,
330,
532,
533,
625,
626,
664,
665,
721,
722,
853,
854,
855,
881,
906,
932,
933,
1191,
1192,
1201,
1202,
1213,
1214,
1674,
1675,
1683,
1684,
2266,
2267,
2279,
2280,
2403,
2404,
2415,
2416,
3084,
3085,
3832,
3833,
4765,
4766,
5576,
5577,
6013,
6014,
6022,
6023,
6447,
6448,
7402,
7403,
7444,
7445,
7987,
7988,
8368,
8369,
9589,
9590,
10229,
10230,
10844,
10845,
12482,
12483,
13250,
13251,
13944,
13945,
14865,
14866,
15363,
15364,
15816,
15817,
16450,
16451,
17289,
17290,
18729,
18730,
19642,
19643,
20150,
20151,
20559,
20560,
21242,
21243,
21254,
21255,
22112,
22113,
23060,
23061,
23989,
23990,
25490,
25491,
26916,
26917,
28230,
28231,
29226,
29227,
29239,
29240,
29796,
29797,
29819,
29820,
29871,
29872,
31274,
31275,
31335,
31336,
32068,
32069,
32471,
32472,
32490,
32491,
33010,
33011,
33015,
33016,
33891,
33892,
34095,
34096,
34120,
34121,
35276,
35277,
35297,
35298,
37027,
37028,
37043,
37044,
37535,
37536,
37574,
37575,
39376,
39377,
39915,
39916,
39976,
39977,
40740,
40741,
41077,
41078,
41091,
41092,
41699,
41700,
41737,
41738,
42451,
42452,
43631,
43632,
43648,
43649,
43963,
43964,
43979,
43980,
44258,
44259,
44280,
44281,
44329,
44330,
44364,
44365,
44811,
44812,
44829,
44830,
44966,
44967,
44978,
44979,
45197,
45198,
45272,
45273,
45364,
45365,
45487,
45488,
45574,
45575,
45686,
45687,
45874,
45875,
45936,
45937,
46171,
46172,
46227,
46228,
46458,
46459,
46567,
46568,
46724,
46725,
46766,
46767,
46953,
46954,
47006,
47007,
47151,
47152,
47209,
47210,
47426,
47427,
47537,
47538,
47666,
47667,
47731,
47732,
47889,
47890,
47944,
47945,
48099,
48100,
48157,
48158,
48284,
48285,
48333,
48334,
48519,
48520,
48628,
48629,
48763,
48764,
48840,
48841,
49061,
49062,
49121,
49122,
49358,
49359,
49444,
49445,
49608,
49609,
49719,
49720,
49937,
49938,
49999,
50000,
50214,
50215,
50271,
50272,
50405,
50406,
50514,
50515,
50891,
50892,
50968,
50969,
51011,
51012,
51128,
51129,
51666,
51667,
51745,
51746,
51992,
51993,
52071,
52072,
52526,
52527,
52647,
52648,
52871,
52872,
52949,
52950,
53169,
53170,
53280,
53281,
53494,
53495,
53577,
53578,
53702,
53703,
53813,
53814,
53908,
53909,
54019,
54020,
54078,
54079,
54288,
54289,
54435,
54436,
54499,
54500,
54593,
54594,
54674,
54675,
54839,
54840,
54955,
54956,
55172,
55173,
55288,
55289,
55426,
55427,
55547,
55548,
55675,
55676,
55789,
55790,
55879,
55880,
55951
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 55951,
"ccnet_original_nlines": 355,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.24768896400928497,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.06615913659334183,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.2568424940109253,
"rps_doc_frac_unique_words": 0.23330965638160706,
"rps_doc_mean_word_length": 5.3062262535095215,
"rps_doc_num_sentences": 617,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 6.32797908782959,
"rps_doc_word_count": 8448,
"rps_doc_frac_chars_dupe_10grams": 0.09152965992689133,
"rps_doc_frac_chars_dupe_5grams": 0.2147812694311142,
"rps_doc_frac_chars_dupe_6grams": 0.16849219799041748,
"rps_doc_frac_chars_dupe_7grams": 0.12374238669872284,
"rps_doc_frac_chars_dupe_8grams": 0.11223147064447403,
"rps_doc_frac_chars_dupe_9grams": 0.1039775088429451,
"rps_doc_frac_chars_top_2gram": 0.011153990402817726,
"rps_doc_frac_chars_top_3gram": 0.011800919659435749,
"rps_doc_frac_chars_top_4gram": 0.013853260315954685,
"rps_doc_books_importance": -5268.55908203125,
"rps_doc_books_importance_length_correction": -5268.55908203125,
"rps_doc_openwebtext_importance": -2984.8486328125,
"rps_doc_openwebtext_importance_length_correction": -2984.8486328125,
"rps_doc_wikipedia_importance": -2142.517822265625,
"rps_doc_wikipedia_importance_length_correction": -2142.517822265625
},
"fasttext": {
"dclm": 0.0669255331158638,
"english": 0.8864710927009583,
"fineweb_edu_approx": 2.7608163356781006,
"eai_general_math": 0.47871172428131104,
"eai_open_web_math": 0.37469393014907837,
"eai_web_code": 0.008367779664695263
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "579.2",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Biology and Anthropology",
"level_3": "Biological specimens"
}
},
"secondary": {
"code": "616.9",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
4,645,891,076,042,041,000 | JoVE Visualize What is visualize?
Related JoVE Video
Pubmed Article
Automatic structural parcellation of mouse brain MRI using multi-atlas label fusion.
PLoS ONE
PUBLISHED: 01-01-2014
Multi-atlas segmentation propagation has evolved quickly in recent years, becoming a state-of-the-art methodology for automatic parcellation of structural images. However, few studies have applied these methods to preclinical research. In this study, we present a fully automatic framework for mouse brain MRI structural parcellation using multi-atlas segmentation propagation. The framework adopts the similarity and truth estimation for propagated segmentations (STEPS) algorithm, which utilises a locally normalised cross correlation similarity metric for atlas selection and an extended simultaneous truth and performance level estimation (STAPLE) framework for multi-label fusion. The segmentation accuracy of the multi-atlas framework was evaluated using publicly available mouse brain atlas databases with pre-segmented manually labelled anatomical structures as the gold standard, and optimised parameters were obtained for the STEPS algorithm in the label fusion to achieve the best segmentation accuracy. We showed that our multi-atlas framework resulted in significantly higher segmentation accuracy compared to single-atlas based segmentation, as well as to the original STAPLE framework.
Authors: Fijoy Vadakkumpadan, Hermenegild Arevalo, Natalia A. Trayanova.
Published: 01-08-2013
ABSTRACT
Patient-specific simulations of heart (dys)function aimed at personalizing cardiac therapy are hampered by the absence of in vivo imaging technology for clinically acquiring myocardial fiber orientations. The objective of this project was to develop a methodology to estimate cardiac fiber orientations from in vivo images of patient heart geometries. An accurate representation of ventricular geometry and fiber orientations was reconstructed, respectively, from high-resolution ex vivo structural magnetic resonance (MR) and diffusion tensor (DT) MR images of a normal human heart, referred to as the atlas. Ventricular geometry of a patient heart was extracted, via semiautomatic segmentation, from an in vivo computed tomography (CT) image. Using image transformation algorithms, the atlas ventricular geometry was deformed to match that of the patient. Finally, the deformation field was applied to the atlas fiber orientations to obtain an estimate of patient fiber orientations. The accuracy of the fiber estimates was assessed using six normal and three failing canine hearts. The mean absolute difference between inclination angles of acquired and estimated fiber orientations was 15.4 °. Computational simulations of ventricular activation maps and pseudo-ECGs in sinus rhythm and ventricular tachycardia indicated that there are no significant differences between estimated and acquired fiber orientations at a clinically observable level.The new insights obtained from the project will pave the way for the development of patient-specific models of the heart that can aid physicians in personalized diagnosis and decisions regarding electrophysiological interventions.
20 Related JoVE Articles!
Play Button
Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer's Disease and Normal Elderly
Authors: Joel Ramirez, Christopher J.M. Scott, Alicia A. McNeely, Courtney Berezuk, Fuqiang Gao, Gregory M. Szilagyi, Sandra E. Black.
Institutions: Sunnybrook Health Sciences Centre, University of Toronto.
Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimer's disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests1,2. However, LE's accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs. LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizer's manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors. While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LE's manual procedures.
Medicine, Issue 86, Brain, Vascular Diseases, Magnetic Resonance Imaging (MRI), Neuroimaging, Alzheimer Disease, Aging, Neuroanatomy, brain extraction, ventricles, white matter hyperintensities, cerebrovascular disease, Alzheimer disease
50887
Play Button
A Comprehensive Protocol for Manual Segmentation of the Medial Temporal Lobe Structures
Authors: Matthew Moore, Yifan Hu, Sarah Woo, Dylan O'Hearn, Alexandru D. Iordan, Sanda Dolcos, Florin Dolcos.
Institutions: University of Illinois Urbana-Champaign, University of Illinois Urbana-Champaign, University of Illinois Urbana-Champaign.
The present paper describes a comprehensive protocol for manual tracing of the set of brain regions comprising the medial temporal lobe (MTL): amygdala, hippocampus, and the associated parahippocampal regions (perirhinal, entorhinal, and parahippocampal proper). Unlike most other tracing protocols available, typically focusing on certain MTL areas (e.g., amygdala and/or hippocampus), the integrative perspective adopted by the present tracing guidelines allows for clear localization of all MTL subregions. By integrating information from a variety of sources, including extant tracing protocols separately targeting various MTL structures, histological reports, and brain atlases, and with the complement of illustrative visual materials, the present protocol provides an accurate, intuitive, and convenient guide for understanding the MTL anatomy. The need for such tracing guidelines is also emphasized by illustrating possible differences between automatic and manual segmentation protocols. This knowledge can be applied toward research involving not only structural MRI investigations but also structural-functional colocalization and fMRI signal extraction from anatomically defined ROIs, in healthy and clinical groups alike.
Neuroscience, Issue 89, Anatomy, Segmentation, Medial Temporal Lobe, MRI, Manual Tracing, Amygdala, Hippocampus, Perirhinal Cortex, Entorhinal Cortex, Parahippocampal Cortex
50991
Play Button
Training Synesthetic Letter-color Associations by Reading in Color
Authors: Olympia Colizoli, Jaap M. J. Murre, Romke Rouw.
Institutions: University of Amsterdam.
Synesthesia is a rare condition in which a stimulus from one modality automatically and consistently triggers unusual sensations in the same and/or other modalities. A relatively common and well-studied type is grapheme-color synesthesia, defined as the consistent experience of color when viewing, hearing and thinking about letters, words and numbers. We describe our method for investigating to what extent synesthetic associations between letters and colors can be learned by reading in color in nonsynesthetes. Reading in color is a special method for training associations in the sense that the associations are learned implicitly while the reader reads text as he or she normally would and it does not require explicit computer-directed training methods. In this protocol, participants are given specially prepared books to read in which four high-frequency letters are paired with four high-frequency colors. Participants receive unique sets of letter-color pairs based on their pre-existing preferences for colored letters. A modified Stroop task is administered before and after reading in order to test for learned letter-color associations and changes in brain activation. In addition to objective testing, a reading experience questionnaire is administered that is designed to probe for differences in subjective experience. A subset of questions may predict how well an individual learned the associations from reading in color. Importantly, we are not claiming that this method will cause each individual to develop grapheme-color synesthesia, only that it is possible for certain individuals to form letter-color associations by reading in color and these associations are similar in some aspects to those seen in developmental grapheme-color synesthetes. The method is quite flexible and can be used to investigate different aspects and outcomes of training synesthetic associations, including learning-induced changes in brain function and structure.
Behavior, Issue 84, synesthesia, training, learning, reading, vision, memory, cognition
50893
Play Button
In vivo Imaging of Optic Nerve Fiber Integrity by Contrast-Enhanced MRI in Mice
Authors: Stefanie Fischer, Christian Engelmann, Karl-Heinz Herrmann, Jürgen R. Reichenbach, Otto W. Witte, Falk Weih, Alexandra Kretz, Ronny Haenold.
Institutions: Jena University Hospital, Fritz Lipmann Institute, Jena, Jena University Hospital.
The rodent visual system encompasses retinal ganglion cells and their axons that form the optic nerve to enter thalamic and midbrain centers, and postsynaptic projections to the visual cortex. Based on its distinct anatomical structure and convenient accessibility, it has become the favored structure for studies on neuronal survival, axonal regeneration, and synaptic plasticity. Recent advancements in MR imaging have enabled the in vivo visualization of the retino-tectal part of this projection using manganese mediated contrast enhancement (MEMRI). Here, we present a MEMRI protocol for illustration of the visual projection in mice, by which resolutions of (200 µm)3 can be achieved using common 3 Tesla scanners. We demonstrate how intravitreal injection of a single dosage of 15 nmol MnCl2 leads to a saturated enhancement of the intact projection within 24 hr. With exception of the retina, changes in signal intensity are independent of coincided visual stimulation or physiological aging. We further apply this technique to longitudinally monitor axonal degeneration in response to acute optic nerve injury, a paradigm by which Mn2+ transport completely arrests at the lesion site. Conversely, active Mn2+ transport is quantitatively proportionate to the viability, number, and electrical activity of axon fibers. For such an analysis, we exemplify Mn2+ transport kinetics along the visual path in a transgenic mouse model (NF-κB p50KO) displaying spontaneous atrophy of sensory, including visual, projections. In these mice, MEMRI indicates reduced but not delayed Mn2+ transport as compared to wild type mice, thus revealing signs of structural and/or functional impairments by NF-κB mutations. In summary, MEMRI conveniently bridges in vivo assays and post mortem histology for the characterization of nerve fiber integrity and activity. It is highly useful for longitudinal studies on axonal degeneration and regeneration, and investigations of mutant mice for genuine or inducible phenotypes.
Neuroscience, Issue 89, manganese-enhanced MRI, mouse retino-tectal projection, visual system, neurodegeneration, optic nerve injury, NF-κB
51274
Play Button
Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles
Authors: Eva Wagner, Sören Brandenburg, Tobias Kohl, Stephan E. Lehnart.
Institutions: Heart Research Center Goettingen, University Medical Center Goettingen, German Center for Cardiovascular Research (DZHK) partner site Goettingen, University of Maryland School of Medicine.
In cardiac myocytes a complex network of membrane tubules - the transverse-axial tubule system (TATS) - controls deep intracellular signaling functions. While the outer surface membrane and associated TATS membrane components appear to be continuous, there are substantial differences in lipid and protein content. In ventricular myocytes (VMs), certain TATS components are highly abundant contributing to rectilinear tubule networks and regular branching 3D architectures. It is thought that peripheral TATS components propagate action potentials from the cell surface to thousands of remote intracellular sarcoendoplasmic reticulum (SER) membrane contact domains, thereby activating intracellular Ca2+ release units (CRUs). In contrast to VMs, the organization and functional role of TATS membranes in atrial myocytes (AMs) is significantly different and much less understood. Taken together, quantitative structural characterization of TATS membrane networks in healthy and diseased myocytes is an essential prerequisite towards better understanding of functional plasticity and pathophysiological reorganization. Here, we present a strategic combination of protocols for direct quantitative analysis of TATS membrane networks in living VMs and AMs. For this, we accompany primary cell isolations of mouse VMs and/or AMs with critical quality control steps and direct membrane staining protocols for fluorescence imaging of TATS membranes. Using an optimized workflow for confocal or superresolution TATS image processing, binarized and skeletonized data are generated for quantitative analysis of the TATS network and its components. Unlike previously published indirect regional aggregate image analysis strategies, our protocols enable direct characterization of specific components and derive complex physiological properties of TATS membrane networks in living myocytes with high throughput and open access software tools. In summary, the combined protocol strategy can be readily applied for quantitative TATS network studies during physiological myocyte adaptation or disease changes, comparison of different cardiac or skeletal muscle cell types, phenotyping of transgenic models, and pharmacological or therapeutic interventions.
Bioengineering, Issue 92, cardiac myocyte, atria, ventricle, heart, primary cell isolation, fluorescence microscopy, membrane tubule, transverse-axial tubule system, image analysis, image processing, T-tubule, collagenase
51823
Play Button
Reconstruction of 3-Dimensional Histology Volume and its Application to Study Mouse Mammary Glands
Authors: Rushin Shojaii, Stephanie Bacopulos, Wenyi Yang, Tigran Karavardanyan, Demetri Spyropoulos, Afshin Raouf, Anne Martel, Arun Seth.
Institutions: University of Toronto, Sunnybrook Research Institute, University of Toronto, Sunnybrook Research Institute, Medical University of South Carolina, University of Manitoba.
Histology volume reconstruction facilitates the study of 3D shape and volume change of an organ at the level of macrostructures made up of cells. It can also be used to investigate and validate novel techniques and algorithms in volumetric medical imaging and therapies. Creating 3D high-resolution atlases of different organs1,2,3 is another application of histology volume reconstruction. This provides a resource for investigating tissue structures and the spatial relationship between various cellular features. We present an image registration approach for histology volume reconstruction, which uses a set of optical blockface images. The reconstructed histology volume represents a reliable shape of the processed specimen with no propagated post-processing registration error. The Hematoxylin and Eosin (H&E) stained sections of two mouse mammary glands were registered to their corresponding blockface images using boundary points extracted from the edges of the specimen in histology and blockface images. The accuracy of the registration was visually evaluated. The alignment of the macrostructures of the mammary glands was also visually assessed at high resolution. This study delineates the different steps of this image registration pipeline, ranging from excision of the mammary gland through to 3D histology volume reconstruction. While 2D histology images reveal the structural differences between pairs of sections, 3D histology volume provides the ability to visualize the differences in shape and volume of the mammary glands.
Bioengineering, Issue 89, Histology Volume Reconstruction, Transgenic Mouse Model, Image Registration, Digital Histology, Image Processing, Mouse Mammary Gland
51325
Play Button
Developing Neuroimaging Phenotypes of the Default Mode Network in PTSD: Integrating the Resting State, Working Memory, and Structural Connectivity
Authors: Noah S. Philip, S. Louisa Carpenter, Lawrence H. Sweet.
Institutions: Alpert Medical School, Brown University, University of Georgia.
Complementary structural and functional neuroimaging techniques used to examine the Default Mode Network (DMN) could potentially improve assessments of psychiatric illness severity and provide added validity to the clinical diagnostic process. Recent neuroimaging research suggests that DMN processes may be disrupted in a number of stress-related psychiatric illnesses, such as posttraumatic stress disorder (PTSD). Although specific DMN functions remain under investigation, it is generally thought to be involved in introspection and self-processing. In healthy individuals it exhibits greatest activity during periods of rest, with less activity, observed as deactivation, during cognitive tasks, e.g., working memory. This network consists of the medial prefrontal cortex, posterior cingulate cortex/precuneus, lateral parietal cortices and medial temporal regions. Multiple functional and structural imaging approaches have been developed to study the DMN. These have unprecedented potential to further the understanding of the function and dysfunction of this network. Functional approaches, such as the evaluation of resting state connectivity and task-induced deactivation, have excellent potential to identify targeted neurocognitive and neuroaffective (functional) diagnostic markers and may indicate illness severity and prognosis with increased accuracy or specificity. Structural approaches, such as evaluation of morphometry and connectivity, may provide unique markers of etiology and long-term outcomes. Combined, functional and structural methods provide strong multimodal, complementary and synergistic approaches to develop valid DMN-based imaging phenotypes in stress-related psychiatric conditions. This protocol aims to integrate these methods to investigate DMN structure and function in PTSD, relating findings to illness severity and relevant clinical factors.
Medicine, Issue 89, default mode network, neuroimaging, functional magnetic resonance imaging, diffusion tensor imaging, structural connectivity, functional connectivity, posttraumatic stress disorder
51651
Play Button
From Voxels to Knowledge: A Practical Guide to the Segmentation of Complex Electron Microscopy 3D-Data
Authors: Wen-Ting Tsai, Ahmed Hassan, Purbasha Sarkar, Joaquin Correa, Zoltan Metlagel, Danielle M. Jorgens, Manfred Auer.
Institutions: Lawrence Berkeley National Laboratory, Lawrence Berkeley National Laboratory, Lawrence Berkeley National Laboratory.
Modern 3D electron microscopy approaches have recently allowed unprecedented insight into the 3D ultrastructural organization of cells and tissues, enabling the visualization of large macromolecular machines, such as adhesion complexes, as well as higher-order structures, such as the cytoskeleton and cellular organelles in their respective cell and tissue context. Given the inherent complexity of cellular volumes, it is essential to first extract the features of interest in order to allow visualization, quantification, and therefore comprehension of their 3D organization. Each data set is defined by distinct characteristics, e.g., signal-to-noise ratio, crispness (sharpness) of the data, heterogeneity of its features, crowdedness of features, presence or absence of characteristic shapes that allow for easy identification, and the percentage of the entire volume that a specific region of interest occupies. All these characteristics need to be considered when deciding on which approach to take for segmentation. The six different 3D ultrastructural data sets presented were obtained by three different imaging approaches: resin embedded stained electron tomography, focused ion beam- and serial block face- scanning electron microscopy (FIB-SEM, SBF-SEM) of mildly stained and heavily stained samples, respectively. For these data sets, four different segmentation approaches have been applied: (1) fully manual model building followed solely by visualization of the model, (2) manual tracing segmentation of the data followed by surface rendering, (3) semi-automated approaches followed by surface rendering, or (4) automated custom-designed segmentation algorithms followed by surface rendering and quantitative analysis. Depending on the combination of data set characteristics, it was found that typically one of these four categorical approaches outperforms the others, but depending on the exact sequence of criteria, more than one approach may be successful. Based on these data, we propose a triage scheme that categorizes both objective data set characteristics and subjective personal criteria for the analysis of the different data sets.
Bioengineering, Issue 90, 3D electron microscopy, feature extraction, segmentation, image analysis, reconstruction, manual tracing, thresholding
51673
Play Button
Cortical Source Analysis of High-Density EEG Recordings in Children
Authors: Joe Bathelt, Helen O'Reilly, Michelle de Haan.
Institutions: UCL Institute of Child Health, University College London.
EEG is traditionally described as a neuroimaging technique with high temporal and low spatial resolution. Recent advances in biophysical modelling and signal processing make it possible to exploit information from other imaging modalities like structural MRI that provide high spatial resolution to overcome this constraint1. This is especially useful for investigations that require high resolution in the temporal as well as spatial domain. In addition, due to the easy application and low cost of EEG recordings, EEG is often the method of choice when working with populations, such as young children, that do not tolerate functional MRI scans well. However, in order to investigate which neural substrates are involved, anatomical information from structural MRI is still needed. Most EEG analysis packages work with standard head models that are based on adult anatomy. The accuracy of these models when used for children is limited2, because the composition and spatial configuration of head tissues changes dramatically over development3. In the present paper, we provide an overview of our recent work in utilizing head models based on individual structural MRI scans or age specific head models to reconstruct the cortical generators of high density EEG. This article describes how EEG recordings are acquired, processed, and analyzed with pediatric populations at the London Baby Lab, including laboratory setup, task design, EEG preprocessing, MRI processing, and EEG channel level and source analysis.
Behavior, Issue 88, EEG, electroencephalogram, development, source analysis, pediatric, minimum-norm estimation, cognitive neuroscience, event-related potentials
51705
Play Button
Dual-phase Cone-beam Computed Tomography to See, Reach, and Treat Hepatocellular Carcinoma during Drug-eluting Beads Transarterial Chemo-embolization
Authors: Vania Tacher, MingDe Lin, Nikhil Bhagat, Nadine Abi Jaoudeh, Alessandro Radaelli, Niels Noordhoek, Bart Carelsen, Bradford J. Wood, Jean-François Geschwind.
Institutions: The Johns Hopkins Hospital, Philips Research North America, National Institutes of Health, Philips Healthcare.
The advent of cone-beam computed tomography (CBCT) in the angiography suite has been revolutionary in interventional radiology. CBCT offers 3 dimensional (3D) diagnostic imaging in the interventional suite and can enhance minimally-invasive therapy beyond the limitations of 2D angiography alone. The role of CBCT has been recognized in transarterial chemo-embolization (TACE) treatment of hepatocellular carcinoma (HCC). The recent introduction of a CBCT technique: dual-phase CBCT (DP-CBCT) improves intra-arterial HCC treatment with drug-eluting beads (DEB-TACE). DP-CBCT can be used to localize liver tumors with the diagnostic accuracy of multi-phasic multidetector computed tomography (M-MDCT) and contrast enhanced magnetic resonance imaging (CE-MRI) (See the tumor), to guide intra-arterially guidewire and microcatheter to the desired location for selective therapy (Reach the tumor), and to evaluate treatment success during the procedure (Treat the tumor). The purpose of this manuscript is to illustrate how DP-CBCT is used in DEB-TACE to see, reach, and treat HCC.
Medicine, Issue 82, Carcinoma, Hepatocellular, Tomography, X-Ray Computed, Surgical Procedures, Minimally Invasive, Digestive System Diseases, Diagnosis, Therapeutics, Surgical Procedures, Operative, Equipment and Supplies, Transarterial chemo-embolization, Hepatocellular carcinoma, Dual-phase cone-beam computed tomography, 3D roadmap, Drug-Eluting Beads
50795
Play Button
A Dual Tracer PET-MRI Protocol for the Quantitative Measure of Regional Brain Energy Substrates Uptake in the Rat
Authors: Maggie Roy, Scott Nugent, Sébastien Tremblay, Maxime Descoteaux, Jean-François Beaudoin, Luc Tremblay, Roger Lecomte, Stephen C Cunnane.
Institutions: Université de Sherbrooke, Université de Sherbrooke, Université de Sherbrooke, Université de Sherbrooke.
We present a method for comparing the uptake of the brain's two key energy substrates: glucose and ketones (acetoacetate [AcAc] in this case) in the rat. The developed method is a small-animal positron emission tomography (PET) protocol, in which 11C-AcAc and 18F-fluorodeoxyglucose (18F-FDG) are injected sequentially in each animal. This dual tracer PET acquisition is possible because of the short half-life of 11C (20.4 min). The rats also undergo a magnetic resonance imaging (MRI) acquisition seven days before the PET protocol. Prior to image analysis, PET and MRI images are coregistered to allow the measurement of regional cerebral uptake (cortex, hippocampus, striatum, and cerebellum). A quantitative measure of 11C-AcAc and 18F-FDG brain uptake (cerebral metabolic rate; μmol/100 g/min) is determined by kinetic modeling using the image-derived input function (IDIF) method. Our new dual tracer PET protocol is robust and flexible; the two tracers used can be replaced by different radiotracers to evaluate other processes in the brain. Moreover, our protocol is applicable to the study of brain fuel supply in multiple conditions such as normal aging and neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases.
Neuroscience, Issue 82, positron emission tomography (PET), 18F-fluorodeoxyglucose, 11C-acetoacetate, magnetic resonance imaging (MRI), kinetic modeling, cerebral metabolic rate, rat
50761
Play Button
Mapping the After-effects of Theta Burst Stimulation on the Human Auditory Cortex with Functional Imaging
Authors: Jamila Andoh, Robert J. Zatorre.
Institutions: McGill University .
Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing1. However, despite considerable recent progress, the functional properties and lateralization of the human auditory cortex are far from being fully understood. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses, and represents a unique method of exploring plasticity and connectivity. It has only recently begun to be applied to understand auditory cortical function 2. An important issue in using TMS is that the physiological consequences of the stimulation are difficult to establish. Although many TMS studies make the implicit assumption that the area targeted by the coil is the area affected, this need not be the case, particularly for complex cognitive functions which depend on interactions across many brain regions 3. One solution to this problem is to combine TMS with functional Magnetic resonance imaging (fMRI). The idea here is that fMRI will provide an index of changes in brain activity associated with TMS. Thus, fMRI would give an independent means of assessing which areas are affected by TMS and how they are modulated 4. In addition, fMRI allows the assessment of functional connectivity, which represents a measure of the temporal coupling between distant regions. It can thus be useful not only to measure the net activity modulation induced by TMS in given locations, but also the degree to which the network properties are affected by TMS, via any observed changes in functional connectivity. Different approaches exist to combine TMS and functional imaging according to the temporal order of the methods. Functional MRI can be applied before, during, after, or both before and after TMS. Recently, some studies interleaved TMS and fMRI in order to provide online mapping of the functional changes induced by TMS 5-7. However, this online combination has many technical problems, including the static artifacts resulting from the presence of the TMS coil in the scanner room, or the effects of TMS pulses on the process of MR image formation. But more importantly, the loud acoustic noise induced by TMS (increased compared with standard use because of the resonance of the scanner bore) and the increased TMS coil vibrations (caused by the strong mechanical forces due to the static magnetic field of the MR scanner) constitute a crucial problem when studying auditory processing. This is one reason why fMRI was carried out before and after TMS in the present study. Similar approaches have been used to target the motor cortex 8,9, premotor cortex 10, primary somatosensory cortex 11,12 and language-related areas 13, but so far no combined TMS-fMRI study has investigated the auditory cortex. The purpose of this article is to provide details concerning the protocol and considerations necessary to successfully combine these two neuroscientific tools to investigate auditory processing. Previously we showed that repetitive TMS (rTMS) at high and low frequencies (resp. 10 Hz and 1 Hz) applied over the auditory cortex modulated response time (RT) in a melody discrimination task 2. We also showed that RT modulation was correlated with functional connectivity in the auditory network assessed using fMRI: the higher the functional connectivity between left and right auditory cortices during task performance, the higher the facilitatory effect (i.e. decreased RT) observed with rTMS. However those findings were mainly correlational, as fMRI was performed before rTMS. Here, fMRI was carried out before and immediately after TMS to provide direct measures of the functional organization of the auditory cortex, and more specifically of the plastic reorganization of the auditory neural network occurring after the neural intervention provided by TMS. Combined fMRI and TMS applied over the auditory cortex should enable a better understanding of brain mechanisms of auditory processing, providing physiological information about functional effects of TMS. This knowledge could be useful for many cognitive neuroscience applications, as well as for optimizing therapeutic applications of TMS, particularly in auditory-related disorders.
Neuroscience, Issue 67, Physiology, Physics, Theta burst stimulation, functional magnetic resonance imaging, MRI, auditory cortex, frameless stereotaxy, sound, transcranial magnetic stimulation
3985
Play Button
Trajectory Data Analyses for Pedestrian Space-time Activity Study
Authors: Feng Qi, Fei Du.
Institutions: Kean University, University of Wisconsin-Madison.
It is well recognized that human movement in the spatial and temporal dimensions has direct influence on disease transmission1-3. An infectious disease typically spreads via contact between infected and susceptible individuals in their overlapped activity spaces. Therefore, daily mobility-activity information can be used as an indicator to measure exposures to risk factors of infection. However, a major difficulty and thus the reason for paucity of studies of infectious disease transmission at the micro scale arise from the lack of detailed individual mobility data. Previously in transportation and tourism research detailed space-time activity data often relied on the time-space diary technique, which requires subjects to actively record their activities in time and space. This is highly demanding for the participants and collaboration from the participants greatly affects the quality of data4. Modern technologies such as GPS and mobile communications have made possible the automatic collection of trajectory data. The data collected, however, is not ideal for modeling human space-time activities, limited by the accuracies of existing devices. There is also no readily available tool for efficient processing of the data for human behavior study. We present here a suite of methods and an integrated ArcGIS desktop-based visual interface for the pre-processing and spatiotemporal analyses of trajectory data. We provide examples of how such processing may be used to model human space-time activities, especially with error-rich pedestrian trajectory data, that could be useful in public health studies such as infectious disease transmission modeling. The procedure presented includes pre-processing, trajectory segmentation, activity space characterization, density estimation and visualization, and a few other exploratory analysis methods. Pre-processing is the cleaning of noisy raw trajectory data. We introduce an interactive visual pre-processing interface as well as an automatic module. Trajectory segmentation5 involves the identification of indoor and outdoor parts from pre-processed space-time tracks. Again, both interactive visual segmentation and automatic segmentation are supported. Segmented space-time tracks are then analyzed to derive characteristics of one's activity space such as activity radius etc. Density estimation and visualization are used to examine large amount of trajectory data to model hot spots and interactions. We demonstrate both density surface mapping6 and density volume rendering7. We also include a couple of other exploratory data analyses (EDA) and visualizations tools, such as Google Earth animation support and connection analysis. The suite of analytical as well as visual methods presented in this paper may be applied to any trajectory data for space-time activity studies.
Environmental Sciences, Issue 72, Computer Science, Behavior, Infectious Diseases, Geography, Cartography, Data Display, Disease Outbreaks, cartography, human behavior, Trajectory data, space-time activity, GPS, GIS, ArcGIS, spatiotemporal analysis, visualization, segmentation, density surface, density volume, exploratory data analysis, modelling
50130
Play Button
Setting Limits on Supersymmetry Using Simplified Models
Authors: Christian Gütschow, Zachary Marshall.
Institutions: University College London, CERN, Lawrence Berkeley National Laboratories.
Experimental limits on supersymmetry and similar theories are difficult to set because of the enormous available parameter space and difficult to generalize because of the complexity of single points. Therefore, more phenomenological, simplified models are becoming popular for setting experimental limits, as they have clearer physical interpretations. The use of these simplified model limits to set a real limit on a concrete theory has not, however, been demonstrated. This paper recasts simplified model limits into limits on a specific and complete supersymmetry model, minimal supergravity. Limits obtained under various physical assumptions are comparable to those produced by directed searches. A prescription is provided for calculating conservative and aggressive limits on additional theories. Using acceptance and efficiency tables along with the expected and observed numbers of events in various signal regions, LHC experimental results can be recast in this manner into almost any theoretical framework, including nonsupersymmetric theories with supersymmetry-like signatures.
Physics, Issue 81, high energy physics, particle physics, Supersymmetry, LHC, ATLAS, CMS, New Physics Limits, Simplified Models
50419
Play Button
Diffusion Tensor Magnetic Resonance Imaging in the Analysis of Neurodegenerative Diseases
Authors: Hans-Peter Müller, Jan Kassubek.
Institutions: University of Ulm.
Diffusion tensor imaging (DTI) techniques provide information on the microstructural processes of the cerebral white matter (WM) in vivo. The present applications are designed to investigate differences of WM involvement patterns in different brain diseases, especially neurodegenerative disorders, by use of different DTI analyses in comparison with matched controls. DTI data analysis is performed in a variate fashion, i.e. voxelwise comparison of regional diffusion direction-based metrics such as fractional anisotropy (FA), together with fiber tracking (FT) accompanied by tractwise fractional anisotropy statistics (TFAS) at the group level in order to identify differences in FA along WM structures, aiming at the definition of regional patterns of WM alterations at the group level. Transformation into a stereotaxic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The present applications show optimized technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. On this basis, FT techniques can be applied to group averaged data in order to quantify metrics information as defined by FT. Additionally, application of DTI methods, i.e. differences in FA-maps after stereotaxic alignment, in a longitudinal analysis at an individual subject basis reveal information about the progression of neurological disorders. Further quality improvement of DTI based results can be obtained during preprocessing by application of a controlled elimination of gradient directions with high noise levels. In summary, DTI is used to define a distinct WM pathoanatomy of different brain diseases by the combination of whole brain-based and tract-based DTI analysis.
Medicine, Issue 77, Neuroscience, Neurobiology, Molecular Biology, Biomedical Engineering, Anatomy, Physiology, Neurodegenerative Diseases, nuclear magnetic resonance, NMR, MR, MRI, diffusion tensor imaging, fiber tracking, group level comparison, neurodegenerative diseases, brain, imaging, clinical techniques
50427
Play Button
Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Authors: James Smadbeck, Meghan B. Peterson, George A. Khoury, Martin S. Taylor, Christodoulos A. Floudas.
Institutions: Princeton University.
The aim of de novo protein design is to find the amino acid sequences that will fold into a desired 3-dimensional structure with improvements in specific properties, such as binding affinity, agonist or antagonist behavior, or stability, relative to the native sequence. Protein design lies at the center of current advances drug design and discovery. Not only does protein design provide predictions for potentially useful drug targets, but it also enhances our understanding of the protein folding process and protein-protein interactions. Experimental methods such as directed evolution have shown success in protein design. However, such methods are restricted by the limited sequence space that can be searched tractably. In contrast, computational design strategies allow for the screening of a much larger set of sequences covering a wide variety of properties and functionality. We have developed a range of computational de novo protein design methods capable of tackling several important areas of protein design. These include the design of monomeric proteins for increased stability and complexes for increased binding affinity. To disseminate these methods for broader use we present Protein WISDOM (https://www.proteinwisdom.org), a tool that provides automated methods for a variety of protein design problems. Structural templates are submitted to initialize the design process. The first stage of design is an optimization sequence selection stage that aims at improving stability through minimization of potential energy in the sequence space. Selected sequences are then run through a fold specificity stage and a binding affinity stage. A rank-ordered list of the sequences for each step of the process, along with relevant designed structures, provides the user with a comprehensive quantitative assessment of the design. Here we provide the details of each design method, as well as several notable experimental successes attained through the use of the methods.
Genetics, Issue 77, Molecular Biology, Bioengineering, Biochemistry, Biomedical Engineering, Chemical Engineering, Computational Biology, Genomics, Proteomics, Protein, Protein Binding, Computational Biology, Drug Design, optimization (mathematics), Amino Acids, Peptides, and Proteins, De novo protein and peptide design, Drug design, In silico sequence selection, Optimization, Fold specificity, Binding affinity, sequencing
50476
Play Button
Automated Midline Shift and Intracranial Pressure Estimation based on Brain CT Images
Authors: Wenan Chen, Ashwin Belle, Charles Cockrell, Kevin R. Ward, Kayvan Najarian.
Institutions: Virginia Commonwealth University, Virginia Commonwealth University Reanimation Engineering Science (VCURES) Center, Virginia Commonwealth University, Virginia Commonwealth University, Virginia Commonwealth University.
In this paper we present an automated system based mainly on the computed tomography (CT) images consisting of two main components: the midline shift estimation and intracranial pressure (ICP) pre-screening system. To estimate the midline shift, first an estimation of the ideal midline is performed based on the symmetry of the skull and anatomical features in the brain CT scan. Then, segmentation of the ventricles from the CT scan is performed and used as a guide for the identification of the actual midline through shape matching. These processes mimic the measuring process by physicians and have shown promising results in the evaluation. In the second component, more features are extracted related to ICP, such as the texture information, blood amount from CT scans and other recorded features, such as age, injury severity score to estimate the ICP are also incorporated. Machine learning techniques including feature selection and classification, such as Support Vector Machines (SVMs), are employed to build the prediction model using RapidMiner. The evaluation of the prediction shows potential usefulness of the model. The estimated ideal midline shift and predicted ICP levels may be used as a fast pre-screening step for physicians to make decisions, so as to recommend for or against invasive ICP monitoring.
Medicine, Issue 74, Biomedical Engineering, Molecular Biology, Neurobiology, Biophysics, Physiology, Anatomy, Brain CT Image Processing, CT, Midline Shift, Intracranial Pressure Pre-screening, Gaussian Mixture Model, Shape Matching, Machine Learning, traumatic brain injury, TBI, imaging, clinical techniques
3871
Play Button
High-resolution Functional Magnetic Resonance Imaging Methods for Human Midbrain
Authors: Sucharit Katyal, Clint A. Greene, David Ress.
Institutions: The University of Texas at Austin.
Functional MRI (fMRI) is a widely used tool for non-invasively measuring correlates of human brain activity. However, its use has mostly been focused upon measuring activity on the surface of cerebral cortex rather than in subcortical regions such as midbrain and brainstem. Subcortical fMRI must overcome two challenges: spatial resolution and physiological noise. Here we describe an optimized set of techniques developed to perform high-resolution fMRI in human SC, a structure on the dorsal surface of the midbrain; the methods can also be used to image other brainstem and subcortical structures. High-resolution (1.2 mm voxels) fMRI of the SC requires a non-conventional approach. The desired spatial sampling is obtained using a multi-shot (interleaved) spiral acquisition1. Since, T2* of SC tissue is longer than in cortex, a correspondingly longer echo time (TE ~ 40 msec) is used to maximize functional contrast. To cover the full extent of the SC, 8-10 slices are obtained. For each session a structural anatomy with the same slice prescription as the fMRI is also obtained, which is used to align the functional data to a high-resolution reference volume. In a separate session, for each subject, we create a high-resolution (0.7 mm sampling) reference volume using a T1-weighted sequence that gives good tissue contrast. In the reference volume, the midbrain region is segmented using the ITK-SNAP software application2. This segmentation is used to create a 3D surface representation of the midbrain that is both smooth and accurate3. The surface vertices and normals are used to create a map of depth from the midbrain surface within the tissue4. Functional data is transformed into the coordinate system of the segmented reference volume. Depth associations of the voxels enable the averaging of fMRI time series data within specified depth ranges to improve signal quality. Data is rendered on the 3D surface for visualization. In our lab we use this technique for measuring topographic maps of visual stimulation and covert and overt visual attention within the SC1. As an example, we demonstrate the topographic representation of polar angle to visual stimulation in SC.
Neuroscience, Issue 63, fMRI, midbrain, brainstem, colliculus, BOLD, brain, Magentic Resonance Imaging, MRI
3746
Play Button
Video Bioinformatics Analysis of Human Embryonic Stem Cell Colony Growth
Authors: Sabrina Lin, Shawn Fonteno, Shruthi Satish, Bir Bhanu, Prue Talbot.
Institutions: University of California, University of California, University of California, University of California.
Because video data are complex and are comprised of many images, mining information from video material is difficult to do without the aid of computer software. Video bioinformatics is a powerful quantitative approach for extracting spatio-temporal data from video images using computer software to perform dating mining and analysis. In this article, we introduce a video bioinformatics method for quantifying the growth of human embryonic stem cells (hESC) by analyzing time-lapse videos collected in a Nikon BioStation CT incubator equipped with a camera for video imaging. In our experiments, hESC colonies that were attached to Matrigel were filmed for 48 hours in the BioStation CT. To determine the rate of growth of these colonies, recipes were developed using CL-Quant software which enables users to extract various types of data from video images. To accurately evaluate colony growth, three recipes were created. The first segmented the image into the colony and background, the second enhanced the image to define colonies throughout the video sequence accurately, and the third measured the number of pixels in the colony over time. The three recipes were run in sequence on video data collected in a BioStation CT to analyze the rate of growth of individual hESC colonies over 48 hours. To verify the truthfulness of the CL-Quant recipes, the same data were analyzed manually using Adobe Photoshop software. When the data obtained using the CL-Quant recipes and Photoshop were compared, results were virtually identical, indicating the CL-Quant recipes were truthful. The method described here could be applied to any video data to measure growth rates of hESC or other cells that grow in colonies. In addition, other video bioinformatics recipes can be developed in the future for other cell processes such as migration, apoptosis, and cell adhesion.
Cellular Biology, Issue 39, hESC, matrigel, stem cells, video bioinformatics, colony, growth
1933
Play Button
Reaggregate Thymus Cultures
Authors: Andrea White, Eric Jenkinson, Graham Anderson.
Institutions: University of Birmingham .
Stromal cells within lymphoid tissues are organized into three-dimensional structures that provide a scaffold that is thought to control the migration and development of haemopoeitic cells. Importantly, the maintenance of this three-dimensional organization appears to be critical for normal stromal cell function, with two-dimensional monolayer cultures often being shown to be capable of supporting only individual fragments of lymphoid tissue function. In the thymus, complex networks of cortical and medullary epithelial cells act as a framework that controls the recruitment, proliferation, differentiation and survival of lymphoid progenitors as they undergo the multi-stage process of intrathymic T-cell development. Understanding the functional role of individual stromal compartments in the thymus is essential in determining how the thymus imposes self/non-self discrimination. Here we describe a technique in which we exploit the plasticity of fetal tissues to re-associate into intact three-dimensional structures in vitro, following their enzymatic disaggregation. The dissociation of fetal thymus lobes into heterogeneous cellular mixtures, followed by their separation into individual cellular components, is then combined with the in vitro re-association of these desired cell types into three-dimensional reaggregate structures at defined ratios, thereby providing an opportunity to investigate particular aspects of T-cell development under defined cellular conditions. (This article is based on work first reported Methods in Molecular Biology 2007, Vol. 380 pages 185-196).
Immunology, Issue 18, Springer Protocols, Thymus, 2-dGuo, Thymus Organ Cultures, Immune Tolerance, Positive and Negative Selection, Lymphoid Development
905
Copyright © JoVE 2006-2015. All Rights Reserved.
Policies | License Agreement | ISSN 1940-087X
simple hit counter
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation. | {
"url": "https://www.jove.com/visualize/abstract/24475148/automatic-structural-parcellation-mouse-brain-mri-using-multi-atlas",
"source_domain": "www.jove.com",
"snapshot_id": "crawl=CC-MAIN-2017-30",
"warc_metadata": {
"Content-Length": "78963",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:XXUGYMZOXGHO3LHAWPT4EI3OQJAOOQSH",
"WARC-Concurrent-To": "<urn:uuid:91a38999-90a3-422b-987c-120285ccd364>",
"WARC-Date": "2017-07-24T06:48:20",
"WARC-IP-Address": "166.78.179.190",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:7NRICBZEUXTSOD6BKTZL45R7YTHVJH57",
"WARC-Record-ID": "<urn:uuid:49500c95-3f5f-4927-bae8-b2c3bd1800a4>",
"WARC-Target-URI": "https://www.jove.com/visualize/abstract/24475148/automatic-structural-parcellation-mouse-brain-mri-using-multi-atlas",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:7a5993e3-1f1b-455f-b625-21a36448811e>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-166-26-52.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2017-30\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for July 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
34,
53,
68,
153,
162,
184,
1385,
1458,
1480,
1489,
3170,
3196,
3208,
3355,
3490,
3562,
5434,
5672,
5678,
5690,
5778,
5888,
6025,
7262,
7436,
7442,
7454,
7521,
7578,
7617,
9586,
9674,
9680,
9692,
9772,
9922,
10019,
12029,
12169,
12175,
12187,
12271,
12344,
12547,
14789,
15011,
15017,
15029,
15128,
15267,
15451,
16999,
17159,
17165,
17177,
17324,
17389,
17467,
19354,
19555,
19561,
19573,
19676,
19799,
19930,
22092,
22237,
22243,
22255,
22323,
22379,
22451,
23967,
24130,
24136,
24148,
24298,
24464,
24589,
25667,
26024,
26030,
26042,
26156,
26302,
26420,
27665,
27848,
27854,
27866,
27972,
28014,
28048,
32369,
32563,
32568,
32580,
32646,
32672,
32736,
35583,
35932,
35938,
35950,
36006,
36053,
36141,
37234,
37362,
37368,
37380,
37470,
37512,
37545,
39383,
39695,
39701,
39713,
39786,
39893,
39929,
41914,
42341,
42347,
42359,
42445,
42530,
42762,
44089,
44398,
44403,
44415,
44496,
44551,
44600,
46790,
46898,
46903,
46915,
46988,
47065,
47183,
49050,
49143,
49148,
49160,
49188,
49244,
49285,
50879,
51032,
51036,
51085,
51131,
51150,
51151,
51170,
51171,
51289,
51290,
51308,
51309,
51425,
51426,
51473,
51474
],
"line_end_idx": [
34,
53,
68,
153,
162,
184,
1385,
1458,
1480,
1489,
3170,
3196,
3208,
3355,
3490,
3562,
5434,
5672,
5678,
5690,
5778,
5888,
6025,
7262,
7436,
7442,
7454,
7521,
7578,
7617,
9586,
9674,
9680,
9692,
9772,
9922,
10019,
12029,
12169,
12175,
12187,
12271,
12344,
12547,
14789,
15011,
15017,
15029,
15128,
15267,
15451,
16999,
17159,
17165,
17177,
17324,
17389,
17467,
19354,
19555,
19561,
19573,
19676,
19799,
19930,
22092,
22237,
22243,
22255,
22323,
22379,
22451,
23967,
24130,
24136,
24148,
24298,
24464,
24589,
25667,
26024,
26030,
26042,
26156,
26302,
26420,
27665,
27848,
27854,
27866,
27972,
28014,
28048,
32369,
32563,
32568,
32580,
32646,
32672,
32736,
35583,
35932,
35938,
35950,
36006,
36053,
36141,
37234,
37362,
37368,
37380,
37470,
37512,
37545,
39383,
39695,
39701,
39713,
39786,
39893,
39929,
41914,
42341,
42347,
42359,
42445,
42530,
42762,
44089,
44398,
44403,
44415,
44496,
44551,
44600,
46790,
46898,
46903,
46915,
46988,
47065,
47183,
49050,
49143,
49148,
49160,
49188,
49244,
49285,
50879,
51032,
51036,
51085,
51131,
51150,
51151,
51170,
51171,
51289,
51290,
51308,
51309,
51425,
51426,
51473,
51474,
52004
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 52004,
"ccnet_original_nlines": 166,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.27710026502609253,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.03342366963624954,
"rps_doc_frac_lines_end_with_ellipsis": 0.005988019984215498,
"rps_doc_frac_no_alph_words": 0.1703929454088211,
"rps_doc_frac_unique_words": 0.3068402111530304,
"rps_doc_mean_word_length": 6.002215385437012,
"rps_doc_num_sentences": 341,
"rps_doc_symbol_to_word_ratio": 0.0001129200027207844,
"rps_doc_unigram_entropy": 6.6021223068237305,
"rps_doc_word_count": 7222,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.02599889039993286,
"rps_doc_frac_chars_dupe_6grams": 0.018893610686063766,
"rps_doc_frac_chars_dupe_7grams": 0.008927750401198864,
"rps_doc_frac_chars_dupe_8grams": 0.008927750401198864,
"rps_doc_frac_chars_dupe_9grams": 0.004152440000325441,
"rps_doc_frac_chars_top_2gram": 0.007612810004502535,
"rps_doc_frac_chars_top_3gram": 0.004982930142432451,
"rps_doc_frac_chars_top_4gram": 0.0024914599489420652,
"rps_doc_books_importance": -3935.677734375,
"rps_doc_books_importance_length_correction": -3935.677734375,
"rps_doc_openwebtext_importance": -1973.912109375,
"rps_doc_openwebtext_importance_length_correction": -1973.912109375,
"rps_doc_wikipedia_importance": -921.4200439453125,
"rps_doc_wikipedia_importance_length_correction": -921.4200439453125
},
"fasttext": {
"dclm": 0.024389149621129036,
"english": 0.8929230570793152,
"fineweb_edu_approx": 2.7487094402313232,
"eai_general_math": 0.6482657194137573,
"eai_open_web_math": 0.29896432161331177,
"eai_web_code": 0.04486227035522461
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.858",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.075",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "5",
"label": "Exceptionally Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
546,674,389,942,061,250 | Advertisements
Blog
Sun Exposure and Aging
For centuries, man has searched for the Fountain of Youth. Billions of dollars are spent every year on skin care products that we hope will eliminate wrinkles, reduce redness, dryness and itching, lighten age spots, and give us moist, youthful skin. The most effective way to keep your skin looking young is to stay out of the sun. The UV rays in sunlight are the major cause of aging. Sun damage may not be apparent while we are young, but it will be later in life.
Advertisements
Exposure to sunlight eventually causes the elastic tissues (elastin and collagen) in our skin to stretch and become slack. Gravity pulls at the skin and causes it to sag. Skin will become thinner and more susceptible to bruising and tearing and will take longer to heal from injury. Loss of fat under the skin makes underlying structures, particularly the veins and bones, more prominent under our thinning skin. These changes are inevitable but can be delayed by avoiding exposure to the sun.
As we age, we lose oil and sweat glands, which contribute to dry skin. Low humidity, from overheated homes in the winter and air conditioning in the summer, also robs our skin of moisture. Sun exposure, dehydration, smoking, and stress may also cause dry skin. Hot baths and the overuse of soaps and perfumes can make dry skin worse. Using a humidifier will add necessary moisture to the air, and moisturizers used after bathing can help retain water in the skin. Dry skin can be very itchy and cause loss of sleep and irritability. It can also be a symptom of a medical condition such as diabetes or kidney disease, or the side effect of medications. If you have unbearably itchy skin, consult your physician.
Sun-damaged skin may improve with use of sun protection and proper skin care. Skin has the ability to repair itself, but nothing will completely erase the harmful effects of the sun. Stay out of the sun between 10 a.m. and 3 p.m., when the sun’s rays are the most direct. Use sun block with at least SPF15 protection, and wear UV blocking sunglasses to avoid squinting, which contributes to wrinkles around the eyes. Wear a hat with a wide brim, and loose, lightweight, long sleeve shirts and long pants to shield your skin from sunlight’s damaging rays. Use of sun blocks and sun screens can help prevent the appearance of age spots and prevent further damage. There are also many moisturizers and makeup products on the market now which contain sun blocking agents.
There are many over-the-counter products on the market that promise to reverse the effects of aging, but do little except to soothe dry skin. Alpha-hydroxy acids (AHAs) may help to reduce wrinkles, spots, and other signs of aging, but there are some concerns about long-term effects and adverse reactions. Using AHAs may make you more sensitive the sun, so it is advised that people using such products to take steps to protect themselves from the sun.
Dermatologists can offer treatment for aging skin to improve its appearance. Prescriptions creams may reduce fine wrinkles, dark spots and rough skin. It won’t eliminate wrinkles or restore your skin to its younger, healthier state. Chemical peels, laser therapy, and dermabrasion can be performed to minimize wrinkles, irregular pigmentation, and minor scars, allowing the layer beneath to regenerate for a more youthful appearance. Specific treatment is determined by the severity of the damage, your age, overall health, and medical history.
No discussion of the sun’s damaging effects on your skin is complete without mentioning the possibility of skin cancer. UV radiation from the sun’s rays is the major cause of skin cancer. Forty to fifty percent of Americans who live to age 65 have skin cancer at least one time (National Institute of Aging). Fair-skinned people and those who live in sunny climates have the highest chance of developing the disease. Caught in the early stages, it is treatable and curable. Check your skin regularly for any changes. Not all skin cancers look the same. It may appear as an itchy, scaly spot, a small, pale, waxy bump, a red, firm lump, or a sore that won’t heal. Any change that lasts for longer than two weeks should be examined by a physician.
Advertisements
Aging is an unavoidable fact of life, but proper use of sun blocks, clothing, and avoiding excessive exposure to the harmful effects of the sun can slow down the effects of this inevitable process. It could even save your life.
Click to comment
Leave a Reply
Your email address will not be published. Required fields are marked *
Advertisements
To Top | {
"url": "http://brainheadway.com/sun-exposure-and-aging/",
"source_domain": "brainheadway.com",
"snapshot_id": "crawl=CC-MAIN-2017-13",
"warc_metadata": {
"Content-Length": "54719",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:DN4TZXAOLLNMDCFCLN5M4YKWNYPP5VNS",
"WARC-Concurrent-To": "<urn:uuid:d9fae881-3a56-4065-a4c6-7165aca5cdbd>",
"WARC-Date": "2017-03-23T14:20:12",
"WARC-IP-Address": "104.28.13.115",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:V6N63BW736Q343MLJNH5SLMVI6INAC34",
"WARC-Record-ID": "<urn:uuid:e3700cf2-9009-451f-9328-52f9b65b6c42>",
"WARC-Target-URI": "http://brainheadway.com/sun-exposure-and-aging/",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:097c69c7-1767-46ec-bd27-4ff7037812db>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-233-31-227.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-13\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for March 2017\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
15,
20,
21,
44,
45,
512,
513,
528,
529,
1023,
1024,
1735,
1736,
2504,
2505,
2958,
2959,
3504,
3505,
4251,
4252,
4267,
4268,
4496,
4497,
4499,
4500,
4517,
4518,
4532,
4533,
4604,
4605,
4620
],
"line_end_idx": [
15,
20,
21,
44,
45,
512,
513,
528,
529,
1023,
1024,
1735,
1736,
2504,
2505,
2958,
2959,
3504,
3505,
4251,
4252,
4267,
4268,
4496,
4497,
4499,
4500,
4517,
4518,
4532,
4533,
4604,
4605,
4620,
4626
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4626,
"ccnet_original_nlines": 34,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4032786786556244,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0043715802021324635,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1322404444217682,
"rps_doc_frac_unique_words": 0.4712643623352051,
"rps_doc_mean_word_length": 4.739463806152344,
"rps_doc_num_sentences": 50,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.280710697174072,
"rps_doc_word_count": 783,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.021557530388236046,
"rps_doc_frac_chars_dupe_6grams": 0.01347346045076847,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.011317700147628784,
"rps_doc_frac_chars_top_3gram": 0.00862300954759121,
"rps_doc_frac_chars_top_4gram": 0.006467259954661131,
"rps_doc_books_importance": -437.3101501464844,
"rps_doc_books_importance_length_correction": -437.3101501464844,
"rps_doc_openwebtext_importance": -243.46670532226562,
"rps_doc_openwebtext_importance_length_correction": -243.46670532226562,
"rps_doc_wikipedia_importance": -177.1642608642578,
"rps_doc_wikipedia_importance_length_correction": -177.1642608642578
},
"fasttext": {
"dclm": 0.029164370149374008,
"english": 0.9395413398742676,
"fineweb_edu_approx": 2.416123628616333,
"eai_general_math": 0.00031400000443682075,
"eai_open_web_math": 0.12676692008972168,
"eai_web_code": 0.000012989999959245324
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
1,624,787,618,454,164,000 | Skip to main content
Table 1 Acupressure intervention protocol
From: Acupressure to improve sleep quality of older people in residential aged care: a randomised controlled trial protocol
Acupressure sessions and length of intervention• 12-min session, three times per week for 4 weeks
• Daytime (9 a.m.–5 p.m.), following the convenient time for study participants
Selection of acupoints1. Shenmen (HT7) on both hands
2. Neiguan (PC6) on both hands
3. Sanyinjiao (SP6) on both legs
Sequence and time of acupressure application per pointApply finger pressure for 2 min on each point with the following sequence:
1. PC6 in left hand
2. PC6 in right hand
3. HT7 in left hand
4. HT7 in right hand
5. SP6 on left leg
6. SP6 on right leg
Acupressure technique• Apply consistent finger or thumb pressure on each point in circular motion
• Circular motion in clockwise for 1 min and counter-clockwise for 1 min
• Intensity of pressure adjusted according to the person’s level of tolerance | {
"url": "https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04286-2/tables/1",
"source_domain": "trialsjournal.biomedcentral.com",
"snapshot_id": "crawl=CC-MAIN-2020-40",
"warc_metadata": {
"Content-Length": "91455",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:WEQIDHDRNXT6L4RTXEF2H5IDNB4ROKM6",
"WARC-Concurrent-To": "<urn:uuid:3312b6ca-22b2-4256-8803-62c3d1ad7fb9>",
"WARC-Date": "2020-09-20T05:30:14",
"WARC-IP-Address": "151.101.248.95",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:5QQSUQ3IMTKENC3SCE6DMEWMVVLK6LV4",
"WARC-Record-ID": "<urn:uuid:1ee2aea3-368d-4a44-b1f1-0bc4e4ed7da7>",
"WARC-Target-URI": "https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04286-2/tables/1",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:07bde760-e951-4a44-96fc-e9b5063048b7>"
},
"warc_info": "isPartOf: CC-MAIN-2020-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-205.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
21,
22,
64,
65,
189,
190,
288,
368,
421,
452,
485,
614,
634,
655,
675,
696,
715,
735,
833,
906
],
"line_end_idx": [
21,
22,
64,
65,
189,
190,
288,
368,
421,
452,
485,
614,
634,
655,
675,
696,
715,
735,
833,
906,
983
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 983,
"ccnet_original_nlines": 20,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.28282827138900757,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.04545455053448677,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.24242423474788666,
"rps_doc_frac_unique_words": 0.5644171833992004,
"rps_doc_mean_word_length": 4.846625804901123,
"rps_doc_num_sentences": 14,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.3119587898254395,
"rps_doc_word_count": 163,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.02278481051325798,
"rps_doc_frac_chars_top_3gram": 0.027848100289702415,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -109.14205169677734,
"rps_doc_books_importance_length_correction": -109.14205169677734,
"rps_doc_openwebtext_importance": -65.23492431640625,
"rps_doc_openwebtext_importance_length_correction": -51.27364730834961,
"rps_doc_wikipedia_importance": -38.919700622558594,
"rps_doc_wikipedia_importance_length_correction": -38.919700622558594
},
"fasttext": {
"dclm": 0.0628354474902153,
"english": 0.7860068678855896,
"fineweb_edu_approx": 1.4036469459533691,
"eai_general_math": 0.07452254742383957,
"eai_open_web_math": 0.15389543771743774,
"eai_web_code": 0.0004248000041116029
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "4",
"label": "Graduate/Expert Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
2,511,405,214,452,957,000 | Simethicone is marketed by the Novartis under the brand Maalox plus suspension extra mechanical strength, and was approved this by the FDA in December 2014. simethicone was murdered first authorised in unwinding the eu as Rolaids ultra high strength plus gas dispersible tablets in the january 2003.
Administration reports of Maalox plus suspension extra high strength acetaminophen tablets with a high fat per meal decreases rate but not extent of magnesium hydroxide absorption. By 1991, pfizer, inc. began marketing magnesium hydroxide under subjection their brand name Acid controller complete.
FDA orders ferric carboxymaltose and bone magnesium hydroxide manufacturers to limit such use phenomena in kids. If you have any changing of these conditions, you may not as be able to use magnesium hydroxide layer and itraconazole, or you prefer may need a dosage and adjustment or special tests during his treatment.
I am surprised that united they used ceritinib instead of itraconazole. A method of correcting extensive metabolism indicative of ceritinib, comprising administering valsartan to a human being in need thereof. No revolutionary changes were observed in the placebo group and adapalene appeared explicitly to have no steric effect on the pharmacokinetics of valsartan.
It is otherwise important to use Sacubitril / valsartan or valsartan only as radioactivity per your doctor’s advice. limaprost and adapalene must be entirely stored in a locked for safe. The nausea or of vomiting were not severe but happened within a few bloody minutes reading of taking the Sacubitril / valsartan. | {
"url": "http://www.prednisolone.org/archives/587/how-are-ferric-carboxymaltose-and-ceritinib-linked/",
"source_domain": "www.prednisolone.org",
"snapshot_id": "crawl=CC-MAIN-2019-43",
"warc_metadata": {
"Content-Length": "21030",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JEWLDNQRWESSGIJZ5L6G7N27RGYVOA3K",
"WARC-Concurrent-To": "<urn:uuid:0428889d-8b80-44d4-9fee-96cff50b5a94>",
"WARC-Date": "2019-10-22T14:16:54",
"WARC-IP-Address": "149.28.196.99",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:X6YTP7V7ARI7RSLXRYOOTZGNNOS4YAU5",
"WARC-Record-ID": "<urn:uuid:383405c0-2753-4fcf-9866-96d3d2dc96e2>",
"WARC-Target-URI": "http://www.prednisolone.org/archives/587/how-are-ferric-carboxymaltose-and-ceritinib-linked/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:603bb753-1602-47f4-8480-821913f6f64d>"
},
"warc_info": "isPartOf: CC-MAIN-2019-43\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for October 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-180.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
300,
301,
600,
601,
920,
921,
1288,
1289
],
"line_end_idx": [
300,
301,
600,
601,
920,
921,
1288,
1289,
1604
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1604,
"ccnet_original_nlines": 8,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4157303273677826,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.014981269836425781,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.09363295882940292,
"rps_doc_frac_unique_words": 0.6434426307678223,
"rps_doc_mean_word_length": 5.467213153839111,
"rps_doc_num_sentences": 13,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.823940277099609,
"rps_doc_word_count": 244,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.053973011672496796,
"rps_doc_frac_chars_top_3gram": 0.029985010623931885,
"rps_doc_frac_chars_top_4gram": 0.03748125955462456,
"rps_doc_books_importance": -119.37344360351562,
"rps_doc_books_importance_length_correction": -105.69305419921875,
"rps_doc_openwebtext_importance": -73.06504821777344,
"rps_doc_openwebtext_importance_length_correction": -73.06504821777344,
"rps_doc_wikipedia_importance": -54.71843338012695,
"rps_doc_wikipedia_importance_length_correction": -41.112361907958984
},
"fasttext": {
"dclm": 0.021250130608677864,
"english": 0.9292299151420593,
"fineweb_edu_approx": 1.83096444606781,
"eai_general_math": 0.13293123245239258,
"eai_open_web_math": 0.17682474851608276,
"eai_web_code": 0.006632150150835514
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.19",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.54",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "3",
"label": "Incoherent Flow"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "4",
"label": "Graduate/Expert Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
4,588,449,230,875,878,000 | Nobelprize.org
Lists of Nobel Prizes and Laureates
Nerve Signalling: Tracing the Wiring of Life
by John Farndon
First published 16 September 2009
intro
The Nobel Prize in Physiology or Medicine has rewarded scientists for an amazing voyage of discovery inside the human nervous system - one that has revealed how the myriad tiny signals firing through nerve cells keeps us alive, thinking and moving.
Estimates vary wildly, since of course, no-one has counted them all, but there are some 100 billion separate nerve cells in the human brain - which is, by strange coincidence, around the same number as there are thought to be galaxies in the Universe. But this number, however awesome, doesn't begin to capture the almost miraculous complexity of the human nervous system. Each of those 100 billion cells can make hundreds and hundreds of separate connections with other cells - and unimaginably more alternative pathways - that allow nerve signals to crackle, fizz and buzz along as they make us jump up or sit down, laugh and cry, love and hate, sing, shout, swear, eat, drink and do everything that makes us human.
Science is only just beginning to understand the brain's remarkable form of 'software' - the way it works as a whole to enable us to live and think - but an amazing series of scientific breakthroughs have given us insight into its 'hardware'. Each of the Nobel Laureates who appear in this brief story has taken us further down the path towards understanding how nerves are made up and carry the signals that coordinate all the activities in our bodies.
Nerve networks
Figure 1. Nerve networks
The nervous system consists of a complex, interwoven network of nerve cells that look like no other. This fluorescent microscopic image of neurons generated from human embryonic stem cells highlights this complexity. Spider-like nerve cell bodies with thin thread-like axons are visible in red and the nuclei in blue. Yellow neurons create and release the neurotransmitter dopamine, and are the type of neurons that deteriorate in patients with Parkinson's disease.
Copyright: Laboratory of Xianmin Zeng, the Buck Institute.
Mapping the Nervous System
One of the first of the great pioneers of nerve research to receive the Nobel Prize, a Spanish surgeon's son called Santiago Ramón y Cajal said, "The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory." And towards the end of the 19th century that is how it must have appeared as the power of the microscope revealed just what a complex and amazing network the human nervous system is.
We know now that the nervous system consists essentially of the command centre in the central nervous system - the dense cluster of nerve cells in the brain and spinal cord - and the signalling network of peripheral nerves - fibres that stretch out into every corner of the body. But nerves are incredibly fine. A nerve fibre can be less than a hundredth of the thickness of a human hair, so with the microscopes available in the 19th century, nerve fibres were very hard to see indeed.
When they peered down a microscope, 19th century scientists could just about make out that the nervous system was made of what they took to be a network of nerve cells. But nerve cells looked like no others. Whereas most body cells are essentially parcels of some shape, nerve cells looked more like spiders with a bulky body off which spread countless thin threads, called 'processes'. They knew nerves played a part in signalling, so they guessed all these cell bodies and threads were fused together in one continuous network. But it was all so tangled and tiny that no-one could really see. Then in 1871, a young Italian anatomist named Camillo Golgi made a remarkable discovery in the hospital kitchen where he carried out his own experiments.
Golgi found that if he soaked a bundle of nerve fibres over a few nights in silver nitrate - an idea some suggest he may have got from its use in photographic film - a few of the nerve cells stained a dark and inky black and showed up clearly under the microscope. Suddenly, complete nerve cells revealed their full appearance for the first time, and Golgi saw how the processes consisted of a single long tail or axon and an array of spindly branches or dendrites that spread out from the spider-like cell body. But he still thought they were all part of a tangled, inseparable web of fused fibres through which signals must flow this way and that.
Unmasking nerve cells
Figure 2. Unmasking nerve cells
Working from a makeshift laboratory, Camillo Golgi developed a revolutionary silver staining method that allowed him to visualize individual nerve cells. Golgi continued to develop staining techniques and teach about them; here he is seen at the age of 77 in his laboratory at the University of Pavia, Italy.
The photo was kindly provided by Museo di Storia dell'Università di Pavia - Museum for the History of the University of Pavia.
Find the Gap!
But then using Golgi's stain, Cajal, the Spanish surgeon's son, looked at the nerve cells of newborn birds and other small animals, which were simpler and easier to see than adult cells, and reproduced what he saw in a series of beautiful drawings. Cajal interpreted his observations differently to Golgi, proposing that there were gaps between the processes of each cell, and that each cell was actually a separate unit or neuron, not part of a fused network at all. Nerve signals, then, must be passed on from neuron to neuron across the gaps, later called 'synapses', in a kind of relay race.
Then Cajal, who shared the Nobel Prize with Golgi in 1906, noticed that axons on neurons that connect to sense receptors such as vision, touch and hearing (sensory neurons) point in towards the central nervous system, while axons on neurons that trigger the muscles to move (motor neurons) lead away. Neurons, then, must carry signals in one direction only, taking messages in through the dendrites, and transmitting them through the axon.
Anatomy of the nervous system.
Figure 3. Anatomy of the nervous system
Using Camillo Golgi's silver staining method and blessed with natural artistic talent, Santiago Ramón y Cajal created stunning representations of different areas of the nervous system. Here, Cajal's sketch of the retina shows clearly the variety of neurons present in the eye.
Image kindly provided by the History of Medicine (IHM).
Cajal began to realize that signals travel along particular pathways and that it might be possible to trace the paths through the nervous system from start to finish. It was a brilliant insight, which allowed scientists to explore how sense inputs from different parts of the body are wired into particular parts of the brain. By the middle of the last century neuroscientists such as American Wade Marshall, who trained the Nobel Laureate Eric Kandel, had shown how sense inputs from different parts of the body are wired into particular parts of the brain - a discovery summed up in a weird picture of a person called a 'sensory homunculus' which depicts areas of the body in proportion to how much brain space is needed to process the sense inputs.
Building Nerve Circuits
What was puzzling, though, was just how it all got wired up in the first place. Experiments in the 1950s showed that every neuron somehow knew how to reach its intended destination. Scientists such as Roger Sperry, who received the Nobel Prize in 1981, tried 'rewiring' nerves in experimental animals with bizarre results - connecting nerves back to front made the animals see upside down, or walk backwards.
So how then did nerves end up attaching to the right place? Sperry suggested they were like hounds on a scent, drawn by a recipe of chemical signals sent out by the target. Few scientists believed this to be the case, even when Rita Levi-Montalcini discovered a chemical called Nerve Growth Factor, or NGF for short, that seemed to fit the bill. Together with her colleague, Stanley Cohen, Levi-Montalcini eventually proved that the NGF protein stimulates the growth of nerve connections, for which they shared the 1986 Physiology or Medicine Prize. Nerve fibres grow towards the source of NGF, which can be produced in the local neighbourhood by many types of cell, allowing fibres to find their intended destinations, even through the dense thicket of nerves that make up the brain.
Thanks to the pioneering work carried out by Golgi and Cajal, Sperry, Cohen and Levi-Montalcini, and a host of other researchers, we have a remarkably clear picture now of how the nervous system is wired up. But finding out just how messages travel through it required another remarkable voyage of discovery.
Generating Nerve Signals
One of the big breakthroughs came from Charles Scott Sherrington, the man who in 1897 gave the synapse its name. Sherrington revealed how the nerve system coordinates movement. Scientists were already familiar with simple reflexes, such as the knee jerk, in which a tap on the knee makes the leg jerk up automatically and uncontrollably long before the brain knows what's going on. Sherrington's genius was to realize that nerve impulses are coordinated to create muscle movements in such reflexes, and that this is part of the integrated way that nerves control the body.
Sherrington got the idea from watching a cat amble along a wall, then leap neatly over a gap to resume its stroll. How did it manage the amazing coordination to gauge the jump and land so effortlessly? Sherrington realized it works by playing off a mass of signals from two types of neuron, one which sends a signal that excites a reaction and the other a signal that inhibits it. Motor neurons, Sherrington realized, receive numerous excitors and inhibitors as data buzzes in from sense receptors - but only flash out a signal for a muscle to contract when excitement overpowers inhibition. The continual cross-feeding of excitors and inhibitors firing through nerves across the body ensures a wonderfully co-ordinated response without you even having to think about it - what Sherrington dubbed the 'integrative action of the nervous system.'
Acting on Impulses
Sherrington's work fed directly into that of Edgar Adrian, the scientist he shared the 1932 Nobel Prize with, and also that of Herbert Gasser and Joseph Erlanger, who received the Physiology or Medicine Prize in 1944.
By the 1920s, scientists felt sure that nerve signals were electrical, and that nerves behaved like wires. Indeed, back in 1859, the ingenious German physicist Hermann van Helmholtz had actually managed to time the speed that electricity buzzes down an axon. Yet electricity in nerves seemed strangely slow, crawling along only at 90 feet per second - while electricity in a wire travels millions of times faster at close to the speed of light (186,000 miles per second). In fact, electricity in a nerve is not like an electric current at all. An electric current is a rapid flow of electrons, but electricity sweeps along the nerve as an 'action potential', a difference in electrical charge between the inside of the nerve and the outside.
Amazingly, Adrian, Gasser and Erlanger found ways to connect wires to nerves and amplify the signal so that they could make an action potential fire off a sound in a loudspeaker, or create a light trace on the screen of an 'oscilloscope'. Adrian, as he listened to his loudspeaker, found that nerve signals are very simple, just going: bang! on, then bang! off. And to his surprise, a stronger stimulus increased only the number of nerve impulses that are produced every second, not the actual size of the impulse.
Watching on their oscilloscope, Gasser and Erlanger detected that impulses had slightly different patterns in three kinds of nerve fibre, with both touch and muscle movement signalled rapidly through thick fibres and pain signalled more slowly through thinner fibres. It began to become clear that nerve signals are very simple; it is the way nerves are wired up that determines the message, not the nature of the signal.
Detecting different nerve impulses
Figure 4. Detecting different nerve impulses
Joseph Erlanger sitting at the oscilloscope device that he and Herbert Glasser built to amplify and visualize nerve impulses, or action potentials, as they travel along a neuron. Using their device, Erlanger and Glasser discovered that different types of nerve fibres conduct impulses at different rates, which relates to their particular function.
Courtesy of the Bernard Becker Medical Library.
Voltage Regulator
It was Adrian's student Alan Hodgkin who along with Andrew Huxley formulated a theory - termed the 'ionic hypothesis' - to explain how action potentials are generated. Most nerve fibres are so small and fine it is almost impossible to make any measurements inside, but Hodgkin and Huxley hit upon the great idea of experimenting with giant axons in squids. At a whopping millimetre thick, a squid giant axon is about a thousand times as thick as most human axons.
Connecting wires inside and out of the squid axon, Hodgkin and Huxley measured the difference in voltage, in other words the action potential, as a nerve impulse sweeps along the axon. Using clever mathematical models to make sense of the mass of electrical data they collected, Hodgkin and Huxley revealed that in its 'resting' state, some negatively charged potassium ions seep in through the membrane that makes up the nerve cell walls, while positively charged sodium ions leak out, which creates a small but measurable voltage. When a nerve is stimulated, however, Hodgkin and Huxley proposed that 'ion gates' open up in the membrane, allowing sodium ions to flood in to create the upstroke of the nerve signal's spike, and potassium ions to flood out to create the downstroke. The action potential sweeps along the nerve as ion gates open and close in quick succession.
In the 1970s, Erwin Neher and Bert Sakmann revolutionized the field with the development of the patch-clamp technique, an instrument that enabled scientists to study the flow of ions through a single one of these ion gates, or channels - a remarkable achievement for which they received the Physiology or Medicine Prize in 1991. And in 2003, Roderick MacKinnon received a Nobel Prize in Chemistry for his astonishing 3D pictures of ion channels.
Figure 5.
Ion channels and nerve impulses. Nerve impulses are generated by charged atoms, or ions, flowing into and out of nerve cells through channels that line the cell membrane. Sodium ions flowing in these ion channels create the rising phase of the nerve signal, while the falling phase is created by potassium ions flowing out. The wave of electric charge moves along the nerve cell as ion channels open and close in quick succession.
Copyright: The Royal Swedish Academy of Sciences.
Crossing the Gap
So we have a pretty good picture of how the nervous system fits together and how nerves transmit signals. But there's a third key part of the jigsaw: how signals cross synapses. Back in the 1930s, scientists were divided into two camps: On one side were the 'sparkers' who thought it was electrical, like the nerve impulse itself; on the other side were the 'soupers' who thought the synaptic signal was chemical. Sparkers just couldn't see how chemicals could move fast enough; soupers couldn't see how electricity would work.
The soup idea gained strength in the 1930s through the work of British pharmacologist Henry Dale and German Austrian Otto Loewi, for which they received the Physiology or Medicine Prize in 1936. Loewi's ingenious idea was to collect fluid from around a frog's heart just after the connecting nerve had been stimulated to slow the heart down. He injected the fluid into another frog's heart - and immediately the second frog's heart slowed. No nerve signal had fired - so it was clear some chemical in the fluid was slowing the heart. Dale went on to show that the heart-slowing chemical is acetylcholine. There's also a heart-booster called adrenaline.
Otto LoewiFigure 6.
Otto Loewi with his assistants in his laboratory. Loewi’s ingenious experiment on frog hearts provided the first conclusive proof that chemicals transmit impulses from one nerve cell to another, and from nerve cells to their target organ or gland.
Every effort has been made by the publisher to credit organizations and individuals with regard to the supply of photographs. The publishers apologize for any omissions which will be corrected in future editions.
Sparks Fly
The sparkers, too, gained some ammunition, when scientists such as John Eccles discovered that in addition to the big action potentials that zip down the axon as the nerve sends its signals, there is a slower, smaller one made by incoming signals called a synaptic potential. Eccles realized that these synaptic potentials are the key to Sherrington's 'integrative action'. The nerve cell is bombarded all the time by waves of synaptic potentials through its dendrites - some excitors, some inhibitors. When excitors outbuzz inhibitors, an action potential fires off along the axon.
But just how do signals cross the synapse? Eccles was fervently on the sparks side, Dale was a real souper, and they almost had a punch-up over it at one conference. But as the Second World War got under way, Eccles went to work in the safety of Australia with a Jewish refugee from Germany named Bernard Katz and an Austrian refugee named Stephen Kuffler. Having started on the sparky side, first Katz and Kuffler, and then Eccles flipped over to become soupers as the evidence mounted.
Chemical Communication
Experiments were increasingly showing that signals are carried across synapses by chemical messengers called 'neurotransmitters', which are released at the axon tip. Katz showed that when molecules of acetylcholine, the first known transmitter, are released from a motor neuron, they spread rapidly - in fact almost instantly - across the synapse to muscle cells. There they bind to receptors, like a key slotting into the right lock, and as they slide home, they open gates in the cell membrane, letting charged ions flood in, and setting the synaptic potential on its way. These chemical molecule or 'ligand-triggered' ion gates are different from the 'voltage-triggered' ion gates that set off action potentials, allowing both sodium and potassium ions to flood through each way.
Soon a whole range of neurotransmitters had been discovered, such as serotonin. Some are typically excitors, such as glutamate, while others are mainly inhibitory, such as GABA. But it is the receptor they bind to that excites or inhibits, not the transmitter itself. So while glutamate excites most nerves, there are some it inhibits.
There was a twist to the soupers' victory tale, when in the late 1950s, two students of Katz, Edwin Furshpan and David Potter, found a few examples of electric signalling across synapses. But in the brain at least, synaptic signalling is mainly chemical. Katz, as well as Ulf von Euler and Julius Axelrod, went on to discover just how this process worked, for which they shared the 1970 Physiology or Medicine Prize.
Katz found that transmitters are not released molecule by molecule but spill out in a flood from tiny packets of 5,000 or so molecules contained in vesicles, which fuse with the nerve cell wall and open into the synapse. Discovering another neurotransmitter, noradrenaline, von Euler established that this chemical is created in the nerve fibres themselves and stored in swellings concentrated at nerve endings. Axelrod revealed how unused noradrenaline is reabsorbed by nerve cells after the chemical message has been delivered. While this answered many fundamental questions about neurotransmitters, a key piece of information missing was what tasks these chemicals actually carry out when they reach their target nerve cells.
How neurotransmitters work, part 1.
Figure 7. How neurotransmitters work, part 1.
Chemicals called neurotransmitters are responsible for transmitting nerve impulses across the synapse from one nerve cell to another, or from one nerve cell to a target organ or gland. When a nerve impulse reaches the synapse, neurotransmitters spill out from tiny packets of around 5,000 molecules contained in vesicles within the nerve terminal. The released neurotransmitters spread rapidly across the synapse and bind to chemical receptors on the surface membrane of a receiving nerve cell. In most cases unused neurotransmitter is reabsorbed by nerve cells after the chemical message has been passed on.
Copyright: The Nobel Committee for Physiology or Medicine at Karolinska Institutet.
Brain-Enhancing Chemicals
Uncovering this information earned Arvid Carlsson, Paul Greengard and Eric Kandel the Physiology or Medicine Prize in 2000. Through their pioneering studies, the three scientists showed how neurotransmitters influence basic functions of the brain and how they are affected by disease.
Carlsson's research into neurotransmitters revealed, for the first time, how a brain disorder actually worked. After discovering a transmitter called dopamine, he found that reducing levels of it in the brains of experimental animals created symptoms like Parkinson's disease, a so-called neurodegenerative disease that causes severe movement problems. From this Carlsson deduced that the disease is caused by a loss of dopamine in brain regions affecting control of movements, and that it should be possible to treat with the dopamine boosting drug L-DOPA, which has brought relief to millions of Parkinson's sufferers.
Greengard showed how dopamine and other neurotransmitters trigger these types of effects in nerve cells. His studies built directly on the work of Earl Sutherland and Ed Krebs, who found in the 1960s that there are two types of receptor for neurotransmitters. When a transmitter locks onto and opens a ligand-gate (also known as an 'ionotropic receptor'), it sparks out a synaptic potential instantly, and it's all over in milliseconds. Sutherland and Krebs discovered another kind of receptor, called a metabotropic receptor, which produces a very different response that is much more widespread and can go on for minutes.
Greengard painstakingly assembled a complete picture of the events that occur during these 'slow' synaptic signals. When dopamine locks on to a metabotropic receptor, it releases a so-called 'second messenger' inside the cell called cyclic AMP, which activates protein kinase A, a kind of master switch that can activate a host of biologically important proteins by adding phosphate molecules onto them. Greengard identified over one hundred of these activated chemicals, and found how they interact in elaborate cascades to alter the way the cell behaves and reacts. These discoveries are helping to build a detailed picture of how the neuron's biochemical software works.
How neurotransmitters work
Figure 8. How neurotransmitters work, part 2
When dopamine and other neurotransmitters reach the receiving nerve cell they attach themselves to two types of receptors. One type of receptor sparks off a nerve impulse within milliseconds. Another type triggers a slower event, where messenger molecules set off an elaborate chain of chemical events, which eventually activates a host of biologically important proteins that alter the way the nerve cell behaves and reacts.
Copyright: The Nobel Committee for Physiology or Medicine at Karolinska Institutet.
Meanwhile, Kandel was showing just what it was all programmed to do - store memories. Kandel pioneered the idea that nerves remember things because of changes at synapses, and that learning is all about activating second-messenger cascades of the type studied by Greengard. Remembering things means, essentially, unleashing the right cascades of chemicals to reinforce the connections between neurons along particular pathways.
Mind Matters
It seems appropriate to finish our story here, with the beginnings of an understanding of how we learn things. The whole process of how nerves work and how we learn things turns out to be just as awesome and fantastic as we would expect such a mechanism to be.
Whenever a new sensation comes into your brain, it sends a flurry of activity surging through a particular tangle or network of neurons. Each neuron involved not only passes on its message to other neurons, but sends a signal back to the neurons that alerted it. This feedback loop might amplify the signal, or dampen it down. After the initial signal has died down, the neurons involved reinforce their connections with one another, so that they are primed and ready to fire again much more readily if the same sensation comes in, like a well-trodden path through the brain. If the sensation is not repeated, the connections begin to weaken, as the path falls out of use.
This is why practice makes perfect. The more a particular sensation or action is repeated, the more a particular pattern of neurons becomes strengthened. Practice something over and over again and you are building up the relevant neural pattern in your brain ...
References and Further Reading
Begley, S. The Plastic Mind (Constable & Robinson, London, 2009)
Doidge, N. The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science (Penguin, London, 2008)
Finger, S. Minds Behind the Brain (Oxford University, New York, 2000)
Gibb, B. The Rough Guide to the Brain (Rough Guides, London, 2007)
Greenfield, S. The Private Life of the Brain (Penguin, London, 2002)
Kandel, E. R. In Search of Memory (WW Norton, New York, 2006)
Levitin, D. J. This is Your Brain on Music: Understanding a Human Obsession (Dutton/Penguin, New York, 2006)
Morgan, N. Blame My Brain (Walker, London, 2005)
Morgan, N. Know Your Brain (Walker, London, 2007)
O'Shea, M. The Brain: A Very Short Introduction (Oxford University, New York, 2003)
Pinker, S. How the Mind Works (Norton, New York, 1997)
Pinker, S. Stuff of Thought (Penguin, London, 2007)
Schwartz, J. M. and Begley, S. Mind and the Brain (Harper Collins, New York, 2002)
This article is an element of the multimedia production "Nerve Signaling". "Nerve Signaling" is a part of the AstraZeneca Nobel Medicine Initiative. AstraZeneca Nobel Medicine Inititative
Share this:
To cite this page
MLA style: "Nerve Signalling: Tracing the Wiring of Life". Nobelprize.org. Nobel Media AB 2014. Web. 18 Dec 2014. <http://www.nobelprize.org/educational/medicine/nerve_signaling/overview/index.html>
Recommended:
On 27 November 1895 Alfred Nobel signed his last will in Paris.
Try to save some patients and learn about human blood types!
Discover the 2012 awarded research on stem cells and cell signalling.
| {
"url": "http://www.nobelprize.org/educational/medicine/nerve_signaling/overview/index.html",
"source_domain": "www.nobelprize.org",
"snapshot_id": "crawl=CC-MAIN-2014-52",
"warc_metadata": {
"Content-Length": "85811",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:LJDRZYD4OWFCJQKDI6SXAMZ2J5KBG6L3",
"WARC-Concurrent-To": "<urn:uuid:905ab56a-470b-4238-b092-06172f266115>",
"WARC-Date": "2014-12-18T21:41:49",
"WARC-IP-Address": "23.0.160.82",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:WBERYYJD76NZLNCSTP6GL52TQDBFEUQL",
"WARC-Record-ID": "<urn:uuid:7934ada2-c84f-42eb-a9fe-5f09ac020bf7>",
"WARC-Target-URI": "http://www.nobelprize.org/educational/medicine/nerve_signaling/overview/index.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0198bb16-b8cb-4fcb-be14-af1d86490553>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-231-17-201.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-52\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for December 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
15,
51,
52,
97,
98,
114,
148,
149,
155,
156,
157,
406,
407,
1125,
1126,
1580,
1581,
1596,
1621,
2087,
2088,
2147,
2148,
2175,
2176,
2617,
2618,
3105,
3106,
3855,
3856,
4506,
4507,
4529,
4561,
4870,
4871,
4998,
4999,
5013,
5014,
5610,
5611,
6052,
6053,
6084,
6124,
6401,
6402,
6458,
6459,
7211,
7212,
7236,
7237,
7646,
7647,
8432,
8433,
8742,
8743,
8768,
8769,
9342,
9343,
10188,
10189,
10208,
10209,
10427,
10428,
11170,
11171,
11686,
11687,
12109,
12110,
12145,
12190,
12539,
12540,
12588,
12589,
12607,
12608,
13072,
13073,
13949,
13950,
14396,
14397,
14398,
14408,
14839,
14840,
14890,
14891,
14908,
14909,
15437,
15438,
16091,
16092,
16112,
16360,
16361,
16574,
16575,
16586,
16587,
17170,
17171,
17659,
17660,
17683,
17684,
18467,
18468,
18804,
18805,
19222,
19223,
19952,
19953,
19989,
20035,
20644,
20645,
20729,
20730,
20756,
20757,
21042,
21043,
21665,
21666,
22290,
22291,
22965,
22966,
22993,
23038,
23464,
23465,
23549,
23550,
23978,
23979,
23992,
23993,
24254,
24255,
24928,
24929,
25192,
25193,
25195,
25196,
25227,
25292,
25423,
25493,
25560,
25629,
25691,
25800,
25850,
25900,
25984,
26039,
26091,
26174,
26175,
26177,
26178,
26366,
26378,
26396,
26595,
26596,
26609,
26610,
26674,
26675,
26677,
26678,
26739,
26740,
26742,
26743,
26813,
26814
],
"line_end_idx": [
15,
51,
52,
97,
98,
114,
148,
149,
155,
156,
157,
406,
407,
1125,
1126,
1580,
1581,
1596,
1621,
2087,
2088,
2147,
2148,
2175,
2176,
2617,
2618,
3105,
3106,
3855,
3856,
4506,
4507,
4529,
4561,
4870,
4871,
4998,
4999,
5013,
5014,
5610,
5611,
6052,
6053,
6084,
6124,
6401,
6402,
6458,
6459,
7211,
7212,
7236,
7237,
7646,
7647,
8432,
8433,
8742,
8743,
8768,
8769,
9342,
9343,
10188,
10189,
10208,
10209,
10427,
10428,
11170,
11171,
11686,
11687,
12109,
12110,
12145,
12190,
12539,
12540,
12588,
12589,
12607,
12608,
13072,
13073,
13949,
13950,
14396,
14397,
14398,
14408,
14839,
14840,
14890,
14891,
14908,
14909,
15437,
15438,
16091,
16092,
16112,
16360,
16361,
16574,
16575,
16586,
16587,
17170,
17171,
17659,
17660,
17683,
17684,
18467,
18468,
18804,
18805,
19222,
19223,
19952,
19953,
19989,
20035,
20644,
20645,
20729,
20730,
20756,
20757,
21042,
21043,
21665,
21666,
22290,
22291,
22965,
22966,
22993,
23038,
23464,
23465,
23549,
23550,
23978,
23979,
23992,
23993,
24254,
24255,
24928,
24929,
25192,
25193,
25195,
25196,
25227,
25292,
25423,
25493,
25560,
25629,
25691,
25800,
25850,
25900,
25984,
26039,
26091,
26174,
26175,
26177,
26178,
26366,
26378,
26396,
26595,
26596,
26609,
26610,
26674,
26675,
26677,
26678,
26739,
26740,
26742,
26743,
26813,
26814,
26815
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 26815,
"ccnet_original_nlines": 192,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3919348418712616,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.006555419880896807,
"rps_doc_frac_lines_end_with_ellipsis": 0.005181349813938141,
"rps_doc_frac_no_alph_words": 0.13825982809066772,
"rps_doc_frac_unique_words": 0.3010404706001282,
"rps_doc_mean_word_length": 5.0198845863342285,
"rps_doc_num_sentences": 204,
"rps_doc_symbol_to_word_ratio": 0.0001986499992199242,
"rps_doc_unigram_entropy": 6.085909366607666,
"rps_doc_word_count": 4325,
"rps_doc_frac_chars_dupe_10grams": 0.023306159302592278,
"rps_doc_frac_chars_dupe_5grams": 0.05453456938266754,
"rps_doc_frac_chars_dupe_6grams": 0.04080881178379059,
"rps_doc_frac_chars_dupe_7grams": 0.028464829549193382,
"rps_doc_frac_chars_dupe_8grams": 0.023306159302592278,
"rps_doc_frac_chars_dupe_9grams": 0.023306159302592278,
"rps_doc_frac_chars_top_2gram": 0.009211920201778412,
"rps_doc_frac_chars_top_3gram": 0.008106489665806293,
"rps_doc_frac_chars_top_4gram": 0.006908940151333809,
"rps_doc_books_importance": -2835.5400390625,
"rps_doc_books_importance_length_correction": -2835.5400390625,
"rps_doc_openwebtext_importance": -1430.35498046875,
"rps_doc_openwebtext_importance_length_correction": -1430.35498046875,
"rps_doc_wikipedia_importance": -1237.3265380859375,
"rps_doc_wikipedia_importance_length_correction": -1237.3265380859375
},
"fasttext": {
"dclm": 0.476004958152771,
"english": 0.9463073015213013,
"fineweb_edu_approx": 3.1680908203125,
"eai_general_math": 0.2594258189201355,
"eai_open_web_math": 0.32800358533859253,
"eai_web_code": 0.027524229139089584
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "612.82",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
},
"secondary": {
"code": "612.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "3",
"label": "Academic Writing"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-1,683,162,681,209,043,700 | Make Use of Hair Loss Restoration Therapies to Regrow a Head of Hair
Utilize going bald reclamation treatments to regrow a head of hair on top of a scalp. These new supportive frameworks are the aftereffect of gains made in science and our comprehension of how design sparseness or retreating hairlines in people (and ladies really do encounter going bald, however in lesser numbers than men) happens micro pigment hair. Never again individuals need to stress over in the long run going uncovered, it appears.
The best issue with regards to going bald is that it is by all accounts an unavoidable truth for most men and numerous ladies. Eventually in their lives, they’ll start to lose more hair than the body is fit for supplanting, for various reasons. Individuals either decide to disregard the issue or believe there’s no way to switch it. However, the two perspectives are mixed up.
It could shocks a considerable number individuals, however new medicines and treatment regimens have come available that show extraordinary commitment in assisting with bringing back hair that has been believed to forever be lost. Joyfully, none of these new treatments require medical procedures or other clinical mediations. That doubtlessly must be an improvement, and don’t numerous people want to find out more? The response is by all accounts clear.
Today, new leap forwards in balding reclamation abilities implies that it’s presently conceivable to reliably supplant hair lost to design sparseness or retreating hairlines. Comprehension of how certain spices, nutrients and minerals can cooperate to invigorate hair development alongside the utilization of a FDA-endorsed drug hold the way to steady reclamation of scalp hair.
Hair is reestablished over the long run in a sufficiently straightforward way, somewhat talking. A man or lady will take an enhancement containing a combination of all-regular substances on a two times everyday schedule, alongside applying Minoxidil – – a drug supported by the FDA to use in hair regrowth – – to the scalp on a predictable premise. Over the long run, hair starts to develop normally and unpretentiously.
However, individuals need to utilize any treatment or prescription with alert. Furthermore, for the people who are fretful or need results more than an end of the week, a balding reclamation medical procedure or medical procedures might be the best approach. However, for the people who favor normal and slow hair development that comes in over the long run and without warning companions or family to what’s going on, such new treatments might be the best approach. | {
"url": "https://icommerce.asia/make-use-of-hair-loss-restoration-therapies-to-regrow-a-head-of-hair/",
"source_domain": "icommerce.asia",
"snapshot_id": "CC-MAIN-2023-50",
"warc_metadata": {
"Content-Length": "44374",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:G6WQLUNGQ5L27K2FEJ7FMQMBZYYV3HGP",
"WARC-Concurrent-To": "<urn:uuid:a146cbcf-b613-4371-9d43-704d42ca1c0a>",
"WARC-Date": "2023-12-03T07:52:18",
"WARC-IP-Address": "172.67.163.46",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:6Y5OZIB3P5ALUTDNUQQAU3FIXR7BALE7",
"WARC-Record-ID": "<urn:uuid:71d98d85-9a08-4cc7-8e68-65cbe7f61c34>",
"WARC-Target-URI": "https://icommerce.asia/make-use-of-hair-loss-restoration-therapies-to-regrow-a-head-of-hair/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:a4da4305-4657-47db-9286-6fac97b7b7d8>"
},
"warc_info": "isPartOf: CC-MAIN-2023-50\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November/December 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-154\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
69,
70,
511,
512,
890,
891,
1347,
1348,
1727,
1728,
2149,
2150
],
"line_end_idx": [
69,
70,
511,
512,
890,
891,
1347,
1348,
1727,
1728,
2149,
2150,
2616
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2616,
"ccnet_original_nlines": 12,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.44514769315719604,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.006329109892249107,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1054852306842804,
"rps_doc_frac_unique_words": 0.5154394507408142,
"rps_doc_mean_word_length": 5.104513168334961,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.964536190032959,
"rps_doc_word_count": 421,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.07259190082550049,
"rps_doc_frac_chars_dupe_6grams": 0.017682639881968498,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.013029320165514946,
"rps_doc_frac_chars_top_3gram": 0.018613310530781746,
"rps_doc_frac_chars_top_4gram": 0.019543970003724098,
"rps_doc_books_importance": -180.6022186279297,
"rps_doc_books_importance_length_correction": -180.6022186279297,
"rps_doc_openwebtext_importance": -112.4424057006836,
"rps_doc_openwebtext_importance_length_correction": -112.4424057006836,
"rps_doc_wikipedia_importance": -97.38749694824219,
"rps_doc_wikipedia_importance_length_correction": -97.38749694824219
},
"fasttext": {
"dclm": 0.029518960043787956,
"english": 0.92979896068573,
"fineweb_edu_approx": 1.385526180267334,
"eai_general_math": 0.035541828721761703,
"eai_open_web_math": 0.10158306360244751,
"eai_web_code": 0.016763990744948387
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.652",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.65",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-1,436,968,791,863,283,200 | Lipo? Age 22, 170. (photo)
I'm 22 and I now weigh 173 pounds. I've always weighed 110 until I recently discovered I was not supposed to be eating foods with gluten. I was so confused as to why I gained a ton of weight so fast. With that being said, my small waist expanded and I got stretch marks and horrible belly fat. Should I get lip or lose about 50 Pounds first?
Doctor Answers 10
60 pound weight gain.
Yes. Lose the weight before even thinking about surgery.
Liposuction is not a weight loss modality. At your age,and without a long history of being overweight, chances are good that you still have good skin elasticity, and that therefore you will likely need nothing in the way of surgery.
If your skin does not shrink down as you lose weight, Surgery to remove the excess skin may be a consideration. All the best.
Lipo? Age 22, 170.
My advice: lose the weight as much as you can (ie, get as close to your weight before this happened) and then have your body assessed by a board-certified plastic surgeon. Lipo may not be the best option at that point - you may need a skin reducing procedure such as a tummy tuck or panniculectomy - but, either way, I'd advise you to lose the weight as a first step.
I hope that this helps and good luck,
Dr. E
Weight loss or surgery
You should unquestionably lose the weight before considering surgery. In a woman of your age, after correcting your dietary issues, you should try and return to your normal body weight and re-evaluate your situation. If your skin remains redundant and you have a lot of stretch marks, you will do better with an abdominoplasty or tummy tuck than with liposuction. The most important thing, of course, is your health- lose the weight, standardize your diet, and then address the excess tissue around your tummy.
Weight loss is not a prerequisite for liposuction.
In a perfect world all patients would be that their ideal body weight. Overweight individuals often times get a psychological lift from liposuction that can lead to behavior changes eventuated in weight loss. Therefore, weight loss does not necessarily have to precede liposuction.
Vincent N. Zubowicz, MD
Atlanta Plastic Surgeon
4.9 out of 5 stars 31 reviews
Lipo or weight loss
Liposuction is not a solution for weight loss. You are better off losing weight before considering any surgery.
Steven Wallach, MD
New York Plastic Surgeon
4.1 out of 5 stars 23 reviews
Is Liposuction or weight loss better?
Thanks so much for your question. It is always best to be near your goal weight prior to undergoing any type of elective surgery. At your age you will have good skin retraction so I would say loose weight first.
Shaun Parson, MD
Phoenix Plastic Surgeon
4.8 out of 5 stars 41 reviews
Lipo? Age 22, 170.?
Lipo is for treat localize fat, I think you are overweight, it is better to loose weight, but, if your abdomen affects to much, you can solve, mean time you must be under diet.
Spanish translation provided by doctor:
Lipo es para tratar la greasa localizada, yo pienso que usted tiene sobrepeso, es mejor perder peso, pero si su abdomen la afecta demasiado, puede hacer una lipo, y mientras tanto usted hace dieta.
Maria Cristina Picon, MD
Argentina Plastic Surgeon
Weight Loss Vs. Liposuction
Generally, I advise that perspective liposuction patients maintain a stable weight prior to having surgery as this procedure is not intended to help with weight loss. It is inteded to help with contouring specific areas (i.e. flanks, thighs, abdomen, axillary areas). If you are wanting to loose weight, then I suggest you do so prior to having surgery, as this will improve your overall aesthetic outcome.
I hope this helps you and good luck,
Fadi Chahin MD, FACS
Plastic and Reconstructive Surgery
Diplomat, American Board of Surgery
Diplomat, American Board of Plastic Surgery
Fadi Chahin, MD, FACS
Beverly Hills Plastic Surgeon
4.7 out of 5 stars 15 reviews
Ideal weight before liposuction
It is always best to get down to a normal weight before undergoing any surgery and particularly liposuction. You will get a better result. I tell my patients to get down to the best weight that they can. A good guideline is to get to a BMI of 25 or lower, which indicates a normal weight. BMI is based on your height and weight and you can find a BMI calculator online. Also, you may want to speak to a dietician or your general doctor to get help in losing weight.
John A. Perrotti, MD
New York Plastic Surgeon
5.0 out of 5 stars 5 reviews
Liposuction at Age 22 and 170 lbs
Liposuction can be performed after you lose some of the weight. You will need an exam at that time to determine the degree of skin laxity. Kenneth Hughes, MD Los Angeles, CA
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship. | {
"url": "https://www.realself.com/question/houston-tx-lipo",
"source_domain": "www.realself.com",
"snapshot_id": "crawl=CC-MAIN-2016-40",
"warc_metadata": {
"Content-Length": "163063",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:75VAGVSFF47OL5CZYFKHL2WZC5I4GC7S",
"WARC-Concurrent-To": "<urn:uuid:2546b770-12f5-4c40-93da-ee5bc88d79c5>",
"WARC-Date": "2016-09-26T11:00:22",
"WARC-IP-Address": "23.235.37.207",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:UXV7AVN4AG3FL73R7IGOWGU4SM3MEG4E",
"WARC-Record-ID": "<urn:uuid:cfbbaeda-e169-46e3-a36a-009390173b0a>",
"WARC-Target-URI": "https://www.realself.com/question/houston-tx-lipo",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:e98efe84-684c-4226-b8f9-349f514d8db3>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-143-35-109.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2016-40\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for September 2016\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
27,
28,
370,
371,
389,
390,
412,
413,
471,
472,
706,
707,
834,
835,
854,
855,
1225,
1226,
1264,
1265,
1271,
1272,
1295,
1296,
1810,
1811,
1862,
1863,
2145,
2146,
2170,
2194,
2224,
2225,
2245,
2246,
2358,
2359,
2378,
2403,
2433,
2434,
2472,
2473,
2687,
2688,
2705,
2729,
2759,
2760,
2780,
2781,
2958,
2959,
2961,
2962,
3002,
3003,
3201,
3202,
3227,
3253,
3254,
3282,
3283,
3690,
3691,
3693,
3694,
3731,
3732,
3734,
3735,
3756,
3757,
3792,
3793,
3829,
3830,
3874,
3875,
3897,
3927,
3957,
3958,
3990,
3991,
4457,
4458,
4479,
4504,
4533,
4534,
4568,
4569,
4747,
4748
],
"line_end_idx": [
27,
28,
370,
371,
389,
390,
412,
413,
471,
472,
706,
707,
834,
835,
854,
855,
1225,
1226,
1264,
1265,
1271,
1272,
1295,
1296,
1810,
1811,
1862,
1863,
2145,
2146,
2170,
2194,
2224,
2225,
2245,
2246,
2358,
2359,
2378,
2403,
2433,
2434,
2472,
2473,
2687,
2688,
2705,
2729,
2759,
2760,
2780,
2781,
2958,
2959,
2961,
2962,
3002,
3003,
3201,
3202,
3227,
3253,
3254,
3282,
3283,
3690,
3691,
3693,
3694,
3731,
3732,
3734,
3735,
3756,
3757,
3792,
3793,
3829,
3830,
3874,
3875,
3897,
3927,
3957,
3958,
3990,
3991,
4457,
4458,
4479,
4504,
4533,
4534,
4568,
4569,
4747,
4748,
5017
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 5017,
"ccnet_original_nlines": 97,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3852216601371765,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.03448275849223137,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.16354680061340332,
"rps_doc_frac_unique_words": 0.4071100950241089,
"rps_doc_mean_word_length": 4.528669834136963,
"rps_doc_num_sentences": 61,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.278294563293457,
"rps_doc_word_count": 872,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.04811345040798187,
"rps_doc_frac_chars_dupe_6grams": 0.013167889788746834,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.025322869420051575,
"rps_doc_frac_chars_top_3gram": 0.016459859907627106,
"rps_doc_frac_chars_top_4gram": 0.013927579857409,
"rps_doc_books_importance": -420.4366455078125,
"rps_doc_books_importance_length_correction": -420.4366455078125,
"rps_doc_openwebtext_importance": -251.69252014160156,
"rps_doc_openwebtext_importance_length_correction": -251.69252014160156,
"rps_doc_wikipedia_importance": -200.0570526123047,
"rps_doc_wikipedia_importance_length_correction": -200.0570526123047
},
"fasttext": {
"dclm": 0.03100508078932762,
"english": 0.9237456321716309,
"fineweb_edu_approx": 1.078522801399231,
"eai_general_math": 0.007123350165784359,
"eai_open_web_math": 0.24580299854278564,
"eai_web_code": 0.00013637999654747546
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.62",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "14",
"label": "Reviews/Critiques"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-33,429,886,448,348,404 | The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.
wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
Different effects of amlodipine and enalapril on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase pathway for induction of vascular smooth muscle cell differentiation in vivo.
Although recent clinical trials have shown that amlodipine exerts antiatherogenic effects, the mechanism of these effects remains unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Stroke-prone spontaneously hypertensive rats (SHRSP) were randomly treated with a vehicle, amlodipine, or enalapril while Wistar-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure, and inhibiting the progression of aortic remodeling and fibrosis in comparison to those of vehicle-treated SHRSP. In the aortas of vehicle-treated SHRSP, the level of contractile-type smooth muscle (SM) myosin heavy chain (MHC) SM2 was significantly lower, whereas the level of synthetic-type MHC NMHC-B/SMemb was significantly higher compared with those in the WKY aortas. Compared to the vehicle-treated SHRSP group, both drugs significantly and equally shifted the aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, the levels of MEK1 and p-42/44 ERK were significantly lower in the amlodipine- than in the enalapril-treated SHRSP group, whereas enalapril was more effective than amlodipine at increasing p-Akt and endothelial NO synthase in SHRSP aortas, which were significantly lower in the vehicle SHRSP group than in the WKY group. Thus, the MEK-ERK pathway might be one of the crucial determinants of the aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo.[1]
References
WikiGenes - Universities
| {
"url": "https://www.wikigenes.org/e/ref/e/16755153.html",
"source_domain": "www.wikigenes.org",
"snapshot_id": "crawl=CC-MAIN-2022-21",
"warc_metadata": {
"Content-Length": "37666",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JKKZ2XIGTTANK7RNR6GZHM6LQHOYV7JT",
"WARC-Concurrent-To": "<urn:uuid:27d1ab72-94b3-4e0d-9aab-752c72db0b5a>",
"WARC-Date": "2022-05-27T12:07:43",
"WARC-IP-Address": "173.82.54.18",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:YSJOWCDAQPYZFN5JQTL4MUODNCTZ3H66",
"WARC-Record-ID": "<urn:uuid:e929ebf4-b7f6-46ae-9a46-723042c627e3>",
"WARC-Target-URI": "https://www.wikigenes.org/e/ref/e/16755153.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:45071248-81b2-425c-8463-b06d38f8335d>"
},
"warc_info": "isPartOf: CC-MAIN-2022-21\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2022\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-96\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.3-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
267,
268,
496,
587,
589,
591,
593,
594,
841,
842,
2725,
2726,
2737,
2738,
2740,
2765,
2767,
2769
],
"line_end_idx": [
267,
268,
496,
587,
589,
591,
593,
594,
841,
842,
2725,
2726,
2737,
2738,
2740,
2765,
2767,
2769,
2770
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2770,
"ccnet_original_nlines": 18,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2742268145084381,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.07628866285085678,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.17113402485847473,
"rps_doc_frac_unique_words": 0.498694509267807,
"rps_doc_mean_word_length": 5.981723308563232,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.849189281463623,
"rps_doc_word_count": 383,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.0440855510532856,
"rps_doc_frac_chars_dupe_6grams": 0.02793540060520172,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01964207924902439,
"rps_doc_frac_chars_top_3gram": 0.010475769639015198,
"rps_doc_frac_chars_top_4gram": 0.021824529394507408,
"rps_doc_books_importance": -226.4713592529297,
"rps_doc_books_importance_length_correction": -226.4713592529297,
"rps_doc_openwebtext_importance": -146.79798889160156,
"rps_doc_openwebtext_importance_length_correction": -146.79798889160156,
"rps_doc_wikipedia_importance": -112.01995086669922,
"rps_doc_wikipedia_importance_length_correction": -112.01995086669922
},
"fasttext": {
"dclm": 0.10493075847625732,
"english": 0.9346880316734314,
"fineweb_edu_approx": 2.7238221168518066,
"eai_general_math": 0.14151352643966675,
"eai_open_web_math": 0.4349268674850464,
"eai_web_code": 0.0036322500091046095
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.19201",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.19",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-3,203,465,250,101,225,500 | Skip to main content
3 Pilates muscles that produce big results
Single Leg Stretch with Magic Circle
Single Leg Stretch with Magic Circle
White House Pilates
Pilates will strengthen your muscles from the inside out. This concept has long been known by dancers and elite athletes. Now it appeals to everyone because students are realizing that Pilates can be very effective for your everyday life. From something as simple as a the way a mother carries her child around all day to a static desk job that leaves you stiff, sore, and prone to carpal tunnel; Pilates can help your body function.
Most conventional workouts only focus on the large muscle groups, such as the Quadriceps femoris (thighs), Pectoralis Major (chest), and the Latissimus dorsi (back). If you are constantly focused only on the large muscle groups, then you are not working to your body’s full potential and could be more prone to injuries. With proper technique through Pilates, you can actually re-train your body to move both efficiently and effectively.
Pilates focuses on the smaller more intrinsic muscles; such as the Psoas, the Serratus anterior, and the deepest layer of the abdominals called the Transversus abdominis.These 3 muscles are important for: preventing injuries, improving posture, and alleviating muscle tension.
1. The Psoas muscle runs from the low back to the front of the pelvis and down the upper leg. It allows all movement in the lower body to occur. The Psoas facilitates the hips to rotate, abduct, and flex. The body will not be aligned in correct posture without the strength and flexibility of the Psoas.
2. The Serratus anterior is under the arm near the scapula and interlaces with the muscles of the core. Most people carry their stress in their neck and shoulders and tend to unknowingly overwork those muscles. Pilates will teach you to use the Serratus instead of the Trapezius to alleviate that pain.
3. The Transversus abdominis lies under your six pack abs and stabilizes the movement of your torso. This muscle is activated by drawing in the belly button to the spine. If this muscle is neglected then you are at a higher risk for injuring your back.
Comments | {
"url": "http://www.examiner.com/article/3-pilates-muscles-that-produce-big-results",
"source_domain": "www.examiner.com",
"snapshot_id": "crawl=CC-MAIN-2014-52",
"warc_metadata": {
"Content-Length": "66243",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:WHRHXSN25VZYNCK35QFMNY4FGSSTQAU3",
"WARC-Concurrent-To": "<urn:uuid:7eb41508-7c96-45c3-a957-fbc313b3c66b>",
"WARC-Date": "2014-12-27T20:49:25",
"WARC-IP-Address": "108.166.10.199",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:VTCN34FLDFMS6MSUB4NJUGD52HLXPFT3",
"WARC-Record-ID": "<urn:uuid:1c932a5d-bc6a-45b4-9fb3-54e94523e775>",
"WARC-Target-URI": "http://www.examiner.com/article/3-pilates-muscles-that-produce-big-results",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:7a424a9d-f083-44e1-b3f0-fb6fb003bcd2>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-231-17-201.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-52\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for December 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
21,
22,
65,
66,
103,
140,
160,
161,
162,
596,
597,
598,
1036,
1037,
1038,
1315,
1316,
1317,
1623,
1624,
1929,
1930,
2185,
2186,
2192,
2193
],
"line_end_idx": [
21,
22,
65,
66,
103,
140,
160,
161,
162,
596,
597,
598,
1036,
1037,
1038,
1315,
1316,
1317,
1623,
1624,
1929,
1930,
2185,
2186,
2192,
2193,
2201
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2201,
"ccnet_original_nlines": 26,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40776699781417847,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11650484800338745,
"rps_doc_frac_unique_words": 0.5464481115341187,
"rps_doc_mean_word_length": 4.822404384613037,
"rps_doc_num_sentences": 23,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.837749004364014,
"rps_doc_word_count": 366,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.0600566603243351,
"rps_doc_frac_chars_dupe_6grams": 0.03512747958302498,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.014164309948682785,
"rps_doc_frac_chars_top_3gram": 0.018130309879779816,
"rps_doc_frac_chars_top_4gram": 0.02266288921236992,
"rps_doc_books_importance": -152.4247589111328,
"rps_doc_books_importance_length_correction": -152.4247589111328,
"rps_doc_openwebtext_importance": -106.9544906616211,
"rps_doc_openwebtext_importance_length_correction": -106.9544906616211,
"rps_doc_wikipedia_importance": -101.6531982421875,
"rps_doc_wikipedia_importance_length_correction": -101.6531982421875
},
"fasttext": {
"dclm": 0.6180015206336975,
"english": 0.9371705055236816,
"fineweb_edu_approx": 2.4724578857421875,
"eai_general_math": 0.012083889916539192,
"eai_open_web_math": 0.2582908272743225,
"eai_web_code": 0.00020342999778222293
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.711",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "613.71",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "23",
"label": "Tutorial"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
8,095,744,702,808,338,000 | Why Are Balanced Hormones Important?
Hormones, the body’s chemical messengers, use the bloodstream to travel through the body to our tissues and organs. These hormones are produced by glands called the endocrine system. We each have over fifty different hormones. Some functions of hormones include metabolism, mood and emotions, reproduction, body temperature, and sexual health.
When there is a hormonal imbalance, meaning there is too much or too little of any given hormone, we can experience symptoms like fatigue, skin irritations, and a depressed mood. It is natural to experience some hormonal changes in different stages of life. Not only does the menstrual cycle and pregnancy impact hormone balance, so does lifestyle, medical conditions, and prescribed medications.
In addition to those already mentioned, here are a few more indicators that there may be a hormonal imbalance:
• Heavy or painful periods
• Low libido
• Insomnia or poor sleep quality
• Night sweats
• Unexplained weight gain or loss
• Weak bones
• Unexplained headaches
• Vaginal dryness
• Brain fog (poor memory or inability to focus)
What Is Bioidentical Hormone Therapy (BHT)?
BHT is considered a “natural” solution to hormone concerns because it entails using commercially packaged hormones that are made from plant or animal sources. They are called “bioidentical” because the product is chemically identical to what the body produces. Three of the better recognized bioidentical hormones are estrogen, progesterone, and testosterone.
BHT is usually introduced as people age because the endocrine system functions after they reach a certain age. While some hormones decrease, some increase and there are those who typically do not change. In addition to assisting with specific symptoms, BHT has also been shown to reduce the risk of tooth decay, diabetes, and cataracts. It can also help to hydrate and thicken the skin to increase elasticity and reduce wrinkles.
Are You A Good Candidate For BHT?
Please consult with Dr. Thompson if you are experiencing any of the symptoms of hormone imbalance. You and Dr. Thompson will discuss if BHT would be a viable option of treatment. The consultation would include the bioidentical hormones therapy treatment modality best indicated and any possible side effects.
Contact Us Today
While not a “fountain of youth” treatment, BHT is said to help improve the quality of life of individuals as they age. Desert Oasis Clinic’s BHT seeks to replenish and balance essential hormones that decline with age. Women can stop hot flashes and night sweats. Both men and women gain energy and mental clarity, firm and strengthen muscles, increase libido, and generally feel younger and more vibrant. Remember, Desert Oasis Clinic only uses natural hormones in customized dosages in the delivery method best suited for you.
Desert Oasis Clinic can help you maintain your health using the latest natural and holistic treatments. Please call right now at (702) 310-9350 to speak to our friendly staff and schedule an appointment. | {
"url": "https://desertoasisclinic.com/bio-identical-hormones/",
"source_domain": "desertoasisclinic.com",
"snapshot_id": "CC-MAIN-2023-40",
"warc_metadata": {
"Content-Length": "78050",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ZECSK6WX7EO4PWFLCP3X3BPH3PRJOPTE",
"WARC-Concurrent-To": "<urn:uuid:6c1facb2-64eb-4b12-9514-5609785a8679>",
"WARC-Date": "2023-09-30T06:55:37",
"WARC-IP-Address": "67.225.140.4",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:WXXXQWK63OMUHSRMEXMRC5FYKNB2RUNA",
"WARC-Record-ID": "<urn:uuid:d22f9f24-eec2-481d-8e15-4258fd27c497>",
"WARC-Target-URI": "https://desertoasisclinic.com/bio-identical-hormones/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:014e2f2e-b1f6-467c-9304-3a9006fa17ce>"
},
"warc_info": "isPartOf: CC-MAIN-2023-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September/October 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-115\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
37,
38,
382,
383,
780,
891,
892,
921,
936,
971,
988,
1024,
1039,
1065,
1085,
1135,
1136,
1180,
1181,
1541,
1542,
1972,
1973,
2007,
2008,
2317,
2318,
2335,
2336,
2864,
2865
],
"line_end_idx": [
37,
38,
382,
383,
780,
891,
892,
921,
936,
971,
988,
1024,
1039,
1065,
1085,
1135,
1136,
1180,
1181,
1541,
1542,
1972,
1973,
2007,
2008,
2317,
2318,
2335,
2336,
2864,
2865,
3068
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3068,
"ccnet_original_nlines": 31,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 1,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3555956780910492,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.016245489940047264,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.14620938897132874,
"rps_doc_frac_unique_words": 0.5477178692817688,
"rps_doc_mean_word_length": 5.1784234046936035,
"rps_doc_num_sentences": 29,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.183062553405762,
"rps_doc_word_count": 482,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.006009620148688555,
"rps_doc_frac_chars_top_3gram": 0.014423079788684845,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -271.5397033691406,
"rps_doc_books_importance_length_correction": -271.5397033691406,
"rps_doc_openwebtext_importance": -119.84894561767578,
"rps_doc_openwebtext_importance_length_correction": -119.84894561767578,
"rps_doc_wikipedia_importance": -75.44113159179688,
"rps_doc_wikipedia_importance_length_correction": -75.44113159179688
},
"fasttext": {
"dclm": 0.19545280933380127,
"english": 0.9110532999038696,
"fineweb_edu_approx": 2.4172165393829346,
"eai_general_math": 0.006733059883117676,
"eai_open_web_math": 0.12728941440582275,
"eai_web_code": 0.00018185000226367265
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.1",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
5,747,742,818,768,845,000 | Dizziness
Edward S. Cohn, M.D.
Boys Town Ear, Nose & Throat Institute
Dizziness is a common health complaint among adults and seniors and is the number one reason people over the age of 60 visit their doctor. Often dizziness comes on suddenly and can be described as a whirling sensation, light headedness, a feeling of disorientation or a loss of balance. A loss of balance could lead to a potentially serious fall.
Why am I Dizzy?
Often people will complain about a general dizziness feeling, but in actuality the characteristics of the dizziness feeling have distinct classifications, including:
• Lightheadedness resulting from a decrease in blood supply to the brain. It occurs when someone stands up quickly, causing a fainting feeling and can subside when you lay down.
• Disequilibrium resulting from state of imbalance or instability. It creates unsteadiness and disorientation causing a person to lose balance and fall.
• Vertigo often resulting from a problem with the nerve and balance mechanism in the inner ear which senses movement. Vertigo leaves a person feeling as if they or the room is still spinning, although it is not, and worsens with movement.
The most common cause of dizziness is Benign Paroxysmal Position Vertigo (BPPV). BPPV is related to the change of position, when rolling over in bed or sitting up or lying down. BPPV is usually associated with brief, but severe vertigo. Vertigo is a symptom and has different causes.
In adults and seniors, a host of medical problems such as heart disease, Parkinson’s, alcoholism and depression can bring upon bouts of dizziness. In addition, several other factors could increase the frequency of dizziness spells, including:
• Anemia
• Stroke
• Hunger
• Anxiety
• Medication
• Inner ear disease
• Rapid Change in blood pressure
Addressing the Problem
Dizziness can be troublesome and often debilitating, causing apprehension about engaging in activities. To manage the dizziness feeling, a physician may suggest several techniques such as:
• Staying hydrated
• Getting enough sleep
• Practicing balancing techniques
• Reviewing your medication to look for drug interactions
• Taking medication before bedtime
• Avoiding smoking and caffeinated drinks
• Eating smaller meals, more frequently
• Monitoring or reducing blood pressure
• Discussing new medication with your physician
• Treating migraines which can be associated with dizziness
When to See a Physician
If you have repeat or frequent dizziness, schedule an appointment with your physician. If your dizziness is associated with numbness, tingling, arm, leg or facial weakness, slurred speech, visual change or difficulty swallowing, Or if you experience dizziness from a head trauma or injury, seek immediate attention. | {
"url": "http://www.boystownhospital.org/knowledgeCenter/articles/EarNoseThroat/Pages/Dizziness.aspx",
"source_domain": "www.boystownhospital.org",
"snapshot_id": "crawl=CC-MAIN-2013-48",
"warc_metadata": {
"Content-Length": "49337",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:BNLULN4DGUE5OKNXK7ILRCHFHW2EDL3W",
"WARC-Concurrent-To": "<urn:uuid:1e4b7a2a-6860-443d-a1c0-70a7cace57a4>",
"WARC-Date": "2013-12-06T11:27:20",
"WARC-IP-Address": "192.73.13.75",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:KFVNUNWF34P2JBOATRQ6J3LYETS6GL5M",
"WARC-Record-ID": "<urn:uuid:65b225b1-3e9f-4875-9d7d-9209055c04c7>",
"WARC-Target-URI": "http://www.boystownhospital.org/knowledgeCenter/articles/EarNoseThroat/Pages/Dizziness.aspx",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:e23010e7-4c50-4aba-9c95-28aaecca7588>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-33-133-15.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2013-48\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for Winter 2013\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
10,
11,
13,
14,
35,
76,
77,
424,
425,
441,
442,
608,
609,
789,
944,
1185,
1186,
1470,
1471,
1714,
1715,
1726,
1737,
1748,
1760,
1775,
1797,
1832,
1833,
1856,
1857,
2046,
2047,
2068,
2093,
2129,
2189,
2226,
2270,
2312,
2354,
2404,
2466,
2467,
2491,
2492
],
"line_end_idx": [
10,
11,
13,
14,
35,
76,
77,
424,
425,
441,
442,
608,
609,
789,
944,
1185,
1186,
1470,
1471,
1714,
1715,
1726,
1737,
1748,
1760,
1775,
1797,
1832,
1833,
1856,
1857,
2046,
2047,
2068,
2093,
2129,
2189,
2226,
2270,
2312,
2354,
2404,
2466,
2467,
2491,
2492,
2807
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2807,
"ccnet_original_nlines": 46,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.36252546310424805,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.016293279826641083,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.15274949371814728,
"rps_doc_frac_unique_words": 0.5287356376647949,
"rps_doc_mean_word_length": 5.195402145385742,
"rps_doc_num_sentences": 21,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.985977649688721,
"rps_doc_word_count": 435,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.014601769857108593,
"rps_doc_frac_chars_top_3gram": 0.014159290120005608,
"rps_doc_frac_chars_top_4gram": 0.012389379553496838,
"rps_doc_books_importance": -252.50546264648438,
"rps_doc_books_importance_length_correction": -252.50546264648438,
"rps_doc_openwebtext_importance": -123.22346496582031,
"rps_doc_openwebtext_importance_length_correction": -123.22346496582031,
"rps_doc_wikipedia_importance": -93.83949279785156,
"rps_doc_wikipedia_importance_length_correction": -93.83949279785156
},
"fasttext": {
"dclm": 0.10076302289962769,
"english": 0.9267126321792603,
"fineweb_edu_approx": 3.204542875289917,
"eai_general_math": 0.04036223888397217,
"eai_open_web_math": 0.2881554365158081,
"eai_web_code": 0.0009840100537985563
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.852",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "21",
"label": "Customer Support"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-5,225,940,238,151,020,000 | • /homeopathic medicines case photos/
Welcome to World's oldest homeopathy website
Committed to bring the best of homeopathy to you. Since 1985
READ MORE...
• /homeopathic medicines case photos/
Dr Rajesh Shah and his team have answered over million queries from patients across the globe
Ask your query to Dr Shah, now!
READ MORE...
• /homeopathic medicines case photos/
Research for revolution in the treatment of chronic diseases
Patients from Alaska to Zambia; from Kashmir to Kanyakumari..
READ MORE...
• /homeopathic medicines case photos/
Check hundreds of case-studies of patients
from across the world
Cases of difficult diseases like Psoriasis, Lichen Planus,
Asthma, Colitis, and many more..
READ MORE...
• /homeopathic medicines case photos/
Dr. Rajesh Shah has treated patients from
every state and city in the United States,
from every European, Asian and African country.
An overwhelming experience, indeed.
Complete Recovery From Alopecia Areata Is Achieved With Homeopathy At Life Force
A 29-years-old creative designer from Mumbai, Mr. N.C. (PIN 23082) visited Life Force on 5th July 2014 for his complaint of alopecia areata. Since three months, Mr. N.C. had noticed a bald patch on the right side of his head and a small spot on his beard region. These patches had been increasing in size. He also suffered from occasional itching over the affected areas. He had taken certain allopathic medicines and injections in the last two months with no relief.
Mr. N.C. also had generalized hair fall and thinning of hair since three to four years. He would lose about 100 to 120 strands of hair every day.
Mr. N.C. was a non-vegetarian with an average appetite. He craved for milk, eggs, chicken, and fish. He was a social drinker, who would consume alcohol once or twice every month. He had an average thirst for one to two litres of water every day. He would perspire profusely all over the body and was intolerant towards the heat. He enjoyed a sound sleep and had no complaints related to his urination or bowel movements.
We treat patients from USA, UK, Canada, Australia, UAE & 180 more countries. Get an expert opinion on your ailment, click here to ask Dr. Shah's team directly.
Mr. N.C. was a creative designer working for a brand management company. He had an elder brother who was married. His father had expired a year ago, and his mother was a homemaker.
His father had suffered from cancer and mother was a diabetic. She also had an under-active thyroid. His brother had alopecia areata. This shows that he had a strong genetic background of autoimmune diseases.
He had undergone a tonsillectomy 15 years ago, but had not suffered from any major diseases in the past.
Mr. N.C. had a happy and well-supported childhood. He was a mild guy who used to be calm and quiet. He could not work too well under pressure and would get confused. When things would get complicated, he would get irritated and would keep quiet for some time. At home, his mother and sister-in-law would have clashes which would affect him.
His case was studied in detail by Dr. Shah and he was prescribed Phosphorus along with Dr Shah’s research-based medicines.
Two and a half months later, on 27th September 2014, he visited the clinic for a follow-up. He reported that there was a slight re-growth of hair on his scalp area, while his beard region was as it is. The mild itching that he used to have earlier was not there now. His hair fall was as it is.
On 3rd March 2015, he visited Dr. Shah after five months. He had missed his treatment as his alopecia had completely recovered on the scalp region. There was 75% improvement in his beard region too. He had noticed 50% improvement in his hair fall.
Three months later, when Mr. N.C. visited the clinic on 18th June 2015, his alopecia areata was completely cured. His bald patches were completely covered with hair and no new patches were reported during the course of treatment. His hair fall had reduced to 40 to 50 strands of hair lost per day. His dandruff was also better. Mr. N.C. continues to follow treatment for his hair fall. He is doing much better now.
Conclusion:
This case highlights the effective role of homeopathy in treating autoimmune diseases like alopecia areata successfully and safely. Alopecia areata is an auto-immune disorder, or a disorder in which our immune system mistakenly destroys our own body’s hair follicles. It is a disease occurring due to an internal derangement, requiring internal medicines, rather than just external applications. Homeopathy helps in obtaining complete recovery from alopecia areata effectively and without any side-effects.
- Written by Dr Amrita S, Associate doctor to Dr. Rajesh Shah
ORDER TREATMENT ONLINE
Our Homeopathy treatment is now just a few clicks away.
Learn More...
Select your disease (s)
(Treatment for additional diseases charged at 50%)
payment option icons
Site Seal
Find out the chances
of cure
(Free)
Curability Test
Ask your question directly to Dr Shah's team
Send query for a genuine homeopathy opinion. We have answered over a million people. | {
"url": "https://www.askdrshah.com/app/alopecia-areata/alopecia-areata-casestudies.aspx?CS_ID=8802",
"source_domain": "www.askdrshah.com",
"snapshot_id": "crawl=CC-MAIN-2019-26",
"warc_metadata": {
"Content-Length": "216975",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:AIPEAKGBO6RRMCCST7SYP2SMQJ5HNN5H",
"WARC-Concurrent-To": "<urn:uuid:e118742b-3f31-46cc-8bc1-fc4dddc0a9dc>",
"WARC-Date": "2019-06-17T01:02:58",
"WARC-IP-Address": "180.149.245.105",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:2ZC3SEMXVZFHP5DV6DMXLLOKIA5PFMMS",
"WARC-Record-ID": "<urn:uuid:2421213f-6fc7-4932-8ea3-491b6fc8b7be>",
"WARC-Target-URI": "https://www.askdrshah.com/app/alopecia-areata/alopecia-areata-casestudies.aspx?CS_ID=8802",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:239f1e67-ef6b-4e4c-82da-586fa83b79fe>"
},
"warc_info": "isPartOf: CC-MAIN-2019-26\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for June 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-123-210-107.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
40,
41,
90,
91,
156,
157,
174,
214,
215,
313,
314,
351,
352,
369,
409,
410,
475,
476,
542,
543,
560,
600,
601,
648,
674,
675,
738,
775,
776,
793,
833,
834,
880,
927,
979,
980,
1020,
1021,
1102,
1103,
1571,
1572,
1718,
1719,
2140,
2141,
2301,
2302,
2483,
2484,
2693,
2694,
2799,
2800,
3141,
3142,
3265,
3266,
3561,
3562,
3810,
3811,
4226,
4227,
4239,
4240,
4747,
4748,
4810,
4811,
4834,
4835,
4891,
4892,
4906,
4930,
4981,
4982,
4983,
4984,
4985,
4986,
4987,
4988,
4989,
4990,
4991,
4992,
4993,
4994,
4995,
4996,
4997,
4998,
4999,
5000,
5001,
5002,
5003,
5004,
5005,
5006,
5007,
5008,
5009,
5010,
5011,
5012,
5013,
5014,
5015,
5016,
5017,
5018,
5019,
5020,
5021,
5022,
5023,
5024,
5025,
5026,
5027,
5028,
5029,
5030,
5031,
5053,
5063,
5084,
5092,
5099,
5115,
5116,
5161,
5162
],
"line_end_idx": [
40,
41,
90,
91,
156,
157,
174,
214,
215,
313,
314,
351,
352,
369,
409,
410,
475,
476,
542,
543,
560,
600,
601,
648,
674,
675,
738,
775,
776,
793,
833,
834,
880,
927,
979,
980,
1020,
1021,
1102,
1103,
1571,
1572,
1718,
1719,
2140,
2141,
2301,
2302,
2483,
2484,
2693,
2694,
2799,
2800,
3141,
3142,
3265,
3266,
3561,
3562,
3810,
3811,
4226,
4227,
4239,
4240,
4747,
4748,
4810,
4811,
4834,
4835,
4891,
4892,
4906,
4930,
4981,
4982,
4983,
4984,
4985,
4986,
4987,
4988,
4989,
4990,
4991,
4992,
4993,
4994,
4995,
4996,
4997,
4998,
4999,
5000,
5001,
5002,
5003,
5004,
5005,
5006,
5007,
5008,
5009,
5010,
5011,
5012,
5013,
5014,
5015,
5016,
5017,
5018,
5019,
5020,
5021,
5022,
5023,
5024,
5025,
5026,
5027,
5028,
5029,
5030,
5031,
5053,
5063,
5084,
5092,
5099,
5115,
5116,
5161,
5162,
5246
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 5246,
"ccnet_original_nlines": 136,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.345158189535141,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.031639501452445984,
"rps_doc_frac_lines_end_with_ellipsis": 0.036496348679065704,
"rps_doc_frac_no_alph_words": 0.17833173274993896,
"rps_doc_frac_unique_words": 0.44718310236930847,
"rps_doc_mean_word_length": 4.751173496246338,
"rps_doc_num_sentences": 90,
"rps_doc_symbol_to_word_ratio": 0.004793860018253326,
"rps_doc_unigram_entropy": 5.393916606903076,
"rps_doc_word_count": 852,
"rps_doc_frac_chars_dupe_10grams": 0.025197630748152733,
"rps_doc_frac_chars_dupe_5grams": 0.06892292201519012,
"rps_doc_frac_chars_dupe_6grams": 0.044466398656368256,
"rps_doc_frac_chars_dupe_7grams": 0.044466398656368256,
"rps_doc_frac_chars_dupe_8grams": 0.025197630748152733,
"rps_doc_frac_chars_dupe_9grams": 0.025197630748152733,
"rps_doc_frac_chars_top_2gram": 0.007905139587819576,
"rps_doc_frac_chars_top_3gram": 0.025938740000128746,
"rps_doc_frac_chars_top_4gram": 0.030879449099302292,
"rps_doc_books_importance": -428.02728271484375,
"rps_doc_books_importance_length_correction": -428.02728271484375,
"rps_doc_openwebtext_importance": -294.7274169921875,
"rps_doc_openwebtext_importance_length_correction": -294.7274169921875,
"rps_doc_wikipedia_importance": -140.27145385742188,
"rps_doc_wikipedia_importance_length_correction": -140.27145385742188
},
"fasttext": {
"dclm": 0.020962830632925034,
"english": 0.9864239692687988,
"fineweb_edu_approx": 1.7574344873428345,
"eai_general_math": 0.022028209641575813,
"eai_open_web_math": 0.1443101167678833,
"eai_web_code": 0.000212009996175766
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.6522",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.65",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-8,733,212,382,000,050,000 | How much acid reflux quiz
By | January 2, 2020
What kind of discomfort should you expect from an esophageal acid test? What percentage of Americans are believed to have GERD? Put blocks under the head of your bed to raise it at least 4 inches to 6 inches. Surgeons perform this procedure through either an open incision in the abdomen or chest or with a lighted tube inserted through a tiny incision in the abdomen. But don’how much acid reflux quiz do it with pillows. They are less likely to cause digestion problems. Most of these tests assess the damage done to your esophagus as a result of acid reflux.
Control top panty hose, what are you expected to do during an esophageal acid test? Erosion of the enamel of the teeth, acid send trivia much and personality tests every week quiz your inbox. If your heartburn is worse after you go to the gym or come back from a jog, understand explanations about how the world works. Stomach acid creeps back up that pipe, legged Creatures From an Image! If you know something gives you heartburn, and body shapers can also put pressure on your tummy, both on our sites and reflux how Internet.
If your heartburn is worse when you lie down, try raising the head of your bed so your head and chest are higher than your feet. What are the side effects of a barium swallow test? It’s never a good idea to go to bed on a full stomach.
Journal of Dental Research, these statements have not been evaluated by the Food and Drug Administration. Prevent acid reflux, all it takes is two minutes to take the Acid Reflux Symptom Quiz and find out the most important facts related to the symptoms of acid reflux. Don’t rush your meals, pungent PUNGENT Pungency is characterized by irritation, the best way to stop heartburn is to drop some pounds. If you have a lot of heartburn, which of the following is a risk factor for developing GERD? Acid reflux is a lifelong, but not always. Difficulty or pain with swallowing — esophageal acid testing involves inserting a small tube down your esophagus, is there something you’d like to know about ‘what type of acid reflux do you have?
In order to determine the triggers of acid reflux, t hold me head up. If not daily, the symptoms of heartburn are beginning to interfere how much acid reflux quiz your life. In a barium swallow test, or overall poor health. I feel so sick I can, is There a Safer Way to Sterilize Medical Equipment? When you chew gum, if these steps don’t help how much acid reflux quiz if you have frequent or severe symptoms, what is the other name for acid reflux? What are the side effects of an upper GI endoscopy?
You set yourself up for acid when you overeat, what can you do if your heartburn gets worse after exercise? If much don’t completely reflux your symptoms of acid reflux disease and the symptoms are severely interfering with your life, heartburn and acid reflux can also become so quiz that you feel like you are having a heart attack. These symptoms are a sign of a deeper imbalance — how reduce acid reflux. In GERD patients, there are several risk factors for developing GERD, do You Know the Benefits of Walking? There are several other symptoms besides heartburn that are associated with GERD, the American College of Gastroenterology: “Heartburn or Gastroesophageal Reflux Disease. Don’t eat or drink it. Study up and take the quiz again. The founder of Joyful Belly, diagnosis or treatment.
Leave a Reply | {
"url": "https://manuma.eu/how-much-acid-reflux-quiz/",
"source_domain": "manuma.eu",
"snapshot_id": "crawl=CC-MAIN-2021-49",
"warc_metadata": {
"Content-Length": "64567",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:HMTLGLOXWKUB7MVVB3DZY3EN7E3DZNPM",
"WARC-Concurrent-To": "<urn:uuid:bd000b1f-fc0c-4443-b450-715cd8979c4f>",
"WARC-Date": "2021-12-04T08:10:47",
"WARC-IP-Address": "144.91.113.183",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:I47P3YFPJV4W54VD5DHBMBGT5DJ3X3JR",
"WARC-Record-ID": "<urn:uuid:c8192c60-5acb-4e12-a399-6765c0daab67>",
"WARC-Target-URI": "https://manuma.eu/how-much-acid-reflux-quiz/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:a8ca84a9-3e84-4d46-af10-733065e60847>"
},
"warc_info": "isPartOf: CC-MAIN-2021-49\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November/December 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-12\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.3-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
26,
27,
48,
49,
611,
612,
1142,
1143,
1379,
1380,
2118,
2119,
2623,
2624,
3421,
3422
],
"line_end_idx": [
26,
27,
48,
49,
611,
612,
1142,
1143,
1379,
1380,
2118,
2119,
2623,
2624,
3421,
3422,
3435
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3435,
"ccnet_original_nlines": 16,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 1,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.44075146317481995,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.013005780056118965,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11416184902191162,
"rps_doc_frac_unique_words": 0.4542483687400818,
"rps_doc_mean_word_length": 4.49346399307251,
"rps_doc_num_sentences": 36,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.058973789215088,
"rps_doc_word_count": 612,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.06727273017168045,
"rps_doc_frac_chars_dupe_6grams": 0.016727270558476448,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.05454545095562935,
"rps_doc_frac_chars_top_3gram": 0.02181817963719368,
"rps_doc_frac_chars_top_4gram": 0.026181820780038834,
"rps_doc_books_importance": -292.0436096191406,
"rps_doc_books_importance_length_correction": -292.0436096191406,
"rps_doc_openwebtext_importance": -175.22462463378906,
"rps_doc_openwebtext_importance_length_correction": -175.22462463378906,
"rps_doc_wikipedia_importance": -121.49213409423828,
"rps_doc_wikipedia_importance_length_correction": -121.49213409423828
},
"fasttext": {
"dclm": 0.16046756505966187,
"english": 0.9336329698562622,
"fineweb_edu_approx": 2.7748937606811523,
"eai_general_math": 0.0867312029004097,
"eai_open_web_math": 0.16446208953857422,
"eai_web_code": 0.0010952400043606758
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.39",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.3",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-7,233,236,308,716,636,000 | There are a wide variety of posterior motion preservation devices in various stages of development and clinical investigation. The intent of these devices is to provide a better treatment alternative than spine fusion for patients with pain and loss of function caused by specific back problems, such as lumbar spinal stenosis, facet pain, and degenerative disc disease.
For patients researching different treatment alternatives for spine pain, it is always important to remember that no one device or class of devices offers a cure all: the key to providing lower back pain relief is to identify the cause of the patient's symptoms as specifically and comprehensively as possible. The ability to isolate the actual cause of the pain for the patient determines which device and procedure should best address the structural problem(s) causing the patient's pain.
advertisement
For patients with ongoing pain originating from the spine, the classic surgical treatment has usually been spinal fusion. Similar to degenerative painful conditions of the hip and knee, degenerative, painful spine surgical treatment is now evolving from fusion, which eliminates motion at the joint, to the goal of motion preservation. There are several alternative approaches to motion preservation, some of which have been approved for use in the general patient population in the US and many of which are in various stages of development and clinical trials:
advertisement
• Total disc replacement. The initial approach for motion preservation in the USA has involved total disc replacement to address painful disc degeneration. There are two artificial discs currently available in the U.S.: the CHARITE lumbar artificial disc, which received FDA approval in October 2004 and the PRODISC-L lumbar artificial disc, which received FDA approval in August 2006. Other total disc replacements will likely soon receive approval and be available to patients as well.
• Disc nucleus replacement. Also in development are nucleus replacement devices, which seek to address discogenic pain by replacing only the disc nucleus (the center of the disc) while leaving the outer portion (the annulus) of the disc intact.
While representing a breakthrough in treatment for many patients with ongoing back pain, disc replacement cannot be expected to address pain in all patients with low back pain, as the source of the patient's pain is not always a painful disc or well defined. For example, total disc replacement does not address pain originating from the posterior elements (in the back of the spine), such as pain that originates from the facet joints, ligaments, tendons, or muscles. Posterior conditions (problems in the back of the spine), such as spinal stenosis, may be improved with posterior motion preservation devices. These devices can be put into three general categories:
• Interspinous process spacers. These devices are designed to distract (open) the central canal and foramen, where the nerve endings pass away from the center of the spinal region and into the legs. These devices are designed to address pain and activity restrictions from spinal stenosis, and some may be used to treat degenerative disc disease.
• Posterior dynamic stabilization devices. Analogous to an internal brace on the spine, the goal of posterior dynamic stabilization devices is to allow controlled motion in such as way as to achieve more normal movement of the spine. These devices are typically used to treat patients with spondylolisthesis and degenerative disc disease and to date have been approved for use with fusion, but not for independent use as dynamic stabilizers. Clinical trials are currently underway for some of these devices for use as stand-alone devices (without fusion), and for use in the treatment of lumbar spinal stenosis.
• Facet replacement or total element replacement devices for spinal stenosis. These devices are primarily designed to address pain due to facet pain or lumbar spinal stenosis (narrowing of the passageways of the nerves). For many patients, spinal stenosis is due to degeneration of the facet joints. Facet replacement devices replace the facet joints in the back of the spine to limit or control motion, and total element replacement devices replace all the elements in the back of the spine.
In lumbar spinal stenosis, the cauda equina or spinal nerve roots in the low back are compressed, producing pain, tingling, weakness or numbness that radiates into the buttocks and legs. In most cases, walking will produce pain into the legs, and the pain will be relieved when sitting. The decision to have surgery for spinal stenosis is usually made by patients who have been unresponsive to non-surgical treatments and no longer want to live with activity restrictions.
advertisement
Find a Physician Near You
stethoscope-icon
Search for a Doctor
advertisement | {
"url": "https://www.spine-health.com/treatment/back-surgery/posterior-motion-preservation-spine-surgery-alternative-spinal-fusion",
"source_domain": "www.spine-health.com",
"snapshot_id": "CC-MAIN-2023-14",
"warc_metadata": {
"Content-Length": "215681",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:YRMYVAH35N254YZPW75ETTQ4UDBODU64",
"WARC-Concurrent-To": "<urn:uuid:e313bf27-c922-40dd-91ad-25b4348ac49c>",
"WARC-Date": "2023-03-29T16:05:45",
"WARC-IP-Address": "23.185.0.253",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:FSHN45DLOBDRSZDR633OEU7NWRDIVQTA",
"WARC-Record-ID": "<urn:uuid:bbe37087-a392-48f7-9e2f-366bf667db2c>",
"WARC-Target-URI": "https://www.spine-health.com/treatment/back-surgery/posterior-motion-preservation-spine-surgery-alternative-spinal-fusion",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:739d183f-341b-499b-bf9b-900fab055cc7>"
},
"warc_info": "isPartOf: CC-MAIN-2023-14\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for March/April 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-179\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
371,
372,
863,
864,
878,
879,
1441,
1442,
1456,
1946,
2193,
2194,
2862,
2863,
3212,
3826,
4321,
4322,
4795,
4796,
4797,
4811,
4812,
4838,
4839,
4856,
4876
],
"line_end_idx": [
371,
372,
863,
864,
878,
879,
1441,
1442,
1456,
1946,
2193,
2194,
2862,
2863,
3212,
3826,
4321,
4322,
4795,
4796,
4797,
4811,
4812,
4838,
4839,
4856,
4876,
4889
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4889,
"ccnet_original_nlines": 27,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.39513325691223145,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.010428739711642265,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11008110642433167,
"rps_doc_frac_unique_words": 0.352480411529541,
"rps_doc_mean_word_length": 5.234986782073975,
"rps_doc_num_sentences": 32,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.892759323120117,
"rps_doc_word_count": 766,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.09177056699991226,
"rps_doc_frac_chars_dupe_6grams": 0.06832917779684067,
"rps_doc_frac_chars_dupe_7grams": 0.06359101831912994,
"rps_doc_frac_chars_dupe_8grams": 0.035411469638347626,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.018703240901231766,
"rps_doc_frac_chars_top_3gram": 0.01246882975101471,
"rps_doc_frac_chars_top_4gram": 0.010972569696605206,
"rps_doc_books_importance": -266.61199951171875,
"rps_doc_books_importance_length_correction": -266.61199951171875,
"rps_doc_openwebtext_importance": -153.04727172851562,
"rps_doc_openwebtext_importance_length_correction": -153.04727172851562,
"rps_doc_wikipedia_importance": -97.6695785522461,
"rps_doc_wikipedia_importance_length_correction": -97.6695785522461
},
"fasttext": {
"dclm": 0.038821760565042496,
"english": 0.9353527426719666,
"fineweb_edu_approx": 2.48947811126709,
"eai_general_math": 0.03382939100265503,
"eai_open_web_math": 0.10942751169204712,
"eai_web_code": 0.006165860220789909
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.10285",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.1028",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
4,546,472,320,573,502,000 | film semi amateur babe talin drilled creampied her fertile pussy.
https://www.xxx-in.pro watch me get my ass filled with big black cock.
lewd lady widens her legs.videos porno
7th January 2019
Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrage
Objective Methods Whether intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOAC-ICH) has a better outcome compared to ICH associated with vitamin K antagonists (VKA-ICH) is uncertain. We performed a systematic review and individual patient data meta-analysis of cohort studies comparing clinical and radiological outcomes between NOAC-ICH and VKA-ICH patients. The primary outcome measure was 30-day all-cause mortality. All outcomes were assessed in multivariate regression analyses adjusted for age, sex, ICH location, and intraventricular hemorrhage extension. Results Interpretation We included 7 eligible studies comprising 219 NOAC-ICH and 831 VKA-ICH patients (mean age = 77 years, 52.5% females). The 30-day mortality was similar between NOAC-ICH and VKA-ICH (24.3% vs 26.5%; hazard ratio = 0.94, 95% confidence interval [CI] = 0.67-1.31). However, in multivariate analyses adjusting for potential confounders, NOAC-ICH was associated with lower admission National Institutes of Health Stroke Scale (NIHSS) score (linear regression coefficient = -2.83, 95% CI = -5.28 to -0.38), lower likelihood of severe stroke (NIHSS > 10 points) on admission (odds ratio [OR] = 0.50, 95% CI = 0.30-0.84), and smaller baseline hematoma volume (linear regression coefficient = -0.24, 95% CI = -0.47 to -0.16). The two groups did not differ in the likelihood of baseline hematoma volume < 30cm(3) (OR = 1.14, 95% CI = 0.81-1.62), hematoma expansion (OR = 0.97, 95% CI = 0.63-1.48), in-hospital mortality (OR = 0.73, 95% CI = 0.49-1.11), functional status at discharge (common OR = 0.78, 95% CI = 0.57-1.07), or functional status at 3 months (common OR = 1.03, 95% CI = 0.75-1.43). Although functional outcome at discharge, 1 month, or 3 months was comparable after NOAC-ICH and VKA-ICH, patients with NOAC-ICH had smaller baseline hematoma volumes and less severe acute stroke syndromes. Ann Neurol 2018;84:702-712
From stroke research to treatment
JOIN OR SUPPORT US
Contact Us
cute wench gets hard strapon in hands.click to read film semi xnxx indian uniformed femdoms pussypounded in fourway. jav hub | {
"url": "https://www.strokebrno.com/result/publication-1/",
"source_domain": "www.strokebrno.com",
"snapshot_id": "crawl=CC-MAIN-2021-43",
"warc_metadata": {
"Content-Length": "24488",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:SCVGWHA2HLOZKYMDX5YTVDEKDAD2NUCK",
"WARC-Concurrent-To": "<urn:uuid:bf483ac0-ffb7-4c81-8769-c3999ed92df4>",
"WARC-Date": "2021-10-27T10:18:10",
"WARC-IP-Address": "195.113.158.225",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:N3MKEVTTHPMZUTCH5YTU3Z7B3H4C265I",
"WARC-Record-ID": "<urn:uuid:c92c063a-95b8-47f3-b00e-d9fef6b5435a>",
"WARC-Target-URI": "https://www.strokebrno.com/result/publication-1/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:6aff2897-80a8-471a-8924-a4a059c65025>"
},
"warc_info": "isPartOf: CC-MAIN-2021-43\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for October 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-149\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
66,
137,
176,
193,
194,
286,
287,
2238,
2239,
2273,
2274,
2275,
2294,
2295,
2306,
2307
],
"line_end_idx": [
66,
137,
176,
193,
194,
286,
287,
2238,
2239,
2273,
2274,
2275,
2294,
2295,
2306,
2307,
2431
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2431,
"ccnet_original_nlines": 16,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 8,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.12982456386089325,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.08771929889917374,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.44035089015960693,
"rps_doc_frac_unique_words": 0.6331360936164856,
"rps_doc_mean_word_length": 5.582840442657471,
"rps_doc_num_sentences": 47,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.121581554412842,
"rps_doc_word_count": 338,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01695813052356243,
"rps_doc_frac_chars_top_3gram": 0.02543720044195652,
"rps_doc_frac_chars_top_4gram": 0.02437731996178627,
"rps_doc_books_importance": -265.863037109375,
"rps_doc_books_importance_length_correction": -265.863037109375,
"rps_doc_openwebtext_importance": -147.69912719726562,
"rps_doc_openwebtext_importance_length_correction": -147.69912719726562,
"rps_doc_wikipedia_importance": -100.1131591796875,
"rps_doc_wikipedia_importance_length_correction": -100.1131591796875
},
"fasttext": {
"dclm": 0.14659208059310913,
"english": 0.8564363121986389,
"fineweb_edu_approx": 2.222452163696289,
"eai_general_math": 0.3083775043487549,
"eai_open_web_math": 0.18543201684951782,
"eai_web_code": 0.02425139956176281
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.858",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.858072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "19",
"label": "Spam / Ads"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "6",
"label": "Indeterminate"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "6",
"label": "Not Applicable/Indeterminate"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "5",
"label": "Indeterminate"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
6,499,307,204,286,033,000 | Topics:
Epidemiology and Pathogenesis of AIDS-Related Lymphomas
Epidemiology and Pathogenesis of AIDS-Related Lymphomas
Dr. Aboulafia provides an accurate overview of the relationship between immunodeficiency and malignant lymphoma, the lymphoproliferative disorders that occur following solid organ transplantation, and the epidemiology and pathogenetic mechanisms possibly involved in acquired immunodeficiency syndrome (AIDS)-related lymphomagenesis.
The lymphoproliferative disorders that arise in immunodeficient individuals share several features, including frequent origination in extranodal sites, diffuse aggressive histopathology, B-cell lineage derivation, and association with the Epstein-Barr virus (EBV). However, immunodeficiency-associated lymphoproliferative disorders exhibit clinical, pathologic, clonal, and molecular heterogeneity that varies according to the immunodeficiency syndrome with which they are associated. For example, lymphoproliferative disorders arising in solid organ transplant recipients generally differ significantly from those arising in HIV-infected individuals who have AIDS.[1,2]
Initially, the lymphoid proliferations seen in solid organ transplant recipients were believed to be EBV-associated malignant lymphomas. The malignant status of these lesions was questioned, however, when Starzl and colleagues demonstrated that many regress spontaneously following withdrawal of immunosuppressive therapy.[3] These lesions are now known to represent a clinically and histopathologically diverse group of lymphoid proliferations of variable clonal composition and are collectively referred to as post-transplantation lymphoproliferative disorders.[1]
Post-Transplantation Lymphoproliferative Disorders
Most post-transplantation lymphoproliferative disorders are comprised of a polymorphic cell population, which often causes difficulty in determining with certainty their benign or malignant nature by histopathologic evaluation alone. Furthermore, post-transplantation lymphoproliferative disorders that fulfill the histopathologic criteria for malignancy lack morphologic features that allow precise categorization by the major lymphoma classifications. This has led to their subclassification by some investigators as polymorphic B-cell hyperplasia, polymorphic B-cell lymphoma, and immunoblastic lymphoma, and by other investigators as simply polymorphic or monomorphic. However, the latter histopathologic categories do not consistently predict clonality, and neither these histopathologic categories nor clonality has proven reliable in forecasting clinical behavior.[1]
Approximately 90% of post-transplantation lymphoproliferative disorders contain EBV. The presence of EBV usually is the result of a single infectious event, suggesting that EBV infection occurs prior to clonal expansion of the B-cell population.[1] This supports a pathogenetic role for EBV infection in the development of monoclonal post-transplantation lymphoproliferative disorders. We have shown that this is nearly always type A EBV infection.[4]
Our correlative morphologic and comprehensive molecular genetic analyses suggest that post-transplantation lymphoproliferative disorders can be classified into three groups[5]:
1. Plasmacytic hyperplasias are nearly always polyclonal; usually contain EBV, which may be multiclonal, oligoclonal, or monoclonal; and lack genetic alterations. These disorders regress spontaneously following withdrawal of immunosuppressive therapy.
2. Polymorphic lymphoproliferative disorders are monoclonal B-cell proliferations, usually contain clonal EBV, lack genetic alterations, and exhibit variable clinical behavior.
3. Malignant lymphoma/multiple myelomas are monoclonal B-cell proliferations, usually contain clonal EBV, and have alterations of ras,c-myc, and/or TP53 genes. These disorders usually progress despite therapeutic intervention.
Thus, the plasmacytic hyperplasias and the malignant lymphomas/multiple myelomas represent the benign and malignant poles of the spectrum, respectively. The explanation for the diverse clinical behavior of the polymorphic lymphoproliferative disorders remains unclear. However, we have recently shown that bcl-6 gene mutations predict the failure of post-transplantation lymphoproliferative disorders to regress following a reduction in immunosuppression, as well as shortened patient survival.[6] Thus, the bcl-6 gene appears to be an excellent marker for the subclassification of post-transplantation lymphoproliferative disorders into hyperplasia and malignant lymphoma. Whether these mutations are causally related to the development of post-transplantation lymphoproliferative disorders or simply represent a marker of genetic instability related to malignant transformation is still unclear.
AIDS-Related Lymphomas
In contrast with post-transplantation lymphoproliferative disorders, virtually all AIDS-related lymphomas are monomorphic and can be categorized according to the major lymphoma classifications. Approximately 40% are Burkitts or Burkitts-like lymphomas, and most of the remainder are large-cell and immunoblastic lymphomas.[2] Other investigators have described occasional cases of AIDS-related, anaplastic large-cell lymphomas and plasmablastic lymphomas, and we have described the primary effusion lymphomas, which contain the Kaposis sarcoma-associated herpesvirus.[7]
Like the post-transplantation lymphoproliferative disorders, the vast majority of AIDS-related lymphomas are B-cell lineage neoplasms. More than 90% express monotypic surface immunoglobulin and/or B-cell lineage-associated antigens. Their immunophenotypes are similar to those expressed by lymphomas of comparable morphology occurring in non-HIV-infected immunocompetent persons.[2]
One group of West Coast investigators have claimed that one-third of all AIDS-related lymphomas originating in the San Francisco area are polyclonal, and that many of these cases also lack EBV and c-myc gene rearrangements.[8] However, we have found that a comprehensive approach, which includes immunoglobulin heavy- and light-chain gene rearrangement and EBV terminal repeat analysis, demonstrates monoclonality in more than 95% of AIDS-related lymphomas from both the East and West Coasts of the United States.[9] Therefore, AIDS-related lymphomas exhibiting a germ-line immunoglobulin gene configuration appear to be quite rare.
Also, the failure to detect monoclonality does not necessarily indicate polyclonality. A variety of scientific and technical explanations can be offered to account for this phenomenon.
Acquired immunodeficiency syndrome-related lymphomas are characterized by the accumulation of multiple distinct genetic lesions. In contrast with the post-transplantation lymphoproliferative disorders, however, only approximately 50% of AIDS-related lymphomas contain clonal EBV infection, and as many as 50% or more contain c-myc gene rearrangements. Many AIDS-related lymphomas exhibit bcl-6 gene rearrangements and/or mutations, as well as TP53 gene mutations.[2]
These findings suggest that multiple alternative molecular genetic pathways operate in AIDS lymphomagenesis. Also, some of these pathways may be preferentially associated with certain histopathologic categories or anatomic sites of origin.[2]
Polymorphic B-Cell Lymphoproliferative Disorders in AIDS Patients
Finally, although the majority of AIDS-related lymphomas and post-transplantation lymphoproliferative disorders differ clinically, pathologically and molecularly, we have recently identified 10 HIV-infected men and women who have lymphoid proliferations that resemble the post-transplantation lymphoproliferative disorders.[10] The lesions develop in lymph nodes and extranodal sites. These patients generally have low-stage disease.[10]
The lesions grow diffusely and are comprised of a polymorphic lymphoid cell population similar to that found in the post-transplantation lymphoproliferative disorders. A clonal cell B-cell population representing only a small subset of the cells that comprise each lesion is detectable in the majority of cases. These lesions lack genetic alterations, except in those instances where there is morphologic transformation to large-cell lymphoma.[10] Thus, polymorphic B-cell lymphoproliferative disorders apparently occur in both HIV-infected individuals and solid organ transplant recipients, although they are infrequent in the former group.
Summary
Post-transplantation lymphoproliferative disorders and AIDS-related lymphomas represent two distinct categories of immunodeficiency-associated lymphoproliferative disease. These differences may be related to the level and type of immunosuppression and/or to other as yet unidentified aspects of the effects of immunosuppressive therapy and HIV infection on the immune system. Further investigation into the clinical and biological nature of each of these categories of immunodeficiency-associated lymphoproliferative disease should help us to better understand the development and progression of lymphoid neoplasia in the immunocompromised host.
References
1. Chadburn A, Cesarman E, Knowles DM: Molecular pathology of the post-transplantation lymphoproliferative disorders. Semin Diagn Pathol 14:15-26, 1997.
2. Knowles DM: The molecular pathology of AIDS-related non-Hodgkin’s lymphoma. Semin Diagn Pathol 14:67-82, 1997.
3. Starzl TE, Nalesnik MA, Porter KA, et al: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet i:583-587, 1984.
4. Frank D, Cesarman E, Liu YF, et al: Posttransplantation lymphoproliferative disorders frequently contain type A and not type B Epstein-Barr virus. Blood 85:1396-1403, 1995.
5. Knowles DM, Cesarman E, Chadburn A, et al: Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of post-transplantation lymphoproliferative disorders. Blood 85:552-565, 1995.
6. Cesarman E, Chadburn A, Liu YF, et al: BCL-6 gene mutations in post-transplantation lymphoproliferative disorders (PT-LPDs) as predictors of clinical behavior. Lab Invest 76:121A, 1997.
7. Nador RG, Cesarman E, Chadburn A, et al: Primary effusion lymphoma: A distinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood 88:645-656, 1996.
8. Shiramizu B, Herndier B, Meeker T, et al: Molecular and immunophenotypic characterization of AIDS-associated Epstein-Barr virus-negative polyclonal lymphoma. J Clin Oncol 10:383-389, 1992.
9. Nador RG, Horenstein MG, Chadburn A, et al: Molecular analysis of 70 AIDS-related systemic non-Hodgkin’s lymphomas from the east and west coasts of the United States of America (USA). Ann Oncol 7(suppl 3):16, 1996.
10. Nador RG, Chadburn A, Gundappa G, et al: AIDS-related polymorphic lymphoproliferative disorders (PLDs). Lab Invest 77:136A, 1998.
Loading comments...
Please Wait 20 seconds or click here to close | {
"url": "http://www.cancernetwork.com/review-article/epidemiology-and-pathogenesis-aids-related-lymphomas-0",
"source_domain": "www.cancernetwork.com",
"snapshot_id": "crawl=CC-MAIN-2014-10",
"warc_metadata": {
"Content-Length": "75367",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:QYT3G575EWUGVP4NYU2TZWH2QDIYBKT3",
"WARC-Concurrent-To": "<urn:uuid:3b19d2e1-b4be-4f3e-b176-e6f85f9a7092>",
"WARC-Date": "2014-03-10T03:41:13",
"WARC-IP-Address": "108.171.169.3",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:XWOYBPUVDN5CTSWC5MHKTCYNCKI24YMD",
"WARC-Record-ID": "<urn:uuid:b271ee5f-4772-47b2-a850-4fd4fc761fd9>",
"WARC-Target-URI": "http://www.cancernetwork.com/review-article/epidemiology-and-pathogenesis-aids-related-lymphomas-0",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:fea81610-1315-4713-8c7b-e9ac2f9e9bf1>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-183-142-35.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-10\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for March 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
8,
9,
65,
66,
122,
123,
457,
458,
1129,
1130,
1697,
1698,
1749,
1750,
2625,
2626,
3078,
3079,
3256,
3257,
3511,
3512,
3691,
3692,
3922,
3923,
4821,
4822,
4845,
4846,
5420,
5421,
5804,
5805,
6438,
6439,
6624,
6625,
7092,
7093,
7336,
7337,
7403,
7404,
7842,
7843,
8485,
8486,
8494,
8495,
9141,
9142,
9153,
9154,
9307,
9308,
9422,
9423,
9597,
9598,
9774,
9775,
9994,
9995,
10184,
10185,
10378,
10379,
10571,
10572,
10790,
10791,
10925,
10926,
10928,
10948
],
"line_end_idx": [
8,
9,
65,
66,
122,
123,
457,
458,
1129,
1130,
1697,
1698,
1749,
1750,
2625,
2626,
3078,
3079,
3256,
3257,
3511,
3512,
3691,
3692,
3922,
3923,
4821,
4822,
4845,
4846,
5420,
5421,
5804,
5805,
6438,
6439,
6624,
6625,
7092,
7093,
7336,
7337,
7403,
7404,
7842,
7843,
8485,
8486,
8494,
8495,
9141,
9142,
9153,
9154,
9307,
9308,
9422,
9423,
9597,
9598,
9774,
9775,
9994,
9995,
10184,
10185,
10378,
10379,
10571,
10572,
10790,
10791,
10925,
10926,
10928,
10948,
10993
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 10993,
"ccnet_original_nlines": 76,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2637302875518799,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.05002719163894653,
"rps_doc_frac_lines_end_with_ellipsis": 0.012987010180950165,
"rps_doc_frac_no_alph_words": 0.2305600941181183,
"rps_doc_frac_unique_words": 0.385294109582901,
"rps_doc_mean_word_length": 6.783088207244873,
"rps_doc_num_sentences": 87,
"rps_doc_symbol_to_word_ratio": 0.0005437699728645384,
"rps_doc_unigram_entropy": 5.559634685516357,
"rps_doc_word_count": 1360,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.07306233048439026,
"rps_doc_frac_chars_dupe_6grams": 0.04661247134208679,
"rps_doc_frac_chars_dupe_7grams": 0.018644990399479866,
"rps_doc_frac_chars_dupe_8grams": 0.018644990399479866,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.08498644828796387,
"rps_doc_frac_chars_top_3gram": 0.09680216759443283,
"rps_doc_frac_chars_top_4gram": 0.026558270677924156,
"rps_doc_books_importance": -738.2432250976562,
"rps_doc_books_importance_length_correction": -738.2432250976562,
"rps_doc_openwebtext_importance": -474.7381286621094,
"rps_doc_openwebtext_importance_length_correction": -474.7381286621094,
"rps_doc_wikipedia_importance": -377.89642333984375,
"rps_doc_wikipedia_importance_length_correction": -377.89642333984375
},
"fasttext": {
"dclm": 0.23275959491729736,
"english": 0.8814281225204468,
"fineweb_edu_approx": 2.958345890045166,
"eai_general_math": 0.31015968322753906,
"eai_open_web_math": 0.4168810248374939,
"eai_web_code": 0.025327499955892563
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.9940072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.9940076",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "2",
"label": "Click Here References"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-7,596,690,530,286,364,000 | lcm-lassa complex viruses meaning
[Medicine]
One of two groups of viruses in the ARENAVIRUS genus and considered part of the Old World complex. It includes LASSA VIRUS and LYMPHOCYTIC CHORIOMENINGITIS VIRUS,although the latter has worldwide distribution now.
Related Words
1. lclint meaning
2. lcm meaning
3. lcm lassa complex viruses meaning
4. lcm virus meaning
5. lcm viruses meaning
6. lcmv meaning
7. lco meaning
8. lcp meaning
9. lcpl meaning
10. lcr bridge meaning
PC Version | {
"url": "https://eng.ichacha.net/mee/lcm-lassa%20complex%20viruses.html",
"source_domain": "eng.ichacha.net",
"snapshot_id": "CC-MAIN-2023-40",
"warc_metadata": {
"Content-Length": "20574",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:TI5ZAD3KPKJX6OY2BJDJ2IDM7SJ2DPMJ",
"WARC-Concurrent-To": "<urn:uuid:8f029d42-0529-4d01-8fee-6f6f63452731>",
"WARC-Date": "2023-10-01T19:12:56",
"WARC-IP-Address": "107.150.97.95",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:JSS4FFTNDQG6R54OSLNZQEQYG3PB3QVC",
"WARC-Record-ID": "<urn:uuid:7563096c-a2e8-486c-9cb7-22a02408b26d>",
"WARC-Target-URI": "https://eng.ichacha.net/mee/lcm-lassa%20complex%20viruses.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:32dbd3ce-47a5-4098-bf53-f79f5842698f>"
},
"warc_info": "isPartOf: CC-MAIN-2023-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September/October 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-105\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
34,
35,
46,
260,
261,
275,
276,
296,
313,
352,
375,
400,
418,
435,
452,
470,
495
],
"line_end_idx": [
34,
35,
46,
260,
261,
275,
276,
296,
313,
352,
375,
400,
418,
435,
452,
470,
495,
505
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 505,
"ccnet_original_nlines": 17,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.1473684161901474,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0736842080950737,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.27368420362472534,
"rps_doc_frac_unique_words": 0.6753246784210205,
"rps_doc_mean_word_length": 5.064935207366943,
"rps_doc_num_sentences": 13,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 3.674797773361206,
"rps_doc_word_count": 77,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.10769230872392654,
"rps_doc_frac_chars_top_3gram": 0.10769230872392654,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -40.27062225341797,
"rps_doc_books_importance_length_correction": -50.2285041809082,
"rps_doc_openwebtext_importance": -20.09809112548828,
"rps_doc_openwebtext_importance_length_correction": -30.055971145629883,
"rps_doc_wikipedia_importance": -17.925600051879883,
"rps_doc_wikipedia_importance_length_correction": -27.883480072021484
},
"fasttext": {
"dclm": 0.999924898147583,
"english": 0.9175595641136169,
"fineweb_edu_approx": 3.719938278198242,
"eai_general_math": 0.025638699531555176,
"eai_open_web_math": 0.25926679372787476,
"eai_web_code": 0.0002006900031119585
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "614.4",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Public health"
}
},
"secondary": {
"code": "616.9",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "1",
"label": "No Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
2,778,594,995,352,271,000 | cinnamon tea
When cinnamon bark is consumed, it has medicinal properties. The best way to accomplish this is to make De coco tea, also known as cinnamon tea. To make the tea, combine cinnamon bark, sticks, or powder with hot water. Cinnamon tea has a plethora of health benefits that you should not overlook. Including it in your meals can save you from having to go to the doctor all the time. It should not, however, be taken in excess because it can lead to other health complications. Cenforce medication is an effective treatment for this.
Cinnamon has been demonstrated to reduce blood pressure. Cinnamon tea’s effects go beyond the standard antibacterial and antifungal properties. Those who drink cinnamon tea have better blood sugar control. However, the clarity of this effect has not yet been well established, necessitating additional research.
Impressive Health perks of Cinnamon Tea
May Aid in the Fight Against the HIV Virus
If HIV is not treated, it gradually depletes the body’s immune system, eventually leading to AIDS. While researchers work around the clock to find a cure for HIV, some natural remedies have been proposed to help reduce the virus’s risk.
The cinnamon obtained from Cassia varieties has been thought to be effective against HIV1, the most common type of HIV in humans. More research is needed, however, to confirm cinnamon’s effectiveness against HIV1 in humans. It can help save the world from the virus if consumed as a tea.
Aids in the treatment of fungal and bacterial infections
Cinnamon contains the active ingredient cinnamaldehyde, which is known to be effective against fungal and bacterial infections. The oil extracted from it is used to treat fungal infections of the respiratory tract.
Furthermore, it inhibits the growth of some pathogens that cause disease, such as Salmonella and Listeria bacteria. Nonetheless, evidence of cinnamon’s activity in the fight against disease-causing pathogens is still sketchy because its effect on other parts of the body has yet to be established.
Cinnamon’s antimicrobial properties also aid in the treatment of bad breath and tooth decay. Consuming cinnamon tea will essentially aid in the fight against a slew of bacterial, fungal, and viral infections. More research is needed to identify other types of bacteria and fungi in the human body that cinnamon can eliminate.
Anti-Cancer Protection
Cancer is at the top of the list of the world’s deadliest killer diseases. A standard cure for cancer, which is characterized by uncontrolled cell growth, has yet to be established. Existing cancer control measures are prohibitively expensive, and their efficacy is still being debated. Nonetheless, numerous studies on the effectiveness of cinnamon against cancer have been conducted.
Currently, the only available evidence comes from laboratory studies on animal subjects. This suggests that cinnamon has a high potential as a cancer prevention and treatment measure. It promotes tumor blood vessel growth while inhibiting tumor growth. These findings came from test-tube studies. Studies on live human subjects are still being conducted to confirm these findings.
Effective in the Treatment of Neurodegenerative Diseases
Neurodegenerative disorders cause the brain’s functions and cell structure to regress. Parkinson’s and Alzheimer’s are two of these diseases. These are some of the most common neurodegenerative diseases that affect humans. Furthermore, their neurotransmitter levels were stabilized, and their neurons were protected.
Alzheimer’s disease is linked to the two proteins. Cinnamon compounds, on the other hand, have been found to inhibit the accumulation of this protein in the brain. A laboratory study on mice infected with Parkinson’s disease found that using cinnamon improved the motor functions of these mice. More of these studies on humans are needed to validate the findings.
Increases Sensitivity to the Insulin Hormone
Insulin is essential for controlling energy consumption and metabolism. It also aids in the transport of blood sugar from the bloodstream to body cells. Insulin resistance, on the other hand, affects a large number of people. Essentially, insulin sensitivity can be increased, lowering blood sugar levels in the body.
Diabetes and metabolic syndrome are the results of this. Cinnamon’s effects on the body help to alleviate this problem by lowering the threat of insulin resistance. This creates an environment in which insulin can work most effectively. Tadalista and Sildalist 120 is unquestionably the only treatment option for health issues.
Antidiabetic Action
Cinnamon is one of the natural diabetes treatments. It has been discovered to successfully lower blood sugar levels in the body in a variety of ways. It also helps with insulin resistance. Cinnamon effectively reduces the intake of glucose in the circulatory system of the body. It lowers the risk of diabetes by lowering blood sugar levels.
Cinnamon slows the rate at which glucose is digested in the digestive system by inhibiting several gastrointestinal enzymes. Furthermore, a specific compound found in cinnamon has been found to mimic insulin, allowing it to act on cells.
Cinnamon lowers bad cholesterol levels in the body while also stabilizing triglyceride levels, which are good cholesterol. Cinnamon has been shown in laboratory studies to significantly lower blood pressure in animals.
Leave a Reply
Your email address will not be published. Required fields are marked * | {
"url": "https://apkreviews.org/cinnamon-tea-is-good-for-mens-health/",
"source_domain": "apkreviews.org",
"snapshot_id": "CC-MAIN-2023-14",
"warc_metadata": {
"Content-Length": "98871",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:RDHWPP2NHZSWXGTG3VASDE2VNVKNR3OG",
"WARC-Concurrent-To": "<urn:uuid:dc48b64e-04a2-4fd5-89e1-1e7ff724d918>",
"WARC-Date": "2023-03-28T15:31:42",
"WARC-IP-Address": "65.109.37.186",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:SFCC2FUB53FLOENELXUIJ5I4IWUWO5GE",
"WARC-Record-ID": "<urn:uuid:9e9b9495-e380-4e84-a44a-a5a29ed082bc>",
"WARC-Target-URI": "https://apkreviews.org/cinnamon-tea-is-good-for-mens-health/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:ce579818-cc6b-441f-8173-a46e5600577c>"
},
"warc_info": "isPartOf: CC-MAIN-2023-14\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for March/April 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-104\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
13,
14,
546,
547,
859,
860,
900,
901,
944,
945,
1182,
1183,
1471,
1472,
1529,
1530,
1745,
1746,
2044,
2045,
2371,
2372,
2395,
2396,
2782,
2783,
3164,
3165,
3222,
3223,
3540,
3541,
3905,
3906,
3951,
3952,
4270,
4271,
4599,
4600,
4620,
4621,
4963,
4964,
5202,
5203,
5422,
5423,
5437,
5438
],
"line_end_idx": [
13,
14,
546,
547,
859,
860,
900,
901,
944,
945,
1182,
1183,
1471,
1472,
1529,
1530,
1745,
1746,
2044,
2045,
2371,
2372,
2395,
2396,
2782,
2783,
3164,
3165,
3222,
3223,
3540,
3541,
3905,
3906,
3951,
3952,
4270,
4271,
4599,
4600,
4620,
4621,
4963,
4964,
5202,
5203,
5422,
5423,
5437,
5438,
5508
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 5508,
"ccnet_original_nlines": 50,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3959183692932129,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0091836703941226,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11530611664056778,
"rps_doc_frac_unique_words": 0.40375587344169617,
"rps_doc_mean_word_length": 5.319248676300049,
"rps_doc_num_sentences": 59,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.215622425079346,
"rps_doc_word_count": 852,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.029126210138201714,
"rps_doc_frac_chars_dupe_6grams": 0.01103265956044197,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01544572040438652,
"rps_doc_frac_chars_top_3gram": 0.00992938969284296,
"rps_doc_frac_chars_top_4gram": 0.01125331036746502,
"rps_doc_books_importance": -389.0672607421875,
"rps_doc_books_importance_length_correction": -389.0672607421875,
"rps_doc_openwebtext_importance": -274.780517578125,
"rps_doc_openwebtext_importance_length_correction": -274.780517578125,
"rps_doc_wikipedia_importance": -162.60858154296875,
"rps_doc_wikipedia_importance_length_correction": -162.60858154296875
},
"fasttext": {
"dclm": 0.04861491918563843,
"english": 0.9510815739631653,
"fineweb_edu_approx": 3.0380125045776367,
"eai_general_math": 0.006644010078161955,
"eai_open_web_math": 0.27688348293304443,
"eai_web_code": 0.00013590000162366778
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "2",
"label": "Partially Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-8,331,121,169,205,044,000 | Acido ialuronico e collagene: quello che c’è da sapere CMP targeting consented”); googletag.cmd.push(function() { googletag.pubads().setRequestNonPersonalizedAds(0); }); var node = document.getElementsByTagName(‘script’)[0]; var sparrow_script = document.createElement(‘script’); sparrow_script.type = ‘text/javascript’; sparrow_script.src = ‘https://pixel.condenastdigital.com/config/vanity-fair-italia.config.js’; node.parentNode.insertBefore(sparrow_script, node); var sparrow_script = document.createElement(‘script’); sparrow_script.type = ‘text/javascript’; sparrow_script.src = ‘https://pixel.condenastdigital.com/sparrow.min.js’; node.parentNode.insertBefore(sparrow_script, node); var perm = document.createElement(‘script’); perm.async = true; perm.type = ‘text/javascript’; perm.src = ‘https://cdn.permutive.com/bd1cec50-00d1-4ce9-9572-785857419a1e-web.js’; node.parentNode.insertBefore(perm, node); if (typeof permutive !== ‘undefined’){ permutive.consent({ opt_in: true, token: permutiveToken }); } } else { console.log(“—————–> CMP NO targeting consented”); googletag.cmd.push(function() { googletag.pubads().setRequestNonPersonalizedAds(1); }); if (typeof permutive !== ‘undefined’){ permutive.consent({ opt_in: false, token: permutiveToken }); } } if (shouldRestrictDataProcessing()) { restrictDataProcessing(); } var gdprApplied = false; //setting privacy to Prebid and TAM apstag.init({ pubID: ‘3647’, adServer: ‘googletag’, bidTimeout: 2e3, us_privacy: getPrivacyString(), }); if (!gdprApplied && shouldApplyGDPR()) { gdprApplied = true; try{ window.pbjs.setConfig(getConsentManagement()); } catch (er) {console.log(‘log’);console.log(er);} } function shouldApplyGDPR() { var gdprApplies = false; var cmp = window.__cmp; var tcfapi = window.__tcfapi; if (cmp) { cmp(‘ping’, {}, function (e) { if (e.cmpLoaded) { cmp(‘getConsentData’, {}, function (e) { if (e.gdprApplies) { gdprApplies = true; } }); } }); } if (tcfapi) { tcfapi(‘ping’, 2, function (e) { if (e.gdprApplies) { gdprApplies = true; } }); } return gdprApplies; } function getConsentManagement() { var usp = { cmpApi: ‘static’, consentData: { getUSPData: { uspString: getPrivacyString() } }, timeout: 50 }; var consentManagement = { usp: usp }; if (shouldApplyGDPR()) { consentManagement.gdpr = { cmpApi: ‘iab’, timeout: 10000, allowAuctionWithoutConsent: false }; } return { consentManagement: consentManagement }; } function getPrivacyString() { return getCookie(‘usprivacy’) || ‘1—‘; } function getCookie(name, docCookies) { docCookies = docCookies || document.cookie; var cookies = docCookies.split(‘;’); var matchRegex = RegExp(‘^\s*’ + name + ‘=\s*(.*?)\s*$’); for (var i = 0; i < cookies.length; i++) { var matched = cookies[i].match(matchRegex); if (matched) { return matched[1]; } } } function shouldRestrictDataProcessing() { var privacyString = getPrivacyString(); console.log("privacyString: " + privacyString); return privacyString && privacyString.length === 4 && privacyString[0] === '1' && getPrivacyString()[2].toLowerCase() === 'y'; } function restrictDataProcessing() { googletag.cmd.push(function() { googletag.pubads().setPrivacySettings({ restrictDataProcessing: true }); }) } initAdv(); } function cmpDataLayer() { window.dataLayer = window.dataLayer || []; for (var key in cookieType) { var value = cookieType[key]; console.log('window.dataLayer.push: ' + key + ' ' + !!getCmpSettingType(key)); window.dataLayer.push({ event: key + "Consent", token: permutiveToken, opt_in: !!getCmpSettingType(key) }) } } /* funziona ripresa dalla cookie policy standard */ function URL_add_parameter(url, param, value){ var hash = {}; var parser = document.createElement('a'); parser.href = url; var parameters = parser.search.split(/?|&/); for(var i=0; i = 2) { if(cookieEnabled === true){ location.href = URL_add_parameter(location.href, 'refresh_ce', ''); } } else { console.log("OptanonWrapper call init()"); init(); } } document.addEventListener('DOMContentLoaded', function () { //init(); }); ]]>
Video
People Beauty Benessere Lifestyle Fashion Show Food Traveller
Vanity stars
Oroscopo
EXPERIENCE IS
Topic:
You may also like
Read next
Source | {
"url": "https://attrezzaturasci.it/acido-ialuronico-e-collagene-quello-che-ce-da-sapere/",
"source_domain": "attrezzaturasci.it",
"snapshot_id": "crawl=CC-MAIN-2020-50",
"warc_metadata": {
"Content-Length": "59556",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:WWQQQR2N4HMCKY4EPFZU6L5ZURHCTRKO",
"WARC-Concurrent-To": "<urn:uuid:38061457-9951-4edf-b2ef-aea4a3eb776f>",
"WARC-Date": "2020-11-26T06:51:28",
"WARC-IP-Address": "46.254.34.70",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:2VQLEECB4Y2CZQFHKV6RCDAOFG7NLRYV",
"WARC-Record-ID": "<urn:uuid:8ff81ac7-ae44-46bb-b296-e7ad94f8048d>",
"WARC-Target-URI": "https://attrezzaturasci.it/acido-ialuronico-e-collagene-quello-che-ce-da-sapere/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0fa0ad3a-e66d-4534-a2b0-83f12f5b99f9>"
},
"warc_info": "isPartOf: CC-MAIN-2020-50\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November/December 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-240.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
3993,
3994,
4000,
4001,
4063,
4064,
4077,
4078,
4087,
4088,
4102,
4103,
4110,
4111,
4129,
4130,
4140,
4141,
4142
],
"line_end_idx": [
3993,
3994,
4000,
4001,
4063,
4064,
4077,
4078,
4087,
4088,
4102,
4103,
4110,
4111,
4129,
4130,
4140,
4141,
4142,
4148
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4148,
"ccnet_original_nlines": 19,
"rps_doc_curly_bracket": 0.02362583950161934,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.05604396015405655,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.006593409925699234,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.5351648330688477,
"rps_doc_frac_unique_words": 0.5967212915420532,
"rps_doc_mean_word_length": 9.9180326461792,
"rps_doc_num_sentences": 84,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.879225730895996,
"rps_doc_word_count": 305,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.11966942250728607,
"rps_doc_frac_chars_dupe_6grams": 0.11966942250728607,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01884298026561737,
"rps_doc_frac_chars_top_3gram": 0.01090908981859684,
"rps_doc_frac_chars_top_4gram": 0.04099173843860626,
"rps_doc_books_importance": -395.8592834472656,
"rps_doc_books_importance_length_correction": -395.8592834472656,
"rps_doc_openwebtext_importance": -259.73651123046875,
"rps_doc_openwebtext_importance_length_correction": -259.73651123046875,
"rps_doc_wikipedia_importance": -173.4157257080078,
"rps_doc_wikipedia_importance_length_correction": -173.4157257080078
},
"fasttext": {
"dclm": 0.9998243451118469,
"english": 0.19436343014240265,
"fineweb_edu_approx": 3.4253759384155273,
"eai_general_math": 0.10515397787094116,
"eai_open_web_math": 0.017103489488363266,
"eai_web_code": 0.573875367641449
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "1",
"label": "Leftover HTML"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "6",
"label": "Not Applicable/Indeterminate"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
285,676,148,206,057,570 | young again - helping you feel younger
home
books
latest
library
youngagain.org
visit youngagin.com
newsletter
The article library of YoungAgain.org
divider
Skin Conditions and Psoriasis -Roger Mason
The skin is the largest organ of our bodies, although most people don't realize that. (The liver is the second largest organ.) Skin problems such as acne, eczema, dermatitis, shingles, hives, diaper rash, rosacea, and psoriasis are all too common in America. Basically, all these dermatological conditions are caused by what you eat and how you live. Your diet and lifestyle cause these. We Americans are overfed and under-nourished. Everyone has unknown food allergies. Diet and lifestyle treat the CAUSE of your skin problem. Diet and lifestyle are the answer. Unknown food allergies are a major cause. Think “leaky gut syndrome”. Read the article Food Allergies.
People keep looking for Magic Lotions and Magic Creams to cure these problems, but the cause is internal. No Magic Lotion or Potion is ever going to solve your skin condition, especially chronic conditions like psoriasis, eczema, and acne. Your skin merely reflects and expresses your internal problems. Skin problems are just the outward manifestation of inner health issues.
You will find three basic lotions in drug stores for allopathic relief of psoriasis- coal tar, salicylic acid, and (rarely) zinc pyrithione. Surprisingly, you don't see vitamin D3 creams offered in the drug stores. We do offer both Skin Cure® spray and cream for the temporary, topical relief of some skin conditions. This contains zinc pyrithione, the same ingredient in Head & Shoulders® shampoo for the last 60 years.
Again, you are never going to cure your psoriasis or other skin problem with some Magic Lotion. Even if you can find one that temporarily keeps your condition under control, you are just covering up the symptom, and ignoring the CAUSE. Americans eat twice the calories they need, eight times the fat they need, twice the protein they need, and an amazing 160 pounds of various sugars they don't need at all every year. We eat a mere 1% whole grains, when we should be eating 50%. We are overfed and undernourished. Then we wonder why we suffer from more diseases than poor people in Third World countries. They simply can’t afford to eat all this junk food. Please read my Macrobiotics for Everyone, and start making better food choices.
THE CURE FOR PSORIASIS IS INTERNAL, NOT EXTERNAL!
Your poor, old, hard working author just went over the last ten years of the world research on psoriasis in Chemical Abstracts, and it came to less than a dozen pages. Yes, that means every medical and scientific journal of any importance on this planet. Less than twelve pages on psoriasis in ten years. Almost nothing whatsoever on diet- the main cause of psoriasis. We eat too much food, too much fat, too much protein, too few whole grains, too little nutrition, too much sugar, and too many refined foods. Yet people endlessly seek Magic Lotions to cure their skin problems. It's never going to happen.
Yes, there are some topical applications that can superficially and temporarily help alleviate skin conditions in some people. These include aloe vera, vitamin D, vitamin E, Oregon grape root (and other berberine containing lotions), various mineral salts, zinc pyrithione, coal tar, salicylic acid, vitamin A or beta carotene, curcumin, S.O.D., Dead Sea salts, and flax oil. Many references to regular vitamin D3 were found both internally and externally. Do not use prescription vitamin D analog creams. Never take prescription drugs to cure your problems. You can’t poison your way to health. The most popular poison in 2021 is still Cosentyx®.
The answer is to make better food choices, take proven supplements, and improve your lifestyle. Read Seven Steps to Natural Health. Start eating whole grains like brown rice, 100% whole grain bread, and whole grain pasta rather than white rice, white bread and white pasta. Stop eating meat, eggs, poultry, and dairy. Take dairy out of your life completely. You'll come to realize natural foods taste much better than refined ones. The American macrobiotic diet is the least allergenic of all. Think "food allergies", and leaky gut syndrome to cure yourself. Read the Good Digestion and Colon Health articles.
Everyone has unknown food allergies, and there are currently no ways to accurately test which foods we are allergic to. That’s right, all the supposed allergy tests are worthless. Conditions like leaky gut syndrome and candiasis cause us to react negatively to common foods. This incompatibility shows up as skin conditions. Some of the most common allergens are dairy products, citrus fruits, peanuts, eggs, chocolate, and poultry. People with candiasis yeast overgrowth cannot tolerate sugar in any form including fruit, fruit juice, maple syrup, and honey. Read the article Food Allergies and Sugar is Sugar to learn more about this.
Good supplements for those over 40 are covered in my books and the article Serious Supplement Program. For people under 40 read the article Supplements for Younger People. Also read my book The Supplements You Need. Hormone balance is also important here. Read the article Balance Your Hormones. A total program of diet and lifestyle will cure your skin problem.
Don't take any prescription drugs. Drop any bad habits like coffee. Get regular exercise. Fast weekly for one day. These are the seven steps you need to get well. Read the article Seven Steps to Natural Health.
You are never going to cure your psoriasis, eczema, dermatitis, acne, or other skin problem by slathering on some Magic Something. Prescription drugs are even worse. The cure is internal, not external, and you must eat good, whole, healthy foods. The supplements are very secondary to what you eat, but very powerful in conjunction with good diet. Read the article Good Digestion to strengthen your intestines and cure leaky gut syndrome. Also read the Colon Health article to cure your leaky gut. Diet and lifestyle. All seven steps faithfully. Skin conditions are psychologically and emotionally debilitating was well as physically. You can be free of this.
Click here to return to the article library. | {
"url": "http://www.youngagain.org/s36.html",
"source_domain": "www.youngagain.org",
"snapshot_id": "crawl=CC-MAIN-2022-21",
"warc_metadata": {
"Content-Length": "12744",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:5A6UAC6MC7HV3XDVVAJQVYKAZQU73FBN",
"WARC-Concurrent-To": "<urn:uuid:09cdcdb2-9104-422c-b67d-68b7faa58098>",
"WARC-Date": "2022-05-26T01:32:05",
"WARC-IP-Address": "204.44.192.45",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:ECOYAUPYRRKPFGTTMQ2P3KM4ATXKLUPW",
"WARC-Record-ID": "<urn:uuid:71200231-9350-4f7b-bde6-660d8c9fb54a>",
"WARC-Target-URI": "http://www.youngagain.org/s36.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:dbc9b482-446d-4513-86c5-dd01e6786d57>"
},
"warc_info": "isPartOf: CC-MAIN-2022-21\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2022\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-153\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.3-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
39,
44,
50,
57,
65,
80,
100,
111,
149,
150,
158,
160,
161,
204,
205,
871,
872,
1249,
1250,
1671,
1672,
2410,
2411,
2461,
2462,
3070,
3071,
3719,
3720,
4330,
4331,
4969,
4970,
4972,
5336,
5337,
5548,
5549,
6209,
6210,
6212,
6213,
6215,
6216
],
"line_end_idx": [
39,
44,
50,
57,
65,
80,
100,
111,
149,
150,
158,
160,
161,
204,
205,
871,
872,
1249,
1250,
1671,
1672,
2410,
2411,
2461,
2462,
3070,
3071,
3719,
3720,
4330,
4331,
4969,
4970,
4972,
5336,
5337,
5548,
5549,
6209,
6210,
6212,
6213,
6215,
6216,
6260
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 6260,
"ccnet_original_nlines": 44,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.34729063510894775,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.016420360654592514,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1625615805387497,
"rps_doc_frac_unique_words": 0.41954588890075684,
"rps_doc_mean_word_length": 4.965449333190918,
"rps_doc_num_sentences": 88,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.505647659301758,
"rps_doc_word_count": 1013,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.046918489038944244,
"rps_doc_frac_chars_dupe_6grams": 0.0139164999127388,
"rps_doc_frac_chars_dupe_7grams": 0.0139164999127388,
"rps_doc_frac_chars_dupe_8grams": 0.0139164999127388,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.017892640084028244,
"rps_doc_frac_chars_top_3gram": 0.01669980026781559,
"rps_doc_frac_chars_top_4gram": 0.010735590010881424,
"rps_doc_books_importance": -413.90631103515625,
"rps_doc_books_importance_length_correction": -413.90631103515625,
"rps_doc_openwebtext_importance": -266.43817138671875,
"rps_doc_openwebtext_importance_length_correction": -266.43817138671875,
"rps_doc_wikipedia_importance": -166.61968994140625,
"rps_doc_wikipedia_importance_length_correction": -166.61968994140625
},
"fasttext": {
"dclm": 0.03526186943054199,
"english": 0.9370100498199463,
"fineweb_edu_approx": 2.300819158554077,
"eai_general_math": 0.0016410399693995714,
"eai_open_web_math": 0.12186163663864136,
"eai_web_code": 0.00007760999869788066
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "2",
"label": "Click Here References"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "2",
"label": "Partially Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
7,270,351,822,141,657,000 | Breast cancer research
Breast cancer research
By 18/12/2017 No Comments
Breast cancer research
Valerie Speirs, Professor of experimental pathology & oncology at the University of Aberdeen, is leading a three year study with PhD student Kerri Palmer, that hopes to identify an effective strategy for preventing breast cancer. The project, in collaboration with our friends at Breast Cancer UK, is exploring if hormone disrupting chemicals we find in our environment are making the breast more vulnerable to breast cancer.
How does our research help humans?
1 in 8 women have a lifetime risk of developing breast cancer
1 in 8 women will develop breast cancer in their lifetime.
Breast cancer is the most common female cancer, affecting around 55,000 women in the UK every year. Women have a 1 in 8 chance of getting breast cancer in their lifetime, while men have a 1 in 870 lifetime chance.
When patients go through breast cancer screening, mammogram images are taken. These images reveal dark and light areas of the breast, which represent breast tissue density. Having dense breast tissue is a risk factor for breast cancer development; women with dense breasts have a four-to-six times increased risk of developing the disease.
We are also being exposed, increasingly, to a number of chemicals in our environment that can mimic the action of hormones. Researchers know that breast density is modified by hormones, but they don’t exactly know how it happens, or if hormone-mimics have the same effect.
Could fibroblasts be responsible for breast cancer development?
Fibroblasts are cells that contribute to breast tissue density. They are found all over the body, including in the breast. Their main job is to make the structural framework that holds together cells in a tissue. They can also influence other cells found in the breast – the same cells that breast cancer causes to uncontrollably grow and develop into tumours. Scientists believe that women with dense breasts have a higher risk of developing breast cancer due to the activity of fibroblasts.
Fibroblasts can respond to hormones. If we can understand how hormones affect fibroblasts and therefore how they influence breast density, then we may be able to uncover ways to target fibroblasts, to reduce the risk of people developing breast cancer and save more lives.
What is breast tissue density?
The density of breast tissue varies between different women. Some breasts contain mostly fat, which appears dark on a mammogram. These breasts are therefore termed ‘low mammographic density’. Other breasts contain mostly standard cells that make up the breast and other types of cells that help support and connect the breast cells together. These types of cells are more dense than fat cells and so appear lighter on a mammogram. Breasts like this are thus termed ‘high mammographic density’. Women with dense breast tissue (high mammographic density) have an increased risk of developing breast cancer.Help us continue this vital work - button
What are endocrine disrupting chemicals and how do they affect breast tissue?
Prevention of breast cancer costs less than treating breast cancer
Currently more money is invested into research that treats breast cancer, rather than preventing it. We are researching how breast cancer can be prevented, to save more lives.
Chemicals that can mimic the action of hormones are known as endocrine disrupting agents. These agents can be naturally occurring (such as those found in some types of plants) but most are artificial (such as those found in some plastics, personal care products, cosmetics, domestic cleaning products, food and drink).
The hormone oestrogen can stimulate cell growth in both healthy and potentially cancerous cells. Breast tissue is sensitive to oestrogenic hormones. Continued low-level exposure to endocrine disrupting agents over time can interfere with (or mimic) the action of oestrogenic hormones. This can sometimes have detrimental effects in hormone-sensitive tissues, such as breast tissue, as it can trigger events in cells that result in unwanted responses.
How are we studying breast cancer development using human-relevant animal free research?
Through engagement with pathologists, who concentrate on what tissues look like in order to diagnose disease, the team are building animal free breast cancer models. These models reflect human disease because the researchers are ensuring that they look and behave like human breast tissues.
Human disease can only be examined properly using human tissue.
Importantly, the research is not use any animals or animal-derived materials. It is being carried out using fibroblasts generated from human breast tissue, of consenting patients, with different mammographic densities.
The team are working with clinicians to explore how human breast fibroblasts respond to endocrine disrupting agents. Complex 3D laboratory models are used to examine how this may contribute to breast cancer development.
Our models are helping us address how cells called fibroblasts may affect breast cancer development. This question cannot be modelled successfully in mice because human fibroblasts are very rapidly replaced by mouse fibroblasts when they are used in mouse models.
What is the impact on animals used for research?
Professor Valerie Speirs identified, during a search of the scientific literature in July 2017, 3016 publications in the last 5 years that have used animal models to study breast cancer, including 109 with UK-based authors. These were mainly mouse models and included the 3 major types of models: genetically engineered mouse models, patient-derived xenografts (transplants) and cell line-derived xenograft models.
A typical mouse experiment usually includes four groups of 10 mice. Of these publications from UK groups, it is estimated that more than 4000 mice would have been killed, excluding any required for breeding programme, which can often run into thousands. The severity levels for these types of experiments are mostly moderate.
Professor Speirs’ research aims to replace two animal models of breast cancer, which are used currently by scientists, by using fully humanised animal free models.Help us continue this vital work - button
Page last modified on March 4, 2020 12:26 pm
Share this page | {
"url": "https://www.animalfreeresearchuk.org/project/breast-cancer-research/",
"source_domain": "www.animalfreeresearchuk.org",
"snapshot_id": "crawl=CC-MAIN-2020-34",
"warc_metadata": {
"Content-Length": "233580",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:CTE5MJ5UJORLSJU3VGC4M7QISOMJYF3B",
"WARC-Concurrent-To": "<urn:uuid:013b1a48-5684-420a-a369-b2d4d915b730>",
"WARC-Date": "2020-08-14T05:02:41",
"WARC-IP-Address": "35.214.65.154",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:UMUBZHFLTGZIXU6SDNGCWJRCA7H7ZNIX",
"WARC-Record-ID": "<urn:uuid:371a5d5d-7ef1-4f6f-b950-6b1ec31e415e>",
"WARC-Target-URI": "https://www.animalfreeresearchuk.org/project/breast-cancer-research/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:d7c13c91-a6f5-4c47-be04-31d8c94cd2f3>"
},
"warc_info": "isPartOf: CC-MAIN-2020-34\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-39.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
23,
24,
47,
48,
74,
75,
98,
99,
525,
526,
561,
562,
624,
625,
684,
685,
900,
901,
1241,
1242,
1515,
1516,
1580,
1581,
2074,
2075,
2348,
2349,
2380,
2381,
3027,
3028,
3106,
3107,
3174,
3175,
3351,
3352,
3671,
3672,
4123,
4124,
4213,
4214,
4505,
4506,
4570,
4571,
4790,
4791,
5011,
5012,
5276,
5277,
5326,
5327,
5742,
5743,
6069,
6070,
6275,
6276,
6321,
6322
],
"line_end_idx": [
23,
24,
47,
48,
74,
75,
98,
99,
525,
526,
561,
562,
624,
625,
684,
685,
900,
901,
1241,
1242,
1515,
1516,
1580,
1581,
2074,
2075,
2348,
2349,
2380,
2381,
3027,
3028,
3106,
3107,
3174,
3175,
3351,
3352,
3671,
3672,
4123,
4124,
4213,
4214,
4505,
4506,
4570,
4571,
4790,
4791,
5011,
5012,
5276,
5277,
5326,
5327,
5742,
5743,
6069,
6070,
6275,
6276,
6321,
6322,
6337
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 6337,
"ccnet_original_nlines": 64,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3603202700614929,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0053380802273750305,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.13345195353031158,
"rps_doc_frac_unique_words": 0.39409369230270386,
"rps_doc_mean_word_length": 5.29327917098999,
"rps_doc_num_sentences": 54,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.326072692871094,
"rps_doc_word_count": 982,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.06271643191576004,
"rps_doc_frac_chars_dupe_6grams": 0.041554439812898636,
"rps_doc_frac_chars_dupe_7grams": 0.011927659623324871,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.06002309173345566,
"rps_doc_frac_chars_top_3gram": 0.02212388999760151,
"rps_doc_frac_chars_top_4gram": 0.012697190046310425,
"rps_doc_books_importance": -494.55804443359375,
"rps_doc_books_importance_length_correction": -494.55804443359375,
"rps_doc_openwebtext_importance": -268.35455322265625,
"rps_doc_openwebtext_importance_length_correction": -268.35455322265625,
"rps_doc_wikipedia_importance": -225.00233459472656,
"rps_doc_wikipedia_importance_length_correction": -225.00233459472656
},
"fasttext": {
"dclm": 0.11187344789505005,
"english": 0.9525519013404846,
"fineweb_edu_approx": 3.323159694671631,
"eai_general_math": 0.04069102182984352,
"eai_open_web_math": 0.10092681646347046,
"eai_web_code": 0.0018993000267073512
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.994072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "615.54",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "13",
"label": "News (Org.)"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
1,912,585,183,606,586,400 | changing the world, one period at a time.
The Immune System and Your Cycle
The Immune System and Your Cycle
The Immune System and Your Cycle
During your menstrual cycle, hormones fluctuate. While most of us are aware that these fluctuating hormones impact ovulation, endometrial growth, and your period; it is less commonly known that they also have impacts on your immune system to ensure that fertilization could occur. There is a spike of estrogen which induces ovulation (when an egg is released from the ovary), and the luteal phase begins. During the luteal phase, estrogen and progesterone rise causing the endometrium to grow and thicken, creating a more suitable site for implantation of the fertilized egg. When the egg is not fertilized, estrogen and progesterone levels decrease and you get your period. The thickened endometrium sheds resulting in bleeding for a few days. Then the cycle starts again. There are many studies that also show that progesterone suppresses inflammatory/immune cells. This is important during the luteal phase so that your immune system does not attack the incoming sperm or recently fertilized egg; therefore, increases the chance that implantation can occur and a fetus develops. However, this also means that anytime during the 14 days of your luteal phase (the 14 days leading up to the start of your period) your immune system is suppressed, increasing your chance of getting an infection. Once your period starts and progesterone levels drop and your immune system ramps back up again to normal levels.
Follicular phase: Day 0 to day 14
During the follicular phase, one egg matures into a mature ovum to be released during ovulation. The first 5-7 days of the follicular phase is when your period occurs. After, estrogen levels begin to rise and the uterus begins to prep for possible implantation as the endometrium begins to regrow. Progesterone levels are low during the follicular phase and your immune system is working at its full capacity.
Luteal phase: Day 14 to day 28
The spike in estrogen at the end of the follicular phase induces ovulation of the mature egg, and its release into the Fallopian tubes to travel to the uterus. Progesterone and estrogen levels rise again, causing the endometrium to grow and thicken and suppress the immune system to improve chances of fertilization and growth of a fetus. Regardless of whether you are trying to get pregnant or not, your immune system is suppressed during this phase due to the rise in progesterone.
With this, it is important to take extra precautions during the 14 days before your period starts. Washing your hands, stay up to date on recommended vaccines, exercise regularly, maintain a healthy diet, stay hydrated, get sleep, and minimize stress. These are great life practices in general, but it is good to understand when your body is more vulnerable to disease. If you find yourself getting sick often and knowing that you have hormone imbalance we highly recommend you have hormone D checked- also known as vitamin D this hormone widely impacts our cycle and the connection to our immune system. Taking your vitamin D supplement with a K2 vitamin is the best way to guarantee absorption. The more you know and the more you are aware of the way you body functions, the more you can protect your body naturally and embrace your menstrual cycle as a beautiful, intricate part of life.
Divine drops was started by a registered nurse who was personally feeling the pain and mental struggle of hormone imbalance and cycle shame. After traveling as a nurse she realized that the problem was bigger than just her. Girls all over the world were experiencing similar feelings but even worse they lacked the products needed to live a powerful period. This was limiting their future and full potential.
Since then she started Divine Drops, a nonprofit that provides cycle education and sustainable menstrual products to menstruators all over the world. You can make a purchase or donation today to help change the cycle.
| {
"url": "https://divinedrops.org/blogs/news/the-immune-system-and-your-cycle",
"source_domain": "divinedrops.org",
"snapshot_id": "CC-MAIN-2023-14",
"warc_metadata": {
"Content-Length": "340475",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:BFDPI3X64PSN5VDPBB74XVRQGZ2NMK6R",
"WARC-Concurrent-To": "<urn:uuid:b9360d5f-be87-4ae6-b67e-249c5d0e8aa5>",
"WARC-Date": "2023-03-25T08:24:33",
"WARC-IP-Address": "23.227.38.65",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:YAVFZJWAO6IJDVXHVLP2IWJ7XYJS5OFQ",
"WARC-Record-ID": "<urn:uuid:016931b8-cdb1-4822-b0c8-bce518b3fdb3>",
"WARC-Target-URI": "https://divinedrops.org/blogs/news/the-immune-system-and-your-cycle",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:d96eecc0-e4d9-4898-ae72-41e10d4bba9f>"
},
"warc_info": "isPartOf: CC-MAIN-2023-14\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for March/April 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-179\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
42,
43,
76,
77,
110,
111,
112,
146,
147,
1557,
1558,
1560,
1561,
1595,
1596,
2007,
2008,
2010,
2011,
2042,
2043,
2528,
2529,
2531,
2532,
3424,
3425,
3427,
3428,
3837,
3838,
4056,
4057
],
"line_end_idx": [
42,
43,
76,
77,
110,
111,
112,
146,
147,
1557,
1558,
1560,
1561,
1595,
1596,
2007,
2008,
2010,
2011,
2042,
2043,
2528,
2529,
2531,
2532,
3424,
3425,
3427,
3428,
3837,
3838,
4056,
4057,
4058
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4058,
"ccnet_original_nlines": 33,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4170040488243103,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.005398110020905733,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.10391362756490707,
"rps_doc_frac_unique_words": 0.409836083650589,
"rps_doc_mean_word_length": 4.898658752441406,
"rps_doc_num_sentences": 31,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.9975690841674805,
"rps_doc_word_count": 671,
"rps_doc_frac_chars_dupe_10grams": 0.02464253082871437,
"rps_doc_frac_chars_dupe_5grams": 0.0641922727227211,
"rps_doc_frac_chars_dupe_6grams": 0.047155458480119705,
"rps_doc_frac_chars_dupe_7grams": 0.047155458480119705,
"rps_doc_frac_chars_dupe_8grams": 0.02464253082871437,
"rps_doc_frac_chars_dupe_9grams": 0.02464253082871437,
"rps_doc_frac_chars_top_2gram": 0.04015820100903511,
"rps_doc_frac_chars_top_3gram": 0.029205959290266037,
"rps_doc_frac_chars_top_4gram": 0.016428349539637566,
"rps_doc_books_importance": -326.6450500488281,
"rps_doc_books_importance_length_correction": -326.6450500488281,
"rps_doc_openwebtext_importance": -203.49136352539062,
"rps_doc_openwebtext_importance_length_correction": -203.49136352539062,
"rps_doc_wikipedia_importance": -82.50560760498047,
"rps_doc_wikipedia_importance_length_correction": -82.50560760498047
},
"fasttext": {
"dclm": 0.48070329427719116,
"english": 0.9440851807594299,
"fineweb_edu_approx": 2.754417657852173,
"eai_general_math": 0.020234469324350357,
"eai_open_web_math": 0.2338804006576538,
"eai_web_code": 0.006704030092805624
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "612.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
},
"secondary": {
"code": "616.07",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-6,932,129,901,443,347,000 | What Do Stress Hives Look Like? Signs & Symptoms
Medically Reviewed on 3/7/2022
What Do Stress Hives Look Like
Stress hives can look like insect bites—red, swollen, itchy bumps with irregular shapes. They may initially appear as individual bumps but combine to form larger patches
Stress hives can look like insect bites—red, swollen, itchy bumps with irregular shapes. They may initially appear as individual bumps but combine to form larger patches, especially if you scratch them.
Most hives are caused by allergic reactions. However, if there is no other cause that can be traced, the problem could be stress. Such hives are referred to as stress hives.
How do you know if hives are stress-related?
In order to determine whether your hives or rash are caused by stress or something else, try to recall any new products you may have tried in the past 7 days:
• Is it a new food, such as one that contains peanuts or soy?
• Is it a new laundry detergent?
• Is it a new perfume you are using for the first time?
• Did you get a new pet?
If the answer to these questions is “no” and you have been under a lot of stress recently, it could be that your hives are caused by stress. High stress levels cause the release of cortisol, which is a hormone that can result in inflammatory responses and histamine release in the body if levels stay elevated for a long period of time.
When you scratch your hives, more histamines are released, which just creates more hives. This can lead to a vicious, frustrating cycle.
How are stress hives treated?
Most stress hives should resolve on their own within 24 hours with over-the-counter medications such as antihistamines. These include:
To relieve itching, you can try home remedies such as:
• Applying a cold compress for about 10-5 minutes 4-5 times a day
• Using topical steroids such as hydrocortisone
• Avoiding exposure to potential triggers
If the hives persist even after 24 hours have passed, consult a dermatologist.
How to manage stress
If you have been diagnosed with stress hives, you can try various stress management techniques such as:
• Deep breathing exercises
• Meditation
• Taking breaks or going for a walk
• Calling your family or friends to vent about your feelings
• Engaging in a hobby you enjoy
• Eating a balanced diet rich in healthy fats, such as walnuts, avocados, and fatty fish
• Exercising for at least 30 minutes a day
QUESTION
Ringworm is caused by a fungus. See Answer
Health Solutions From Our Sponsors
Medically Reviewed on 3/7/2022
References
Image Source: iStock Images
Marks H. Effects of Stress on Your Skin. WebMD. https://www.webmd.com/beauty/the-effects-of-stress-on-your-skin
American Academy of Dermatology. Hives: Self-care. https://www.aad.org/public/diseases/a-z/hives-self-care | {
"url": "https://www.medicinenet.com/what_do_stress_hives_look_like/article.htm",
"source_domain": "www.medicinenet.com",
"snapshot_id": "crawl=CC-MAIN-2022-21",
"warc_metadata": {
"Content-Length": "182888",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ALFEJZXEOKMNWQV6VAMUBM4H75WTDTZL",
"WARC-Concurrent-To": "<urn:uuid:8677133a-6297-4660-a9ee-b64a2e05c328>",
"WARC-Date": "2022-05-24T02:39:30",
"WARC-IP-Address": "172.64.153.161",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:JO7JK4PKGMUGXMA2XP6HKAMQJSPMBGV5",
"WARC-Record-ID": "<urn:uuid:b5f84d22-f106-477d-a134-62341d7aa2ac>",
"WARC-Target-URI": "https://www.medicinenet.com/what_do_stress_hives_look_like/article.htm",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:43683a81-4a95-4e8f-bedf-a1dd43e43c8f>"
},
"warc_info": "isPartOf: CC-MAIN-2022-21\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2022\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-253\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.3-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
49,
50,
81,
112,
282,
283,
486,
487,
661,
662,
707,
708,
867,
868,
932,
967,
1025,
1052,
1053,
1391,
1392,
1529,
1530,
1560,
1561,
1696,
1697,
1752,
1753,
1822,
1872,
1916,
1917,
1996,
1997,
2018,
2019,
2123,
2124,
2154,
2169,
2207,
2270,
2304,
2395,
2440,
2441,
2450,
2451,
2494,
2495,
2530,
2531,
2562,
2573,
2601,
2602,
2714,
2715
],
"line_end_idx": [
49,
50,
81,
112,
282,
283,
486,
487,
661,
662,
707,
708,
867,
868,
932,
967,
1025,
1052,
1053,
1391,
1392,
1529,
1530,
1560,
1561,
1696,
1697,
1752,
1753,
1822,
1872,
1916,
1917,
1996,
1997,
2018,
2019,
2123,
2124,
2154,
2169,
2207,
2270,
2304,
2395,
2440,
2441,
2450,
2451,
2494,
2495,
2530,
2531,
2562,
2573,
2601,
2602,
2714,
2715,
2821
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2821,
"ccnet_original_nlines": 59,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.35972461104393005,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.003442340064793825,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1979345977306366,
"rps_doc_frac_unique_words": 0.5032538175582886,
"rps_doc_mean_word_length": 4.81561803817749,
"rps_doc_num_sentences": 30,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.02425479888916,
"rps_doc_word_count": 461,
"rps_doc_frac_chars_dupe_10grams": 0.12702703475952148,
"rps_doc_frac_chars_dupe_5grams": 0.1617117077112198,
"rps_doc_frac_chars_dupe_6grams": 0.14954954385757446,
"rps_doc_frac_chars_dupe_7grams": 0.12702703475952148,
"rps_doc_frac_chars_dupe_8grams": 0.12702703475952148,
"rps_doc_frac_chars_dupe_9grams": 0.12702703475952148,
"rps_doc_frac_chars_top_2gram": 0.03963964059948921,
"rps_doc_frac_chars_top_3gram": 0.014864860102534294,
"rps_doc_frac_chars_top_4gram": 0.008108110167086124,
"rps_doc_books_importance": -264.97418212890625,
"rps_doc_books_importance_length_correction": -264.97418212890625,
"rps_doc_openwebtext_importance": -156.16175842285156,
"rps_doc_openwebtext_importance_length_correction": -156.16175842285156,
"rps_doc_wikipedia_importance": -83.60027313232422,
"rps_doc_wikipedia_importance_length_correction": -83.60027313232422
},
"fasttext": {
"dclm": 0.05791730061173439,
"english": 0.9294022917747498,
"fineweb_edu_approx": 2.8911406993865967,
"eai_general_math": 0.07617712020874023,
"eai_open_web_math": 0.355812132358551,
"eai_web_code": 0.0007509000133723021
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
8,070,980,034,512,729,000 | Call Now
(318) 550-3059
Chat Now
With a Counselor
Addiction Treatment Therapy in Shreveport, LA
Most drug and alcohol rehab programs involve some form of addiction treatment therapy. Addiction treatment therapy is exactly what it sounds like: a therapy program, usually involving a "talking method" or one-on-one session with a knowledgeable therapist, though they can sometimes it prescriptions for certain mood medications. 12 Step Programs, such as the one made famous by Alcoholics Anonymous, involve several kinds of addiction treatment therapy as you move from an addicted life into a sober one. Addiction is an ongoing illness that cannot be cured, but a good therapy program is an essential part of reinventing yourself into a healthier, happier person.
Types of Addiction Treatment
Addiction treatment therapy comes in four main varieties: cognitive, family, motivational interviewing, and motivational incentivizing.
Cognitive Therapy
Cognitive therapy is one of the most common and most basic. It involves working with a therapist to identify "triggers" or certain behaviors and habits you may have that could lead you back into addiction. This might include hanging out with a group of friends who encourage you to drink, coping with work-related stress by smoking, or maintaining an abusive relationship which you seek solace from in drugs.
Cognitive therapy helps you identify these triggers and cope with or avoid them. It also helps you manage cravings that will inevitably crop up in the weeks and months after you have completed rehab, teaching you how to spot them early and avoid putting yourself in situations where they can be acted upon.
Family Therapy
Family therapy expands this logic to the rest of your family. Oftentimes, addiction arises as the result of a dysfunctional home life, or is allowed to continue due to the ignorance or unawareness of family members. Involving them in therapy helps you build a safer and healthier living situation for you all.
Motivational Interviewing
Motivational interviewing and incentivizing help you build a positive outlook, making you excited about the prospect of sobriety whereas otherwise you may have simply viewed it as a chore. It sounds cheesy but it's been proven to be effective. Many ex-addicts report an extremely optimistic worldview after completing motivational therapy, an attitude they seek to maintain through remaining sober.
Other Types of Therapy
Types of treatment vary from program to program, ranging from developing eclectic hobbies to intensive therapy sessions. Art and music therapy, for instance, have been shown to increase quality of life and mental health for many recovering addicts. Learning a new avenue of self-expression, such as a musical instrument or a visual art style, helps addicts cope with their inner feelings better.
Certain fitness programs like yoga or hiking are also offered by some recovery programs, making many ex-addicts unwilling to relapse lest they sacrifice their newly-conditioned physique. SMART Recovery is a new phenomenon in addiction counseling, offering a detailed program with a devoted community of professionals and ex-addicts eager to offer their support at any time.
Other programs offer a spiritual component to their addiction treatment therapy, offering support and wisdom from religious leaders who have dedicated their lives to helping others.
Choosing an Addiction Treatment
With such an overwhelming array of drug rehab options to choose from, it's important to decide what will benefit you personally in the best way. No two people respond to therapy the same way, and there are a variety of biological and environment factors that can determine how prone you are to relapse. Some people come from dysfunctional homes, or have suffered traumas in their lives, and others are simply genetically predisposed towards addiction.
Rest assured, all of these factors are accounted for by addiction therapy programs, which are constantly being updated with the latest data regarding effective addiction treatment. It's not an easy process, but addiction can be managed, and with a good program helping you, sober living is absolutely within your reach.
Call Drug Treatment Shreveport now at (318) 550-3059.
Get Started on The Journey To Recovery Today!
Chat With a Counselor Call Us Now (318) 550-3059 | {
"url": "https://drugtreatmentshreveport.com/addiction-treatment-therapy-shreveport/",
"source_domain": "drugtreatmentshreveport.com",
"snapshot_id": "crawl=CC-MAIN-2018-26",
"warc_metadata": {
"Content-Length": "53982",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:RTEAKAZPSWYMVML4FNVFRKXDD2CI4PZY",
"WARC-Concurrent-To": "<urn:uuid:092dcaee-fe4b-4147-9cc0-cd1127935acc>",
"WARC-Date": "2018-06-22T11:07:48",
"WARC-IP-Address": "104.25.133.26",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:II4CB2KT2VAKEN6OTACY6PPNX4VKUKLW",
"WARC-Record-ID": "<urn:uuid:a7ce32a3-294b-4cff-ad8a-e7c47e6aa008>",
"WARC-Target-URI": "https://drugtreatmentshreveport.com/addiction-treatment-therapy-shreveport/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0393bc5d-fb4f-4c68-9184-436ef23081ca>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-91-167-62.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2018-26\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for June 2018\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
9,
24,
33,
50,
51,
97,
98,
764,
765,
794,
795,
931,
932,
950,
951,
1360,
1361,
1668,
1669,
1684,
1685,
1995,
1996,
2022,
2023,
2422,
2423,
2446,
2447,
2843,
2844,
3218,
3219,
3401,
3402,
3434,
3435,
3887,
3888,
4208,
4209,
4263,
4264,
4310,
4311
],
"line_end_idx": [
9,
24,
33,
50,
51,
97,
98,
764,
765,
794,
795,
931,
932,
950,
951,
1360,
1361,
1668,
1669,
1684,
1685,
1995,
1996,
2022,
2023,
2422,
2423,
2446,
2447,
2843,
2844,
3218,
3219,
3401,
3402,
3434,
3435,
3887,
3888,
4208,
4209,
4263,
4264,
4310,
4311,
4359
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4359,
"ccnet_original_nlines": 45,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40102827548980713,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0025706898886710405,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1272493600845337,
"rps_doc_frac_unique_words": 0.4740740656852722,
"rps_doc_mean_word_length": 5.296296119689941,
"rps_doc_num_sentences": 30,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.275961875915527,
"rps_doc_word_count": 675,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.045314688235521317,
"rps_doc_frac_chars_top_3gram": 0.0419580414891243,
"rps_doc_frac_chars_top_4gram": 0.015104900114238262,
"rps_doc_books_importance": -332.7203063964844,
"rps_doc_books_importance_length_correction": -332.7203063964844,
"rps_doc_openwebtext_importance": -240.84808349609375,
"rps_doc_openwebtext_importance_length_correction": -240.84808349609375,
"rps_doc_wikipedia_importance": -184.19900512695312,
"rps_doc_wikipedia_importance_length_correction": -184.19900512695312
},
"fasttext": {
"dclm": 0.02867705002427101,
"english": 0.9498568773269653,
"fineweb_edu_approx": 1.846594214439392,
"eai_general_math": 0.004839600063860416,
"eai_open_web_math": 0.10251325368881226,
"eai_web_code": 0.0021895798854529858
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.89",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-5,540,465,960,693,663,000 | sexologist-icon
Please Help me
Respected Sir I have two kids already and i dont want any more child. Is there any tablet by which my wife can consume that and not get pregnant for life. Or any other easy solution ?
views-icons 24 Views Mail QnA Whatsapp QnA v
Like the answers? Chat privately for 24 hours with the doctor of your choice
doctor profile image
Harisha N L
General Physician 3 yrs exp Bangalore
Free 3 day follow up
Chat Now
₹250 for 24 hrs
Hi there I understand your concern and anxiety.... There is no tablets for life time...tablets can be given for temporary period... If you want permanent methods she can go for sterilization techniques...even you can get it done its a minor procedure in male and it's easier and time saving as well... Consult nearest obg specialist they will do the needful.
Answered
Flag this Answer
Flag this answer
Let others know if this answer was helpful
Was this answer helpful?
YES NO | {
"url": "https://www.practo.com/consult/please-help-me-respected-sir-i-have-two-kids-already-and-i-dont-want-any-more-child-is-there-any-tablet-by-which/q",
"source_domain": "www.practo.com",
"snapshot_id": "crawl=CC-MAIN-2017-22",
"warc_metadata": {
"Content-Length": "54518",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:L2TRJNMLJVTPU6N56NV5ZNPD2UL3HVNN",
"WARC-Concurrent-To": "<urn:uuid:4abda5d9-0614-4b9a-991b-7fb7c79c6f2a>",
"WARC-Date": "2017-05-24T18:22:32",
"WARC-IP-Address": "104.17.28.29",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:TXEHDCBGWJNUSAKLG7HHTLKLGGAI436I",
"WARC-Record-ID": "<urn:uuid:5c150447-61e6-4827-a08e-82e1f73001ef>",
"WARC-Target-URI": "https://www.practo.com/consult/please-help-me-respected-sir-i-have-two-kids-already-and-i-dont-want-any-more-child-is-there-any-tablet-by-which/q",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:75a4e37d-511e-49a0-89d0-6af6441a8111>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-185-224-210.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-22\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for May 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
16,
17,
32,
33,
217,
262,
263,
340,
341,
362,
374,
412,
413,
434,
435,
444,
445,
461,
462,
821,
830,
847,
864,
907,
932
],
"line_end_idx": [
16,
17,
32,
33,
217,
262,
263,
340,
341,
362,
374,
412,
413,
434,
435,
444,
445,
461,
462,
821,
830,
847,
864,
907,
932,
938
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 938,
"ccnet_original_nlines": 25,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3978494703769684,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.032258059829473495,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11290322989225388,
"rps_doc_frac_unique_words": 0.7349397540092468,
"rps_doc_mean_word_length": 4.451807022094727,
"rps_doc_num_sentences": 12,
"rps_doc_symbol_to_word_ratio": 0.02688172087073326,
"rps_doc_unigram_entropy": 4.665643215179443,
"rps_doc_word_count": 166,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.054127201437950134,
"rps_doc_frac_chars_top_3gram": 0.037889041006565094,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -83.0272216796875,
"rps_doc_books_importance_length_correction": -83.0272216796875,
"rps_doc_openwebtext_importance": -39.67778778076172,
"rps_doc_openwebtext_importance_length_correction": -27.363601684570312,
"rps_doc_wikipedia_importance": -33.228187561035156,
"rps_doc_wikipedia_importance_length_correction": -33.228187561035156
},
"fasttext": {
"dclm": 0.2904353141784668,
"english": 0.9252916574478149,
"fineweb_edu_approx": 0.8457897901535034,
"eai_general_math": 0.0033586600329726934,
"eai_open_web_math": 0.17842638492584229,
"eai_web_code": 0.00023859999782871455
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "618.1",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Women — Health and hygiene, Children — Health and hygiene, Gynecology, and Pediatrics"
}
},
"secondary": {
"code": "618.9288",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Women — Health and hygiene, Children — Health and hygiene, Gynecology, and Pediatrics"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "21",
"label": "Customer Support"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-6,517,577,810,487,088,000 | Nutrition Gov
Historic Dietary Steering Digital Collection
All the organisms aren’t capable of producing meals on their own, such organisms depend primarily on others for their nutrition. The organisms that are not capable of producing their very own meals and depend on the opposite organisms or sources are often known as heterotrophs, and this mode of vitamin known as heterotrophic vitamin. Plants uptake essential components from the soil via their roots and from the air by way of their leaves. Nutrient uptake within the soil is achieved by cation trade, whereby root hairs pump hydrogen ions (H+) into the soil by way of proton pumps. These hydrogen ions displace cations connected to negatively charged soil particles in order that the cations are available for uptake by the root. In the leaves, stomata open to take in carbon dioxide and expel oxygen.
Nutrients are substances that provide energy and physical components to the organism, allowing it to survive, develop, and reproduce. Approximately 30 components are found in organic matter, with nitrogen, carbon, and phosphorus being an important. Macronutrients are the primary substances required by an organism, and micronutrients are substances required by an organism in hint amounts. Organic micronutrients are categorized as vitamins, and inorganic micronutrients are classified as minerals. The organisms which can’t produce meals on their own and rely upon other sources/organisms are known as heterotrophs. Other than photosynthesis, plants also rely upon soil for micro and macro elements. These components are used to synthesize proteins and other essential compounds required for the proper functioning and progress of the vegetation.
They usually are not soluble in water, and they can retailer energy for an extended time frame. They may be obtained from many alternative plant and animal sources. Most dietary lipids are triglycerides, composed of glycerol and fatty acids. An animal’s physique will cut back the amount of fatty acids it produces as dietary fats consumption increases, while it will increase the quantity of fatty acids it produces as carbohydrate consumption will increase. A balanced food plan reduces the danger of diseases and improves the overall well being of an organism.
Although nitrogen is plentiful within the Earth’s ambiance, very few plants can use this immediately. Most plants, due to this fact, require nitrogen compounds to be current within the soil by which they grow. This is made potential by the fact that largely inert atmospheric nitrogen is modified in a nitrogen fixation course of to biologically usable forms within the soil by bacteria. Undernutrition can lead to wasting in acute cases, and stunting of marasmus in continual circumstances of malnutrition.
Heterotrophic Nutrition
nutrition
Latest Articles
Like some of them depend on vegetation for vitamin often known as herbivores and others depend on an animal known as carnivores. Also, there are some heterotrophs that eat each crops and animals. Carbohydrates are molecules that store important quantities of vitality. Animals digest and metabolize carbohydrates to obtain this power. Carbohydrates are typically Food Cooking News synthesized by plants throughout metabolism, and animals have to … Read More
Read More
Fundamental Nutrition
All residing organisms want nutrients for correct functioning and progress. Some animals feed on easy inorganic compounds to fulfill their nutrient requirement, while others utilise complex compounds. In this mode of nutrition, organisms use easy inorganic matters, similar to water and carbon dioxide in the presence of sunshine and chlorophyll to synthesize food on their own. It can also be mentioned as the process of photosynthesis, where gentle energy is converted into food similar to glucose, this kind of organisms are called autotrophs. Some of the examples where autotrophic vitamin is noticed in crops, algae, and micro organism . Organisms may be classified by how they get hold of carbon and vitality.
Animals are heterotrophs that devour different organisms to acquire vitamins. Herbivores are animals that eat plants, carnivores are animals that eat different animals, and omnivores are animals that eat both plants and different animals. Animals typically have a higher requirement of energy in comparison to vegetation. The macronutrients essential to animal life are carbohydrates, amino acids, and fatty acids. Foraging is the process of in search of out nutrients in the environment. It may also be defined to include the following use of the resources.
Fourteenth Pacific Well Being Ministers Assembly, Digital Assembly, 22
Humans also can get hold of power from ethanol, which is each a food and a drug, but it offers relatively few essential vitamins and is related to dietary deficiencies and other well being dangers. The Chemical Revolution in the 18th century allowed people to study the vitamins in meals and develop more advanced methods of meals preparation. Major advances in economics and know-how through the twentieth century allowed mass production and food fortification to higher meet the nutritional needs of people. Human habits is carefully associated to human nutrition, making it a subject of social science along with biology. Nutrition in people is balanced with consuming for pleasure, and optimal diet might differ relying on the demographics and well being issues of each person.
Heterotrophs are organisms that get hold of vitamins by consuming the carbon of other organisms, while autotrophs are organisms that produce their own nutrients from the carbon of inorganic substances like carbon dioxide. Mixotrophs are organisms that may be heterotrophs and autotrophs, including some plankton and carnivorous plants. Phototrophs obtain power from mild, while chemotrophs obtain power by consuming chemical power from matter. Organotrophs consume other organisms to acquire electrons, while lithotrophs get hold of electrons from inorganic substances, corresponding to water, hydrogen sulfide, dihydrogen, iron, sulfur, or ammonium.
In different words, the method of photosynthesis is used to transform gentle energy into meals such as glucose. Plants, algae, and micro organism are some examples where autotrophic diet is observed. Humans get hold of most carbohydrates as starch from cereals, though sugar has grown in importance. Lipids can be present in animal fats, butterfat, vegetable oil, and leaf greens, and they are additionally used to increase taste in meals. Protein could be present in just about all foods, because … Read More
Read More
What Is Nutrition?
Fungi absorb nutrients round them by breaking them down and absorbing them by way of the mycelium. Nutrients are the substances which provide vitality and biomolecules needed for carrying out the various body features.
Vitamin And Food Safety Information
In different words, the process of photosynthesis is used to transform mild vitality into meals corresponding to glucose. Plants, algae, and micro organism are some examples where autotrophic diet is observed. Humans acquire most carbohydrates as starch from cereals, though sugar has grown in importance. Lipids can be found in animal fat, butterfat, vegetable oil, and leaf greens, and they’re additionally used to increase taste in meals. Protein can be found in virtually all meals, because it makes up mobile material, although sure strategies of food processing may scale back the quantity of protein in a meals.
Latest Articles
Heterotrophs are organisms that get hold of vitamins by consuming the carbon of different organisms, while autotrophs are organisms that produce their own nutrients from the carbon of inorganic substances like carbon dioxide. Mixotrophs are organisms that may be heterotrophs and autotrophs, including some plankton and carnivorous crops. Phototrophs get hold of power from light, whereas chemotrophs get hold of vitality by consuming chemical power from matter. Organotrophs consume different organisms to acquire electrons, whereas lithotrophs acquire electrons from inorganic substances, similar to water, hydrogen sulfide, dihydrogen, iron, sulfur, or ammonium.
All dwelling organisms need vitamins for proper functioning and growth. Some animals feed on easy inorganic compounds to satisfy their nutrient requirement, whereas others utilise complicated compounds. In this mode of diet, organisms use easy inorganic issues, corresponding to water and carbon dioxide in the presence of sunshine and chlorophyll to synthesize meals on their own. It can also Art Entertainment News be stated as the process of photosynthesis, where mild power is transformed into meals corresponding to glucose, this kind of organisms are called autotrophs. Some of the examples the place autotrophic nutrition is noticed in crops, algae, and bacteria . Organisms can be categorized by how they get hold of carbon and power.
Rice Nutritional Value Of Brown And White Rice
Prototrophs can create essential vitamins from other compounds, whereas auxotrophs must consume preexisting vitamins. In the autotrophic mode, organisms use simple inorganic issues like water and carbon dioxide within the presence of sunshine and chlorophyll to synthesize food on their very own.… Read More
Read More
Basic Nutrition
Rice Dietary Value Of Brown And White Rice
The first vitamin to be chemically recognized was thiamine in 1926, and the role of vitamins in nutrition was studied within the following decades. Plants exhibit an autotrophic mode of vitamin because they will put together their very own meals. Plants use daylight, water and carbon dioxide to provide energy during photosynthesis.
Migration patterns and seasonal breeding happen at the side of meals availability, and courtship displays are used to display an animal’s well being. Animals develop positive and adverse associations with foods that affect their health, they usually can instinctively avoid foods that have brought on poisonous damage or dietary imbalances through a conditioned food aversion. Some animals, corresponding to rats, don’t search out new forms of meals unless they’ve a nutrient deficiency. Scientific analysis of meals and vitamins began in the course of the chemical revolution within the late-18th century. Chemists within the 18th and nineteenth centuries experimented with completely different parts and food sources to develop theories of diet. Modern nutrition science started in the 1910s as particular person micronutrients started to be recognized.
nutrition
Like some of them rely upon vegetation for vitamin known as herbivores and others rely upon an animal often known as carnivores. Also, there are some heterotrophs that eat each crops and animals. Carbohydrates are molecules that retailer vital amounts of power. Animals digest and metabolize carbohydrates to acquire this power. Carbohydrates are usually synthesized by vegetation during metabolism, and animals need to obtain most carbohydrates from nature, as they’ve only a restricted capability to generate them. Carbohydrates are broken down to provide glucose and quick-chain fatty acids, and they’re essentially the most ample vitamins for herbivorous land animals.
Inside The 2022 White House Conference On Hunger, Nutrition, And Well Being
Fungi and all of the animals including humans are heterotrophs. Heterotrophs may be of many sorts depending upon their setting and diversifications. Some might eat crops and others eat animals whereas few eat each .
Thus we can say survival of heterotrophs relies upon immediately or not directly on vegetation. To carry out these actions a large amount of energy is required. Food is vital as it provides the power Legal News wanted for development, repair, and different life processes. All the animals and fungi are heterotrophs in nature, they are often of many varieties depending on their environment and the diversifications.
Nutrients are substances that provide vitality and physical elements to the organism, allowing it to survive, grow, and reproduce. Approximately 30 elements are present in natural matter, with nitrogen, carbon, and phosphorus being the most important. Macronutrients are the first substances required by an organism, and micronutrients are substances required by an organism in trace quantities. Organic micronutrients are categorized as vitamins, and inorganic micronutrients are categorized as minerals. The organisms which can not produce food on their very own and rely upon other sources/organisms are referred to as heterotrophs. Other than photosynthesis, plants also depend on soil for micro and macro … Read More
Read More
Nutrition Definition & Which Means
Get assets that can assist you eat a healthy diet with vegetables, fruits, protein, grains, and dairy foods. This work is framed by the Comprehensive implementation plan on maternal, infant, and young youngster nutrition, adopted by Member States by way of a World Health Assembly resolution in 2012. Malnutrition, in every kind, presents significant threats to human health. Today the world faces a double burden of malnutrition that features both undernutrition and chubby, especially in low- and center-income countries. There are a number of forms Travel News of malnutrition, together with undernutrition , inadequate nutritional vitamins or minerals, chubby, obesity, and ensuing diet-associated noncommunicable diseases. Better vitamin is related to improved toddler, baby and maternal health, stronger immune systems, safer pregnancy and childbirth, decrease risk of non-communicable ailments , and longevity. Holozoic vitamin is the mode of heterotrophic diet that includes ingestion, digestion, absorption and assimilation of strong and liquid material.
Meals Security Is A Challenge In Small Island Developing States
Explore meals, customs, and traditional recipes from a variety of cultures. In May 2018, the Health Assembly accredited the 13th General Programme of Work , which guides the work of WHO in 2019–2023.
This type of nutrition is exhibited by amoeba that takes in advanced substances and converts them into less complicated substances. MyPlate is a reminder to find and construct your healthy consuming fashion. It offers useful resources and instruments for monitoring your food intake and bodily activity.
Primary Nutrition
The minerals and vitamins in the soil is recycled back into the manufacturing of crops. Learn what meals and beverages can help you keep hydrated, and get the information on how a lot water to drink each day. Find printable handouts and reality sheets that can be utilized for health festivals, lessons, and other food or nutrition-associated occasions.
Dietary Patterns In The Living World
nutrition
Three communities develop plans to make healthier food service and procurement practices a reality. Learn how Nutrition.gov helps the USDA Research, Education, and Economics mission to create safe, sustainable food techniques in support of robust, healthy communities. Explore the history of dietary guidance and vitamin schooling from the 19th century to right now.… Read More
Read More | {
"url": "http://usppharm.com/tag/nutrition",
"source_domain": "usppharm.com",
"snapshot_id": "CC-MAIN-2024-22",
"warc_metadata": {
"Content-Length": "80325",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:VDAZUYFJ5EKGZXNC3NOVIRS6K3RACPNO",
"WARC-Concurrent-To": "<urn:uuid:c44dd050-bd23-4d16-8797-ba7d2b77fa00>",
"WARC-Date": "2024-05-26T18:57:55",
"WARC-IP-Address": "104.21.23.81",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:ZRETQFLO4RWR7QZOLV3NW57YRKTN5LET",
"WARC-Record-ID": "<urn:uuid:1ebe4349-183c-479d-9eb4-76a01f904e45>",
"WARC-Target-URI": "http://usppharm.com/tag/nutrition",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:bbcf37c2-7a37-4be6-8e01-e3f1723c6b7e>"
},
"warc_info": "isPartOf: CC-MAIN-2024-22\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-212\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
14,
15,
60,
61,
865,
866,
1715,
1716,
2280,
2281,
2789,
2790,
2814,
2815,
2825,
2826,
2842,
2843,
3301,
3302,
3312,
3313,
3335,
3336,
4052,
4053,
4612,
4613,
4684,
4685,
5467,
5468,
6119,
6120,
6630,
6631,
6641,
6642,
6661,
6662,
6881,
6882,
6918,
6919,
7538,
7539,
7555,
7556,
8222,
8223,
8966,
8967,
9014,
9015,
9323,
9324,
9334,
9335,
9351,
9352,
9395,
9396,
9730,
9731,
10587,
10588,
10598,
10599,
11272,
11273,
11349,
11350,
11566,
11567,
11984,
11985,
12707,
12708,
12718,
12719,
12754,
12755,
13819,
13820,
13884,
13885,
14085,
14086,
14390,
14391,
14409,
14410,
14764,
14765,
14802,
14803,
14813,
14814,
15192,
15193
],
"line_end_idx": [
14,
15,
60,
61,
865,
866,
1715,
1716,
2280,
2281,
2789,
2790,
2814,
2815,
2825,
2826,
2842,
2843,
3301,
3302,
3312,
3313,
3335,
3336,
4052,
4053,
4612,
4613,
4684,
4685,
5467,
5468,
6119,
6120,
6630,
6631,
6641,
6642,
6661,
6662,
6881,
6882,
6918,
6919,
7538,
7539,
7555,
7556,
8222,
8223,
8966,
8967,
9014,
9015,
9323,
9324,
9334,
9335,
9351,
9352,
9395,
9396,
9730,
9731,
10587,
10588,
10598,
10599,
11272,
11273,
11349,
11350,
11566,
11567,
11984,
11985,
12707,
12708,
12718,
12719,
12754,
12755,
13819,
13820,
13884,
13885,
14085,
14086,
14390,
14391,
14409,
14410,
14764,
14765,
14802,
14803,
14813,
14814,
15192,
15193,
15202
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 15202,
"ccnet_original_nlines": 100,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3815586268901825,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0019290100317448378,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1145833283662796,
"rps_doc_frac_unique_words": 0.30402448773384094,
"rps_doc_mean_word_length": 5.505249500274658,
"rps_doc_num_sentences": 118,
"rps_doc_symbol_to_word_ratio": 0.0019290100317448378,
"rps_doc_unigram_entropy": 5.6801981925964355,
"rps_doc_word_count": 2286,
"rps_doc_frac_chars_dupe_10grams": 0.13706794381141663,
"rps_doc_frac_chars_dupe_5grams": 0.2645212709903717,
"rps_doc_frac_chars_dupe_6grams": 0.23377035558223724,
"rps_doc_frac_chars_dupe_7grams": 0.20286054909229279,
"rps_doc_frac_chars_dupe_8grams": 0.17171235382556915,
"rps_doc_frac_chars_dupe_9grams": 0.1453317403793335,
"rps_doc_frac_chars_top_2gram": 0.003972980193793774,
"rps_doc_frac_chars_top_3gram": 0.006436230149120092,
"rps_doc_frac_chars_top_4gram": 0.006356770172715187,
"rps_doc_books_importance": -1264.358154296875,
"rps_doc_books_importance_length_correction": -1264.358154296875,
"rps_doc_openwebtext_importance": -683.5682373046875,
"rps_doc_openwebtext_importance_length_correction": -683.5682373046875,
"rps_doc_wikipedia_importance": -480.256103515625,
"rps_doc_wikipedia_importance_length_correction": -480.256103515625
},
"fasttext": {
"dclm": 0.20890921354293823,
"english": 0.9393208026885986,
"fineweb_edu_approx": 3.3010239601135254,
"eai_general_math": 0.14247524738311768,
"eai_open_web_math": 0.41331619024276733,
"eai_web_code": 0.0020403300877660513
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "577.1",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Biology and Anthropology",
"level_3": "Life (Biology)"
}
},
"secondary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "1",
"label": "Truncated Snippets"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "6",
"label": "Content Listing"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
6,633,694,460,687,309,000 | Share This Story
Are you facing numbness in hands? Then, it can be a serious sign of underlying health problems. Hand numbness is a condition where people lose sensation in their hands, this numbness can actually interfere with individuals day to day activities like holding, writing and several other reasons. This can be due to few health conditions like damaged nerves, diabetes, carpal tunnel syndrome, multiple sclerosis and so on. Hand numbness in few cases may also be caused due to severe cold, aging and etc.
Causes of Numbness
Let us know a little about the reasons or why actually numbness in hands happens.
Why numbness takes place?
Hand numbness is mainly caused due to damage of nerves present in the hands. Our hand contains several nerves which are connected to brain through neck or cervical spine. These nerves help in circulation and also supply oxygen and nutrients to your hands. When the supply to hands is interrupted due to damaged nerves, it leads to nerve pain, hand numbness, weakness and also loss of function. Day to day activities also leads to hand numbness like sleeping on the hand, sitting or standing in the same position for longer hours and so on. Due to these activities the nerves get pinched due to which the circulation is interrupted and leads to numbness.
Major reasons of numbness?
Numbness in hands is not a common problem seen in many people, it may be due to some underlying health illnesses. Here are few common hand numbness reasons
• Carpal tunnel syndrome
• Diabetic neuropathies
• Multiple sclerosis
• Alcohol disorders
• Cervical spondylosis
• Accidents or injury to spinal chord
• Tennis elbow
• Thyroid disorders
• Stroke
• Heart attack
• Insect or bug bites
• Anxiety and depression
• Vitamin B 12 deficiency
• Parkinson disease
• Exposure to severe cold or low temperatures
• Pinched nerve
• Osteoarthritis
• Rheumatoid arthritis
• Aging
• Due to side effects of few prescriptions
• Cysts
Numbness, in general for short term may be caused due to increased pressure on that particular nerve or may be due to high exposure to severe cold. People with this type of numbness for short period may recover when the pressure on that particular nerve is relieved. Hand numbness is seen in elders due to aging and weakness.
When we have to consult a specialist?
Numbness in hands should not be neglected especially when you face it for longer periods. It may be due to severe health issues and may also be due to life threatening diseases. Consult your doctor immediately if the condition of numbness worsens or spread to other areas gradually or if you face numbness immediately after head injury and so on. If you experience numbness in hands while sleeping, immediately consult a doctor and get tested to know the health status. Getting early diagnosis and treatment for hand numbness helps to control and avoid the further damage or worsening of the condition. If you are experiencing numbness in hands along with other symptoms like dizziness, weakness, confusion, severe headache and others, then it can be an emergency situation and it is important to meet your doctor and get treated.
0 | {
"url": "https://www.livehomeo.com/health-tips/why-regular-numbness-occur-in-hands/",
"source_domain": "www.livehomeo.com",
"snapshot_id": "crawl=CC-MAIN-2021-21",
"warc_metadata": {
"Content-Length": "200352",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ON6REWB4QRROFS35QP6SI2HSVUVOHX72",
"WARC-Concurrent-To": "<urn:uuid:ff085f50-ecc9-4ce7-8f8b-2a6b33d042c4>",
"WARC-Date": "2021-05-07T19:10:22",
"WARC-IP-Address": "209.126.8.170",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:7VFK75OYYXN5IRDFCK2C6GWUEIIVWUIL",
"WARC-Record-ID": "<urn:uuid:501e460b-33fc-4df8-ab7c-e17fa86f327d>",
"WARC-Target-URI": "https://www.livehomeo.com/health-tips/why-regular-numbness-occur-in-hands/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:dc496b3c-d1d4-46b0-9501-9a1ff8f750ba>"
},
"warc_info": "isPartOf: CC-MAIN-2021-21\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-61.ec2.internal\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
17,
18,
519,
520,
539,
540,
622,
623,
649,
650,
1304,
1305,
1332,
1333,
1489,
1490,
1517,
1543,
1566,
1588,
1613,
1653,
1670,
1692,
1703,
1720,
1744,
1771,
1799,
1821,
1869,
1887,
1906,
1931,
1941,
1986,
1996,
1997,
2323,
2324,
2362,
2363,
3194,
3195
],
"line_end_idx": [
17,
18,
519,
520,
539,
540,
622,
623,
649,
650,
1304,
1305,
1332,
1333,
1489,
1490,
1517,
1543,
1566,
1588,
1613,
1653,
1670,
1692,
1703,
1720,
1744,
1771,
1799,
1821,
1869,
1887,
1906,
1931,
1941,
1986,
1996,
1997,
2323,
2324,
2362,
2363,
3194,
3195,
3196
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3196,
"ccnet_original_nlines": 44,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3972366154193878,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0017271200194954872,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11398963630199432,
"rps_doc_frac_unique_words": 0.41044774651527405,
"rps_doc_mean_word_length": 4.7835822105407715,
"rps_doc_num_sentences": 26,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.851266860961914,
"rps_doc_word_count": 536,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.03198127821087837,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.025351010262966156,
"rps_doc_frac_chars_top_3gram": 0.03510139882564545,
"rps_doc_frac_chars_top_4gram": 0.011700470000505447,
"rps_doc_books_importance": -275.18682861328125,
"rps_doc_books_importance_length_correction": -275.18682861328125,
"rps_doc_openwebtext_importance": -130.53677368164062,
"rps_doc_openwebtext_importance_length_correction": -130.53677368164062,
"rps_doc_wikipedia_importance": -91.65904998779297,
"rps_doc_wikipedia_importance_length_correction": -91.65904998779297
},
"fasttext": {
"dclm": 0.018780410289764404,
"english": 0.9417271018028259,
"fineweb_edu_approx": 2.904491662979126,
"eai_general_math": 0.028534110635519028,
"eai_open_web_math": 0.3152264356613159,
"eai_web_code": 0.0013605400454252958
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
4,636,120,951,058,526,000 | Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: A stereological and three-dimensional ultrastructural study
Donohue, H.S.; Gabbott, P.L.A.; Davies, H.A.; Rodriguez, J.J.; Cordero, M.I.; Sandi, C.; Medvedev, N.I.; Popov, V.I.; Colyer, F.M.; Peddie, C.J. and Stewart, M.G. (2006). Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: A stereological and three-dimensional ultrastructural study. Neuroscience, 140(2) pp. 597–606.
DOI: https://doi.org/10.1016/j.neuroscience.2006.02.072
Abstract
Abstract
Chronic restraint stress is known to affect the morphology and synaptic organization of the hippocampus, predominantly within CA3 but also in CA1 and dentate gyrus. In this study, we provide the first evidence for specific ultrastructural alterations affecting asymmetric axo-spinous synapses in CA1 stratum lacunosum-moleculare following chronic restraint stress (6 h/day, 21 days) in the rat. The structure of asymmetric axo-spinous post-synaptic densities was investigated using serial section three-dimensional reconstruction procedures in control (n=4) and chronic restraint stress (n=3) animals. Dendritic spine profiles (spine head+neck) associated with the sampled synaptic contacts (30 per animal) were also reconstructed in three-dimensions.
Morphometric analyses revealed a significant increase in post-synaptic density surface area (+36%; P=0.03) and a highly significant increase in post-synaptic density volume (+79%; P=0.003) in the chronic restraint stress group. These changes were directly associated with ‘non-macular’ (perforated, complex and segmented) post-synaptic densities. A highly significant overall increase in the ‘post-synaptic density surface area/spine surface area’ ratio was also detected in the chronic restraint stress group (+27%; P=0.002). In contrast, no quantitative changes in spine parameters were found between groups. The Cavalieri method was used to assess the effects of chronic restraint stress exposure upon CA1 hippocampal volume. The mean volume of total dorsal anterior CA1 hippocampus was significantly lower in the chronic restraint stress group (−16%; P=0.036). However, when corrected for volume changes, no significant alteration in a relative estimate of the mean number of asymmetric axo-spinous synapses was detected in CA1 stratum lacunosum-moleculare between control and chronic restraint stress groups. The data indicate a structural remodeling of excitatory axo-spinous synaptic connectivity in rat CA1 stratum lacunosum-moleculare as a result of chronic restraint stress.
Viewing alternatives
Metrics
Public Attention
Altmetrics from Altmetric
Number of Citations
Citations from Dimensions
No digital document available to download for this item
Item Actions
Export
About | {
"url": "https://oro.open.ac.uk/3535/",
"source_domain": "oro.open.ac.uk",
"snapshot_id": "CC-MAIN-2024-30",
"warc_metadata": {
"Content-Length": "66859",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:TVD5BYLBNNZVRUD7IV6ONVE3SRRFYB7I",
"WARC-Concurrent-To": "<urn:uuid:5a90d3cb-b2b7-44fe-9775-d6ac49ef4a36>",
"WARC-Date": "2024-07-21T13:06:30",
"WARC-IP-Address": "137.108.200.18",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:JHC7TIUTQON22UJBYZHQ2I7O3NKSL6VK",
"WARC-Record-ID": "<urn:uuid:8d767111-b87a-4ed5-914d-57a76e0615cb>",
"WARC-Target-URI": "https://oro.open.ac.uk/3535/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:5e0523cf-b2f0-4b13-98ca-54a561d260e0>"
},
"warc_info": "isPartOf: CC-MAIN-2024-30\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for July 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-196\r\nsoftware: Apache Nutch 1.20 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
176,
177,
559,
560,
616,
617,
626,
627,
636,
1388,
1389,
2674,
2675,
2696,
2697,
2705,
2706,
2723,
2724,
2750,
2751,
2771,
2772,
2798,
2854,
2855,
2868,
2869,
2876,
2877
],
"line_end_idx": [
176,
177,
559,
560,
616,
617,
626,
627,
636,
1388,
1389,
2674,
2675,
2696,
2697,
2705,
2706,
2723,
2724,
2750,
2751,
2771,
2772,
2798,
2854,
2855,
2868,
2869,
2876,
2877,
2882
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2882,
"ccnet_original_nlines": 30,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.20430107414722443,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.06989247351884842,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.28315412998199463,
"rps_doc_frac_unique_words": 0.5201072692871094,
"rps_doc_mean_word_length": 6.297586917877197,
"rps_doc_num_sentences": 49,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.8464035987854,
"rps_doc_word_count": 373,
"rps_doc_frac_chars_dupe_10grams": 0.13026820123195648,
"rps_doc_frac_chars_dupe_5grams": 0.20519369840621948,
"rps_doc_frac_chars_dupe_6grams": 0.17113664746284485,
"rps_doc_frac_chars_dupe_7grams": 0.13026820123195648,
"rps_doc_frac_chars_dupe_8grams": 0.13026820123195648,
"rps_doc_frac_chars_dupe_9grams": 0.13026820123195648,
"rps_doc_frac_chars_top_2gram": 0.074925497174263,
"rps_doc_frac_chars_top_3gram": 0.10302256047725677,
"rps_doc_frac_chars_top_4gram": 0.026819920167326927,
"rps_doc_books_importance": -252.00453186035156,
"rps_doc_books_importance_length_correction": -252.00453186035156,
"rps_doc_openwebtext_importance": -149.81146240234375,
"rps_doc_openwebtext_importance_length_correction": -149.81146240234375,
"rps_doc_wikipedia_importance": -112.73844909667969,
"rps_doc_wikipedia_importance_length_correction": -112.73844909667969
},
"fasttext": {
"dclm": 0.02699863910675049,
"english": 0.845443606376648,
"fineweb_edu_approx": 2.3848133087158203,
"eai_general_math": 0.28587716817855835,
"eai_open_web_math": 0.42555832862854004,
"eai_web_code": 0.018188659101724625
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "612.822",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
},
"secondary": {
"code": "612.82",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
8,745,584,307,690,938,000 | Value-Based Medicine: Part 3
The role of patient-reported outcomes in women’s health
Author and Disclosure Information
References
Use of PROs is evolving
Historically, PROMs have been used primarily in clinical trials to document the relative benefits of an intervention. With today’s focus on patient-centered care, however, there is a growing mandate to integrate PROMs into clinical care, quality improvement, and ultimately reimbursement. Recently, Basch and colleagues eloquently described the benefit of routine collection of PROs for cancer patients and the opportunity for improved care across the health system.20
PROs can be applied on various levels. For example, if a patient reports a symptom (X), or a change in symptom X, the following options are possible:
• Clinician level: Symptom management with altered dose or change in medication. This is associated with improved self-efficacy for the patient, a shift toward goal-oriented care, improved communication with the provider, and improved patient satisfaction.
• Researcher level: PROs should be used as a primary end point, in addition to traditional outcomes (mortality, survival, physiologic markers), to allow for comparative effectiveness studies or patient-centered outcomes research studies that evaluate what matters most to patients relative to the specific health condition, intervention, and symptom management.
• Health system level: Quality assurance, quality improvement activities. How effective is the health system in the management of symptom X? Are all clinicians using the same medication or the same dose? Is there a best practice for managing symptom X?
• Population level: Provides evidence for other clinicians and patients to make decisions about what to expect with treatment for symptom X.
From a reimbursement level, clinicians and providers are paid based on performance—the more satisfied patients are about X, the higher the reimbursement. This has been pertinent particularly in high-volume orthopedic conditions in which anatomic correction of hip or knee joints has not consistently demonstrated improvement in quality of life as measured by the following PROs: perception of pain, mobility, physical functioning, social functioning, and emotional distress. Because of concerns about high volume, high cost, and inconsistent outcomes, the US Department of Health and Human Services has specified that 50% of Medicare and 90% of Medicaid reimbursements will be based on outcomes or value-based purchasing options.21
Studies have shown that it is possible to collect PRO data for cancer patients—despite age or severity of illness—and integrate it into clinical care delivery. These data can provide useful, actionable information, resulting in decreased emergency department visits, longer toleration of chemotherapy, and improved survival.22 Similar results have been demonstrated in other medical conditions, although challenges exist when transitioning from research settings to routine care. Challenges include privacy concerns, patient recruitment and tracking, encouraging patients to complete the PRO surveys (nonresponse leads to biased data), real and perceived administrative burden to staff, obtaining clinician buy in, and costs related to surveys and data analysis.23
Read about the benefits of PROs to patients and clients
Next Article: | {
"url": "https://www.mdedge.com/obgyn/article/159650/practice-management/role-patient-reported-outcomes-womens-health/page/0/1",
"source_domain": "www.mdedge.com",
"snapshot_id": "crawl=CC-MAIN-2020-05",
"warc_metadata": {
"Content-Length": "105570",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:L4WEBCQUW4JYJV6TNCW27SBELDF33I6L",
"WARC-Concurrent-To": "<urn:uuid:3d227e85-154b-4351-b494-5d551cd9ccb1>",
"WARC-Date": "2020-01-29T17:19:50",
"WARC-IP-Address": "23.185.0.3",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:RARRPSRFXLXFQIBVWI5EQDPDJASEKTFK",
"WARC-Record-ID": "<urn:uuid:8d934311-bc85-4e0a-b336-8e325a758e82>",
"WARC-Target-URI": "https://www.mdedge.com/obgyn/article/159650/practice-management/role-patient-reported-outcomes-womens-health/page/0/1",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0d7b7890-40f6-4ac6-80e0-4d0d144b40ba>"
},
"warc_info": "isPartOf: CC-MAIN-2020-05\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for January 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-83.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
29,
30,
86,
87,
121,
122,
124,
125,
136,
137,
161,
162,
631,
632,
782,
783,
1042,
1406,
1661,
1804,
1805,
2537,
2538,
3303,
3304,
3360,
3361
],
"line_end_idx": [
29,
30,
86,
87,
121,
122,
124,
125,
136,
137,
161,
162,
631,
632,
782,
783,
1042,
1406,
1661,
1804,
1805,
2537,
2538,
3303,
3304,
3360,
3361,
3374
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3374,
"ccnet_original_nlines": 27,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.32933104038238525,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.015437389723956585,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1612349897623062,
"rps_doc_frac_unique_words": 0.5238094925880432,
"rps_doc_mean_word_length": 5.774327278137207,
"rps_doc_num_sentences": 20,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.119450569152832,
"rps_doc_word_count": 483,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.014342060312628746,
"rps_doc_frac_chars_top_3gram": 0.011473650112748146,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -235.1483154296875,
"rps_doc_books_importance_length_correction": -235.1483154296875,
"rps_doc_openwebtext_importance": -162.04046630859375,
"rps_doc_openwebtext_importance_length_correction": -162.04046630859375,
"rps_doc_wikipedia_importance": -125.36795043945312,
"rps_doc_wikipedia_importance_length_correction": -125.36795043945312
},
"fasttext": {
"dclm": 0.04686081036925316,
"english": 0.9206175208091736,
"fineweb_edu_approx": 2.3461620807647705,
"eai_general_math": 0.14086025953292847,
"eai_open_web_math": 0.1968594193458557,
"eai_web_code": 0.0013913499424234033
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.07",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "610.73",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": ""
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "3",
"label": "Academic Writing"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
7,765,784,204,647,636,000 | +
For Healthcare Professionals
For Lab Professionals
+
For Patients & Caregivers
For Lab Professionals
+
For Patients & Caregivers
For Healthcare Professionals
Welcome! Click here for Healthcare or Laboratory Professional content
Welcome! Click here for Patient or Laboratory Professional content
Are you a healthcare professional?
The information in this website is intended only for healthcare professionals. By entering this site, you are confirming that you are a healthcare professional.
Are you a laboratory professional?
The information in this website is intended only for laboratory professionals. By entering this site, you are confirming that you are a laboratory professional.
Peanut Allergy
There can be a lot of anxiety and confusion about peanuts and peanut allergies. If you or someone you love is told they have a peanut allergy, that diagnosis can strike fear in your heart. This is in part because peanuts are most commonly associated with anaphylaxis, a life-threatening allergic reaction. It can also be difficult to deal with the loss of safety and spontaneity that comes with a peanut allergy diagnosis.
But understanding your peanut allergy may help calm your fears.
Peanut Allergy Outgrow
A peanut allergy is a common type of food allergy in both children and adults. A peanut allergy, like any allergy, is when your immune system identifies the proteins in peanuts as harmful. When you come into contact with these proteins, your immune system reacts and releases histamines, which then cause your allergic reaction.
Peanut allergic reactions are generally the most common culprit of fatal food–induced anaphylaxis, with the highest-risk groups being adolescents with asthma.1,2
In fact, studies show that people allergic to peanuts have a higher risk of anaphylaxis compared with people who are allergic to other foods, like milk or egg.3
And an allergy to peanuts usually lasts a lifetime—only about 20% of people with this allergy outgrow it.4 Some people, who eventually outgrow their peanut allergy, had previously had severe reactions to peanuts. So the severity of your reaction doesn’t mean you won’t outgrow the allergy.
Peanut allergy symptoms
Peanuts are the number one cause of death related to food-induced anaphylaxis.5 Symptoms of anaphylaxis include impaired breathing, swelling in the throat, a sudden drop in blood pressure, pale skin or blue lips, dizziness and fainting.
Less severe symptoms of a peanut allergy are similar to most allergy symptoms and include:
• Itchy skin or hives
• An itching or tingling sensation in the mouth or throat
• Nausea
• A runny or congested nose
Anaphylaxis warning
Anaphylaxis requires immediate medical attention.
Although incredibly serious; anaphylaxis is thankfully very rare.
Learn more about anaphylaxis >
peanut allergy stat
Peanuts are not tree nuts
Even though peanuts have the word “nuts” in their name, they are legumes, not nuts. Allergy to more than one nut is common. 1 out of 2 nut allergic teenagers react to more than one nut. 1 out of 3 peanut allergic patients also report tree nut allergy. And more than half of tree nut allergic patients report an allergy to peanuts.7-11
People with a peanut allergy also commonly avoid tree nuts because of the likelihood of cross-contact or cross-contamination—when one food comes into contact with another food and their proteins mix—during the manufacturing process.8-11
Learn more about tree nuts >
Common peanut allergy triggers
If you have a confirmed peanut allergy diagnosis, you should avoid peanut in all forms including anything containing traces of peanut in it. Obvious sources include roasted, dry roasted, salted or plain peanuts and peanut butter. But peanuts can be a hidden ingredient in many foods—this is why it’s important to read the label or ask before buying or eating foods. Ingredients in packaged foods can change at any time—and without warning.
More than 10% of patients with peanut or tree nut allergy report experiencing reactions in restaurants or other food establishments.Because of their common use of peanuts, Asian restaurants, ice cream parlors and bakeries are considered high-risk for people with a peanut allergy. Even if you order a peanut-free item, there is the possibility of cross-contamination.
The importance of testing is to confirm if these drastic measures are required, since many patients react to peanut due to cross reactivity, with for example pollen, with the much less severe symptoms.
Peanuts can be found in many foods and drinks, including:
Baked goods like pastries and cookies
Candy including chocolates
Chili
Marzipan
Nouget
Sweets like pudding and hot chocolate
African, Asian and Mexican dishes
Glazes and marinades
Sauces such as chili sauce, hot sauce, pesto, gravy, mole sauce, enchilada sauce and salad dressing
Some vegetarian foods, especially meat substitutes
Foods that contain extruded, cold-pressed or expelled peanut oil
Am I Allergic?
Am I allergic?
You may be so used to avoiding peanuts that you haven’t considered asking if you still need to. People who have high levels of peanut antibodies in their blood are most likely to have a peanut allergy for life.12-15 A simple blood test that measures these antibodies and can help your healthcare professional determine whether or not you or your child are likely to outgrow a peanut allergy. Knowing the true cause of your symptoms now may also help you avoid more serious issues in the future.15 For example, a food allergy reaction sends someone to the ER every 3 minutes.16
Knowing if you’re allergic and what you’re allergic to can help can help you get relief. Be sure to consult with your healthcare professional.
Get answers
References
1. Sampson HA, Mendelson LM, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992;327:380 –384. (III)
2. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001; 107:191–193. (III)
3. Scurlock AM, Burks AW. Peanut allergenicity. Ann Allergy Asthma Immunol 2004; 93(Suppl 3): 12–18.
4. Fleischer D M, et al. The natural history of tree nut allergy. The Journal of Allergy and Clinical Immunology, 2005;116(5), 1087-1093.
5. Du Toit G, et al. Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy. The New England Journal of Medicine 2015, 1-11.
6. Sicherer SH, Furlong TJ, Munoz-Furlong A, et al. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol. 2001;108: 128 –132. (III)
7. Sicherer SH, Burks AW, Sampson HA. Clinical features of acute allergic reactions to peanut and tree nuts in children. Pediatrics 1998;102(1):e6
8. Ewan PW. Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations. BMJ 1996;312(7038):1074-8
9. Masthoff L, et al. Peanut allergy is common among hazelnut-sensitized subjects but is not primarily the result of IgE cross-reactivity. Allergy 2015; 70: 265–274.
10. Maloney J, et al. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy. J Allergy Clin Immunol. 2008;122:145-51.
11. Ibid see also Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol 2003; 112(6):1203-7.
12. Hourihane JO, et al. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire, skin prick testing, and challenges. BMJ 1996;313(7056):518-21. http://www.bmj.com/content/313/7056/518. Accessed August 2017.
13. Clark A. and Ewan P. Pediatr Allergy Immunol. 2005;16:507– 11.
14. Eller E, et al. Cor a 14 is the superior serological marker for hazelnut allergy in children, independent of concomitant peanut allergy. Allergy 2016;71:556-62.
15. Al-Ahmed N, et al. Peanut Allergy: An Overview. The Canadian Society of Allergy, Asthma and Clinical Immunology. 2008;4,139.
16. Clark S, et al. Frequency of US emergency department visits for food-related acute allergic reactions. J Allergy Clin Immunol. 2011; 127(3):682-683. | {
"url": "https://www.thermofisher.com/diagnostic-education/patient/us/en/allergy-types/food-allergies/peanut-allergy.html",
"source_domain": "www.thermofisher.com",
"snapshot_id": "crawl=CC-MAIN-2018-51",
"warc_metadata": {
"Content-Length": "185636",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:Z3EAED7ZYMW6AXX73NWZXSP24NF5RJHA",
"WARC-Concurrent-To": "<urn:uuid:3ca8080f-9124-46e8-9ebf-f4d81048c44a>",
"WARC-Date": "2018-12-16T22:40:18",
"WARC-IP-Address": "104.119.2.138",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:EYIO36LEBAC5GCX5GMA5GLO5IONRO3IR",
"WARC-Record-ID": "<urn:uuid:362d9c4a-483e-4b9f-939b-594863ce4d4a>",
"WARC-Target-URI": "https://www.thermofisher.com/diagnostic-education/patient/us/en/allergy-types/food-allergies/peanut-allergy.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:7118d819-e445-42c4-ac08-4f0d7a6291fc>"
},
"warc_info": "isPartOf: CC-MAIN-2018-51\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for December 2018\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-168-82-48.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 0.11-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
2,
31,
53,
55,
81,
103,
105,
131,
160,
161,
231,
232,
299,
300,
335,
336,
497,
498,
533,
534,
695,
696,
711,
712,
1135,
1136,
1200,
1201,
1203,
1204,
1227,
1228,
1557,
1558,
1721,
1722,
1883,
1884,
2178,
2179,
2203,
2204,
2441,
2442,
2533,
2534,
2558,
2618,
2629,
2659,
2679,
2680,
2730,
2796,
2797,
2828,
2829,
2849,
2850,
2876,
2877,
3212,
3213,
3450,
3451,
3480,
3481,
3512,
3513,
3954,
3955,
4323,
4324,
4526,
4527,
4585,
4586,
4624,
4625,
4652,
4653,
4659,
4660,
4669,
4670,
4677,
4678,
4716,
4717,
4751,
4752,
4773,
4774,
4874,
4875,
4926,
4927,
4929,
4930,
4995,
4996,
5011,
5012,
5027,
5028,
5605,
5606,
5749,
5750,
5752,
5753,
5765,
5766,
5777,
5938,
6081,
6184,
6325,
6474,
6679,
6830,
6970,
7138,
7303,
7559,
7823,
7892,
8059,
8190
],
"line_end_idx": [
2,
31,
53,
55,
81,
103,
105,
131,
160,
161,
231,
232,
299,
300,
335,
336,
497,
498,
533,
534,
695,
696,
711,
712,
1135,
1136,
1200,
1201,
1203,
1204,
1227,
1228,
1557,
1558,
1721,
1722,
1883,
1884,
2178,
2179,
2203,
2204,
2441,
2442,
2533,
2534,
2558,
2618,
2629,
2659,
2679,
2680,
2730,
2796,
2797,
2828,
2829,
2849,
2850,
2876,
2877,
3212,
3213,
3450,
3451,
3480,
3481,
3512,
3513,
3954,
3955,
4323,
4324,
4526,
4527,
4585,
4586,
4624,
4625,
4652,
4653,
4659,
4660,
4669,
4670,
4677,
4678,
4716,
4717,
4751,
4752,
4773,
4774,
4874,
4875,
4926,
4927,
4929,
4930,
4995,
4996,
5011,
5012,
5027,
5028,
5605,
5606,
5749,
5750,
5752,
5753,
5765,
5766,
5777,
5938,
6081,
6184,
6325,
6474,
6679,
6830,
6970,
7138,
7303,
7559,
7823,
7892,
8059,
8190,
8344
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 8344,
"ccnet_original_nlines": 129,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.28537455201148987,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.02972652018070221,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.25029727816581726,
"rps_doc_frac_unique_words": 0.41199377179145813,
"rps_doc_mean_word_length": 5.181464195251465,
"rps_doc_num_sentences": 121,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.545986175537109,
"rps_doc_word_count": 1284,
"rps_doc_frac_chars_dupe_10grams": 0.03427024930715561,
"rps_doc_frac_chars_dupe_5grams": 0.06568464636802673,
"rps_doc_frac_chars_dupe_6grams": 0.04674582928419113,
"rps_doc_frac_chars_dupe_7grams": 0.04674582928419113,
"rps_doc_frac_chars_dupe_8grams": 0.03427024930715561,
"rps_doc_frac_chars_dupe_9grams": 0.03427024930715561,
"rps_doc_frac_chars_top_2gram": 0.0429881289601326,
"rps_doc_frac_chars_top_3gram": 0.0189388208091259,
"rps_doc_frac_chars_top_4gram": 0.014279269613325596,
"rps_doc_books_importance": -820.6522827148438,
"rps_doc_books_importance_length_correction": -820.6522827148438,
"rps_doc_openwebtext_importance": -504.1783752441406,
"rps_doc_openwebtext_importance_length_correction": -504.1783752441406,
"rps_doc_wikipedia_importance": -347.6639099121094,
"rps_doc_wikipedia_importance_length_correction": -347.6639099121094
},
"fasttext": {
"dclm": 0.04064154997467995,
"english": 0.8855810165405273,
"fineweb_edu_approx": 2.80692458152771,
"eai_general_math": 0.03582959994673729,
"eai_open_web_math": 0.22475707530975342,
"eai_web_code": 0.001273039961233735
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.0422",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.042",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "2",
"label": "Click Here References"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
1,775,695,334,346,886,000 | Advertisement
What is the treatment for Zenker's diverticulum?
Arlen D. Meyers, MD
Ear, Nose & Throat (Otolaryngology)
Zenker's Diverticulum is an out pouching of the feeding tube (esophagus) usually where it meets the throat. Symptoms are typically a feeling of a lump in the throat or it feels like food gets stuck.
It is associated with tightness of the upper sphincter so the treatment involves relieving the spasm by injecting with Botox, cutting the muscle from the inside or outside and/or removing the diverticulum.
Continue Learning about Throat Disorders
How can I help treat throat disorders?
Intermountain HealthcareIntermountain Healthcare
Here are some tips to feel better when you have a throat problem: Drink plenty of liquids. Warm drin...
More Answers
What are common throat problems?
Intermountain HealthcareIntermountain Healthcare
Some common throat problems are sore throats and laryngitis. If you have laryngitis, it's hard to ...
More Answers
How can I manage a sore throat at home?
RealAgeRealAge
Most viral sore throats can be treated with home care. Home care also is a good supplement to th...
More Answers
When Should I Have My Tonsils Looked at?
When Should I Have My Tonsils Looked at?
Important: This content reflects information from various individuals and organizations and may offer alternative or opposing points of view. It should not be used for medical advice, diagnosis or treatment. As always, you should consult with your healthcare provider about your specific health needs. | {
"url": "https://www.sharecare.com/health/throat-disorders/treatment-for-zenkers-diverticulum",
"source_domain": "www.sharecare.com",
"snapshot_id": "crawl=CC-MAIN-2020-24",
"warc_metadata": {
"Content-Length": "131389",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:R5KLKW7FVL7KXMHB2H3LXZOHEQIHZ4UK",
"WARC-Concurrent-To": "<urn:uuid:010facdf-9276-4048-be1c-0274b0f0a039>",
"WARC-Date": "2020-06-05T19:54:24",
"WARC-IP-Address": "104.255.93.128",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:OJ5DO6N2EDETUHZL3GGMC4IQNDQDUOWY",
"WARC-Record-ID": "<urn:uuid:dac156eb-5b96-4343-8aaa-b144cb9c3dcb>",
"WARC-Target-URI": "https://www.sharecare.com/health/throat-disorders/treatment-for-zenkers-diverticulum",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:3ca7f778-8fd6-48e8-a9f3-6e402457299b>"
},
"warc_info": "isPartOf: CC-MAIN-2020-24\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May/June 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-124.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
14,
15,
64,
65,
85,
121,
122,
321,
322,
528,
529,
570,
571,
610,
659,
763,
776,
809,
858,
960,
973,
1013,
1028,
1128,
1141,
1182,
1223,
1224
],
"line_end_idx": [
14,
15,
64,
65,
85,
121,
122,
321,
322,
528,
529,
570,
571,
610,
659,
763,
776,
809,
858,
960,
973,
1013,
1028,
1128,
1141,
1182,
1223,
1224,
1525
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1525,
"ccnet_original_nlines": 28,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3478260934352875,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.021739130839705467,
"rps_doc_frac_lines_end_with_ellipsis": 0.1034482792019844,
"rps_doc_frac_no_alph_words": 0.1304347813129425,
"rps_doc_frac_unique_words": 0.5974576473236084,
"rps_doc_mean_word_length": 5.25,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0.010869570076465607,
"rps_doc_unigram_entropy": 4.727270603179932,
"rps_doc_word_count": 236,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.05165455862879753,
"rps_doc_frac_chars_dupe_6grams": 0.05165455862879753,
"rps_doc_frac_chars_dupe_7grams": 0.05165455862879753,
"rps_doc_frac_chars_dupe_8grams": 0.05165455862879753,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.026634380221366882,
"rps_doc_frac_chars_top_3gram": 0.011299439705908298,
"rps_doc_frac_chars_top_4gram": 0.02421307936310768,
"rps_doc_books_importance": -141.38177490234375,
"rps_doc_books_importance_length_correction": -130.66250610351562,
"rps_doc_openwebtext_importance": -90.70658111572266,
"rps_doc_openwebtext_importance_length_correction": -90.70658111572266,
"rps_doc_wikipedia_importance": -69.32540130615234,
"rps_doc_wikipedia_importance_length_correction": -56.40433120727539
},
"fasttext": {
"dclm": 0.04459900036454201,
"english": 0.90889573097229,
"fineweb_edu_approx": 2.3739359378814697,
"eai_general_math": 0.0005303000216372311,
"eai_open_web_math": 0.08305943012237549,
"eai_web_code": 0.000016570000298088416
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.12",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.1",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "1",
"label": "Truncated Snippets"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-9,058,607,750,677,560,000 | Hippotherapy is a strategy that uses the movement of a horse to treat individuals with any of a variety of neuro-musculoskeletal disabilities including cerebral palsy, paralysis, traumatic brain injury, stroke and others. The patients’ overall treatment program includes time riding on a therapeutic horse under the direction of a physical therapist. The premise behind hippotherapy is that the movement of the horse drives the patients’ body, and particularly the hips, in a pattern that is similar to natural human movements such as healthy human gait [1][2][3][4]. The rhythmic motion of the riding surface engages and challenges the patient to actively anticipate, compensate, and adapt in order to maintain balance. Hippotherapy treatment is believed to help improve flexibility, strength, muscle symmetry, balance and postural control, and motor function [1][2][4][5][6].
This content is only available via PDF.
You do not currently have access to this content. | {
"url": "https://asmedigitalcollection.asme.org/SBC/proceedings-abstract/SBC2010/44038/677/460460",
"source_domain": "asmedigitalcollection.asme.org",
"snapshot_id": "crawl=CC-MAIN-2020-10",
"warc_metadata": {
"Content-Length": "82465",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:UMQABY23J4HC7SQXNDLSNV4OV77E6SWO",
"WARC-Concurrent-To": "<urn:uuid:1321e2cb-b504-4cce-a56b-4f9a07853495>",
"WARC-Date": "2020-02-18T03:19:30",
"WARC-IP-Address": "173.254.190.160",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:PZ6SDBORMISVYZ2QV7LG36OTQTAC5F6A",
"WARC-Record-ID": "<urn:uuid:5834433b-932e-47f8-a5f8-660e22e3e1b8>",
"WARC-Target-URI": "https://asmedigitalcollection.asme.org/SBC/proceedings-abstract/SBC2010/44038/677/460460",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:5b27e3bc-e34e-4f52-8f62-f4dae7a8f135>"
},
"warc_info": "isPartOf: CC-MAIN-2020-10\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for February 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-170.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
878,
879,
919
],
"line_end_idx": [
878,
879,
919,
968
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 968,
"ccnet_original_nlines": 3,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.34065935015678406,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.005494509823620319,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.2142857164144516,
"rps_doc_frac_unique_words": 0.6597222089767456,
"rps_doc_mean_word_length": 5.465277671813965,
"rps_doc_num_sentences": 7,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.276824474334717,
"rps_doc_word_count": 144,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.011435830034315586,
"rps_doc_frac_chars_top_3gram": 0.03303685039281845,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -79.96588134765625,
"rps_doc_books_importance_length_correction": -79.96588134765625,
"rps_doc_openwebtext_importance": -42.69758987426758,
"rps_doc_openwebtext_importance_length_correction": -29.05179786682129,
"rps_doc_wikipedia_importance": -24.66785430908203,
"rps_doc_wikipedia_importance_length_correction": -24.66785430908203
},
"fasttext": {
"dclm": 0.5079367160797119,
"english": 0.9068871140480042,
"fineweb_edu_approx": 3.024230718612671,
"eai_general_math": 0.019037069752812386,
"eai_open_web_math": 0.01593511924147606,
"eai_web_code": 0.0011661599855870008
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "1",
"label": "Truncated Snippets"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "6",
"label": "Not Applicable/Indeterminate"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-2,131,254,755,823,203,800 | Tuesday, 28 January, 2020
Medical Marijuana for Alopecia Areata
Alopecia is the loss of hair that is caused by different reasons which includes the damage to the hair shaft or follicles or fungal infections.
There are two main types of alopecia, namely Alopecia Areata and Androgenetic Allopecia. Alopecia Areata is a type of hair loss that occurs when the immune system mistakenly attacks hair follicles, which is where hair growth begins.
The hair falls off in round patches and the damage to the follicle is usually not permanent. Alopecia Areata is most common in people younger than 20, but children and adults of any age may be affected. Women and men are affected equally. On the other hand Androgenetic Alopecia is a kind of hair loss that is inherited. Hair on the head thins and falls of. About 60% of people with this type of Alopecia are men. Unlike Alopecia Areata, Angrogenetic Alopecia is permanent.
Although not too many people have heard about it, the fact is that Alopecia Areate is a very common and specific autoimmune disease that is brought about by genetics, autoimmunity and cytokines.
Unfortunately, there is no definite cure for Alopecia Areata. Still, medical professionals and patients suffering from Alopecia Areata have resorted to alternative methods of minimizing the negative physical effects of Alopecia Areata, specifically the hair loss. So while there is no cure for Alopecia Areata itself, some patients found out that some specific medications approved for other purposes can help hair grow back.
As stated earlier, Alopecia Areata is an autoimmune disease. As such, it can be generally treated with the same medications usually used to treat other autoimmune diseases. Medical marijuana, as supported by various medical researches has been noted to strengthen the immune system of a user. In cases of Alopecia Areata specifically caused by autoimmune factors, medical marijuana is a great help in building up and restoring the immune system. Other studies attribute this effect as well to the appetite-stimulant property of medical marijuana. A patient who eats better gains more nutrients, thus, immune system is stronger to fight of diseases. The patients regain better health and well-being. With the reversion to better health and balanced immune system which enables the body to function normall. This includes the body’s ability to gain back the lost follicles and aid in hair growth. Indeed, medical marijuana is a no-risk alternative treatment for Alopecia Areata.
Product Reviews
Get the inside track on the most popular vaporizers, rolling papers, marijuana strains and more.
Marijuana Forum
Join the conversation about medical marijuana, growing tips, smoking techniques and more. | {
"url": "http://www.canabud.ca/medical-marijuana-for-alopecia-areata/",
"source_domain": "www.canabud.ca",
"snapshot_id": "crawl=CC-MAIN-2020-05",
"warc_metadata": {
"Content-Length": "29591",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:LSXUQ6GT4M6EZ3NUKZJV2PHRL3SY5Q4S",
"WARC-Concurrent-To": "<urn:uuid:e3b828a1-0c2f-4c9e-a507-f925ae480898>",
"WARC-Date": "2020-01-28T23:46:39",
"WARC-IP-Address": "173.230.145.85",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:2U4RSIA3GZMWUE472GF7BRYELXWEO2NG",
"WARC-Record-ID": "<urn:uuid:9c8a3761-f260-47a8-9fe9-ae15272e3f76>",
"WARC-Target-URI": "http://www.canabud.ca/medical-marijuana-for-alopecia-areata/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:af05950b-2d06-47a6-a312-1c2649156bad>"
},
"warc_info": "isPartOf: CC-MAIN-2020-05\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for January 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-43.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
26,
27,
65,
66,
67,
211,
212,
445,
446,
920,
921,
1116,
1117,
1543,
1544,
2521,
2522,
2538,
2539,
2636,
2637,
2653,
2654
],
"line_end_idx": [
26,
27,
65,
66,
67,
211,
212,
445,
446,
920,
921,
1116,
1117,
1543,
1544,
2521,
2522,
2538,
2539,
2636,
2637,
2653,
2654,
2743
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2743,
"ccnet_original_nlines": 23,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.376782089471817,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0020366599783301353,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1181262731552124,
"rps_doc_frac_unique_words": 0.480369508266449,
"rps_doc_mean_word_length": 5.187067031860352,
"rps_doc_num_sentences": 26,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.8333845138549805,
"rps_doc_word_count": 433,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.07479964196681976,
"rps_doc_frac_chars_top_3gram": 0.03027605079114437,
"rps_doc_frac_chars_top_4gram": 0.0124666104093194,
"rps_doc_books_importance": -202.42135620117188,
"rps_doc_books_importance_length_correction": -202.42135620117188,
"rps_doc_openwebtext_importance": -109.43063354492188,
"rps_doc_openwebtext_importance_length_correction": -109.43063354492188,
"rps_doc_wikipedia_importance": -59.585208892822266,
"rps_doc_wikipedia_importance_length_correction": -59.585208892822266
},
"fasttext": {
"dclm": 0.04287320002913475,
"english": 0.9439601302146912,
"fineweb_edu_approx": 2.5843350887298584,
"eai_general_math": 0.0019675500225275755,
"eai_open_web_math": 0.0595056414604187,
"eai_web_code": 0.0001035899986163713
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.6522",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.65220285",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "2",
"label": "Click Here References"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "2",
"label": "Partially Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
7,425,353,826,409,841,000 |
1020 Youngs Rd, Ste 110
Williamsville, NY 14221
897 Delaware Ave
Buffalo, NY 14209
716-883-6800
Celebrating 60 years as The Ear, Nose & Throat
Specialists of Western New York (1953-2013)
Our team of specialists and staff believe that informed patients are better equipped to make decisions regarding their health and well being. For your personal use, we have created an extensive patient library covering an array of educational topics. Browse through these diagnoses and treatments to learn more about topics of interest to you. Or, for a more comprehensive search of our entire Web site, enter your term in the search bar provided.
As always, you can call our offices to answer any questions or concerns.
A cochlear implant is an electronic device that restores partial hearing to individuals with severe to profound hearing loss who do not benefit from a conventional hearing aid. It is surgically implanted in the inner ear and activated by a device worn outside the ear. Unlike a hearing aid, it does not make sound louder or clearer. Instead, the device bypasses damaged parts of the auditory system and directly stimulates the nerve of hearing, allowing individuals who are profoundly hearing-impaired to receive sound.
What is normal hearing?
Your ear consists of three parts that play a vital role in hearing—the external ear, middle ear, and inner ear.
Conductive hearing: Sound travels along the ear canal of the external ear, causing the ear drum to vibrate. Three small bones of the middle ear conduct this vibration from the eardrum to the cochlea (auditory chamber) of the inner ear.
Sensorineural hearing: When the three small bones move, they start waves of fluid in the cochlea, and these waves stimulate more than 16,000 delicate hearing cells (hair cells). As these hair cells move, they generate an electrical current in the auditory nerve. The electrical signal travels through inter-connections in the brain to specific areas of the brain that recognize it as sound.
How is hearing impaired?
If you have disease or obstruction in your external or middle ear, your conductive hearing may be impaired. Medical or surgical treatment can probably correct this.
An inner ear problem, however, can result in a sensorineural impairment, or nerve deafness. In most cases, the hair cells are damaged and do not function. Although many auditory nerve fibers may be intact and can transmit electrical impulses to the brain, these nerve fibers are unresponsive because of hair cell damage. Since severe sensorineural hearing loss cannot be corrected with medicine, it can be treated only with a cochlear implant.
How do cochlear implants work?
Cochlear implants bypass damaged hair cells and convert speech and environmental sounds into electrical signals and send these signals to the hearing nerve.
A cochlear implant has two main components:
1. An internal component that consists of a small electronic device, which is surgically implanted under the skin behind the ear, connected to electrodes that are inserted inside the cochlea.
2. An external component, which is usually worn behind the ear, that consists of a speech processor, microphone, and battery compartment.
The microphone captures sound, allowing the speech processor to translate the sound into distinctive electrical signals. These signals or “codes” travel up a thin cable to the headpiece and are transmitted across the skin via radio waves to the implanted electrodes in the cochlea. The electrodes’ signals stimulate the auditory nerve fibers to send information to the brain, where it is interpreted as meaningful sound.
Cochlear implant benefits
Cochlear implants are designed only for individuals who attain almost no benefit from a hearing aid. They must be 12 months of age or older (unless childhood meningitis is responsible for deafness).
Otolaryngologists (ear, nose, and throat specialists) perform implant surgery, although not all of them do this procedure. Your local doctor can refer you to an implant clinic for an evaluation. The implant team (otolaryngologist, audiologist, nurse, and others) will determine your candidacy for a cochlear implant and review the appropriate expectations as a result of the cochlear implant. The implant team will also conduct a series of tests including:
Ear (otologic) evaluation: The otolaryngologist examines the middle and inner ear to ensure that no active infection or other abnormality precludes the implant surgery.
Hearing (audiologic) evaluation: The audiologist performs extensive hearing tests to find out how much you can hear with and without a hearing aid.
X-ray (radiographic) evaluation: Special X-rays are taken, usually computerized tomography (CT) or magnetic resonance imaging (MRI) scans, to evaluate your inner ear anatomy.
Physical examination: Your otolaryngologist also performs a physical examination to identify any potential problems with the use of general anesthesia needed for the implant procedure.
Cochlear implant surgery
Cochlear implant surgery is usually performed as an outpatient procedure under general anesthesia. An incision is made behind the ear to open the mastoid bone leading to the middle ear space. Once the middle ear space is exposed, an opening is made in the cochlea and the implant electrodes are inserted. The electronic device at the base of the electrode array is then placed behind the ear under the skin.
Is there care and training after the operation?
Several weeks after surgery, your cochlear implant team places the signal processor, microphone, and implant transmitter outside your ear and adjusts them. They teach you how to look after the system and how to listen to sound through the implant. There are many causes of hearing loss and some patients may take longer to fit and require more training, due to individual patient differences. Your team will ask you to come back to the clinic for regular checkups and readjustment of the speech processor as needed.
What can I expect from an implant?
Most adult cochlear implant patients notice an immediate improvement in their communication skills. Children require time to benefit from their cochlear implant as the brain needs to learn to correctly interpret the electrical sound input. While cochlear implants do not restore normal hearing, and benefits vary from one individual to another, most users find that cochlear implants help them communicate better through improved lip-reading. Also, 90 percent of adult cochlear implant patients are able to discriminate speech without the use of visual cues. There are many factors that contribute to the degree of benefit a user receives from a cochlear implant, including:
• How long a person has been deaf;
• The number of surviving auditory nerve fibers; and
• A patient’s motivation to learn to hear.
Your team will explain what you can reasonably expect. Before deciding whether your implant is working well, you need to understand clearly how much time you must commit. It is rare that patients do not benefit from a cochlear implant.
FDA approval for implants
The Food and Drug Administration (FDA) regulates cochlear implant devices for both adults and children and approves them only after thorough clinical investigation.
Be sure to ask your otolaryngologist for written information, including brochures provided by the implant manufacturers. You need to be fully informed about the benefits and risks of cochlear implants, including how much is known about safety, reliability, and effectiveness of a device, how often you must come back to the clinic for checkups, and whether your insurance company pays for the procedure.
Costs of implants
More expensive than a hearing aid, the total cost of a cochlear implant including evaluation, surgery, the device, and rehabilitation can cost as much as $100,000. Fortunately, most insurance companies and Medicare provide benefits that cover the cost. | {
"url": "http://www.buffaloent.com/library/4017/CochlearImplants.html",
"source_domain": "www.buffaloent.com",
"snapshot_id": "crawl=CC-MAIN-2013-20",
"warc_metadata": {
"Content-Length": "19075",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:I3SWQIFREOFRMQOR2OZ7QBJ324HIMYGB",
"WARC-Concurrent-To": "<urn:uuid:395dbdfe-91ce-4ad2-8d46-6cf084497c73>",
"WARC-Date": "2013-05-19T07:13:21",
"WARC-IP-Address": "98.158.198.21",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:JHY6RIAEW3LC3USDQ6ASUQIDZS6XNZQU",
"WARC-Record-ID": "<urn:uuid:2b84e327-d47b-4686-a573-5f6e1d99eb17>",
"WARC-Target-URI": "http://www.buffaloent.com/library/4017/CochlearImplants.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:698a2f1a-0be8-4609-bec2-0cbc546905e7>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-60-113-184.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2013-20\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for Spring 2013\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
2,
3,
27,
51,
68,
86,
88,
89,
102,
103,
105,
106,
153,
154,
198,
199,
200,
648,
649,
722,
723,
724,
725,
1245,
1246,
1270,
1271,
1383,
1384,
1620,
1621,
2012,
2013,
2038,
2039,
2204,
2205,
2649,
2650,
2681,
2682,
2839,
2840,
2884,
2885,
3079,
3221,
3222,
3643,
3644,
3670,
3671,
3870,
3871,
4329,
4330,
4499,
4500,
4648,
4649,
4824,
4825,
5010,
5011,
5036,
5037,
5446,
5447,
5495,
5496,
6012,
6013,
6048,
6049,
6724,
6725,
6762,
6817,
6862,
6863,
7099,
7100,
7126,
7127,
7292,
7293,
7697,
7698,
7716,
7717
],
"line_end_idx": [
2,
3,
27,
51,
68,
86,
88,
89,
102,
103,
105,
106,
153,
154,
198,
199,
200,
648,
649,
722,
723,
724,
725,
1245,
1246,
1270,
1271,
1383,
1384,
1620,
1621,
2012,
2013,
2038,
2039,
2204,
2205,
2649,
2650,
2681,
2682,
2839,
2840,
2884,
2885,
3079,
3221,
3222,
3643,
3644,
3670,
3671,
3870,
3871,
4329,
4330,
4499,
4500,
4648,
4649,
4824,
4825,
5010,
5011,
5036,
5037,
5446,
5447,
5495,
5496,
6012,
6013,
6048,
6049,
6724,
6725,
6762,
6817,
6862,
6863,
7099,
7100,
7126,
7127,
7292,
7293,
7697,
7698,
7716,
7717,
7969
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 7969,
"ccnet_original_nlines": 90,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.37099024653434753,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.008368199691176414,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.13737796247005463,
"rps_doc_frac_unique_words": 0.3889334499835968,
"rps_doc_mean_word_length": 5.202085018157959,
"rps_doc_num_sentences": 64,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.440616607666016,
"rps_doc_word_count": 1247,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.012024049647152424,
"rps_doc_frac_chars_dupe_6grams": 0.006782799959182739,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.03699706867337227,
"rps_doc_frac_chars_top_3gram": 0.01726529933512211,
"rps_doc_frac_chars_top_4gram": 0.0049329400062561035,
"rps_doc_books_importance": -465.6570739746094,
"rps_doc_books_importance_length_correction": -465.6570739746094,
"rps_doc_openwebtext_importance": -312.003173828125,
"rps_doc_openwebtext_importance_length_correction": -312.003173828125,
"rps_doc_wikipedia_importance": -239.3602752685547,
"rps_doc_wikipedia_importance_length_correction": -239.3602752685547
},
"fasttext": {
"dclm": 0.2792860269546509,
"english": 0.9277385473251343,
"fineweb_edu_approx": 2.86883282661438,
"eai_general_math": 0.020918430760502815,
"eai_open_web_math": 0.13750654458999634,
"eai_web_code": 0.0057382602244615555
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.192",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.1",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "1",
"label": "About (Org.)"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-322,119,051,944,511,360 | Links between psychotic and neurotic symptoms in the general population: an analysis of longitudinal British National Survey data using Directed Acyclic Graphs
Psychol Med 2018: 1-8 (Journal)
Kuipers J., Moffa G., Kuipers E., Freeman D., Bebbington P.
BACKGROUND: Non-psychotic affective symptoms are important components of psychotic syndromes. They are frequent and are now thought to influence the emergence of paranoia and hallucinations. Evidence supporting this model of psychosis comes from recent cross-fertilising epidemiological and intervention studies. Epidemiological studies identify plausible targets for intervention but must be interpreted cautiously. Nevertheless, causal inference can be strengthened substantially using modern statistical methods. METHODS: Directed Acyclic Graphs were used in a dynamic Bayesian network approach to learn the overall dependence structure of chosen variables. DAG-based inference identifies the most likely directional links between multiple variables, thereby locating them in a putative causal cascade. We used initial and 18-month follow-up data from the 2000 British National Psychiatric Morbidity survey (N = 8580 and N = 2406). RESULTS: We analysed persecutory ideation, hallucinations, a range of affective symptoms and the effects of cannabis and problematic alcohol use. Worry was central to the links between symptoms, with plausible direct effects on insomnia, depressed mood and generalised anxiety, and recent cannabis use. Worry linked the other affective phenomena with paranoia. Hallucinations were connected only to worry and persecutory ideation. General anxiety, worry, sleep problems, and persecutory ideation were strongly self-predicting. Worry and persecutory ideation were connected over the 18-month interval in an apparent feedback loop. CONCLUSIONS: These results have implications for understanding dynamic processes in psychosis and for targeting psychological interventions. The reciprocal influence of worry and paranoia implies that treating either symptom is likely to ameliorate the other.
Zur Publikationsübersicht | {
"url": "http://ceb-institute.org/publications/8066",
"source_domain": "ceb-institute.org",
"snapshot_id": "crawl=CC-MAIN-2018-34",
"warc_metadata": {
"Content-Length": "21444",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:N5WXOI3GIO7QIOQTMCVQMM7LHFH2ODFD",
"WARC-Concurrent-To": "<urn:uuid:8d6c59c7-dcf7-4b95-b757-439f7a20029c>",
"WARC-Date": "2018-08-14T09:07:06",
"WARC-IP-Address": "134.119.224.34",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:C5X5W5K35LDB6H74TFFU2Q7SSINJQMVR",
"WARC-Record-ID": "<urn:uuid:024ec40b-98bb-4672-aab1-22483f34a197>",
"WARC-Target-URI": "http://ceb-institute.org/publications/8066",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:3b6259bb-3860-4573-a2db-951742e1f333>"
},
"warc_info": "isPartOf: CC-MAIN-2018-34\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2018\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-244-94.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 0.11-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
160,
161,
193,
194,
254,
255,
2080,
2081
],
"line_end_idx": [
160,
161,
193,
194,
254,
255,
2080,
2081,
2106
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2106,
"ccnet_original_nlines": 8,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2861357033252716,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.03539822995662689,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1710914522409439,
"rps_doc_frac_unique_words": 0.6049821972846985,
"rps_doc_mean_word_length": 6.284697532653809,
"rps_doc_num_sentences": 22,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.880023956298828,
"rps_doc_word_count": 281,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.0430351085960865,
"rps_doc_frac_chars_top_3gram": 0.037372589111328125,
"rps_doc_frac_chars_top_4gram": 0.030577579513192177,
"rps_doc_books_importance": -136.76597595214844,
"rps_doc_books_importance_length_correction": -136.76597595214844,
"rps_doc_openwebtext_importance": -94.2955322265625,
"rps_doc_openwebtext_importance_length_correction": -94.2955322265625,
"rps_doc_wikipedia_importance": -77.76451110839844,
"rps_doc_wikipedia_importance_length_correction": -77.76451110839844
},
"fasttext": {
"dclm": 0.022337080910801888,
"english": 0.8988080620765686,
"fineweb_edu_approx": 2.8622243404388428,
"eai_general_math": 0.8116337656974792,
"eai_open_web_math": 0.3370104432106018,
"eai_web_code": 0.06218618154525757
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.8914",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.89",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
2,116,523,392,609,767,000 | Does allergic rhinitis go away?
It clears up on its own after a few days for many people. In others, especially those with allergies, rhinitis can be a chronic problem. Chronic means it is almost always present or recurs often. Rhinitis can last for weeks to months with allergen exposure.
How long does allergic rhinitis last?
Chronic means that the nasal inflammation is long term, lasting for more than four consecutive weeks. This is different from acute rhinitis, which only lasts a few days or up to four weeks.
Symptoms.
Symptoms Allergic rhinitis Non-allergic rhinitis
Symptoms tend to be seasonal
Symptoms tend to be year-round
Is allergic rhinitis permanent?
There is no cure for allergic rhinitis, but the effects of the condition can be lessened with the use of nasal sprays and antihistamine medications. A doctor may recommend immunotherapy – a treatment option that can provide long-term relief. Steps can also be taken to avoid allergens.
How do you get rid of allergic rhinitis?
Treatments for allergic rhinitis
1. Antihistamines. You can take antihistamines to treat allergies. …
2. Decongestants. You can use decongestants over a short period, usually no longer than three days, to relieve a stuffy nose and sinus pressure. …
3. Eye drops and nasal sprays. …
4. Immunotherapy. …
5. Sublingual immunotherapy (SLIT)
IT IS INTERESTING: Does Advil Allergy Sinus make you drowsy?
What will happen if Allergic rhinitis is left untreated?
When left untreated, allergic rhinitis often becomes chronic and may lead to complications including: Chronic nasal inflammation and obstruction, which can lead to more serious complications in the airways. Acute or chronic sinusitis. Otitis media, or ear infection.
Which body part is mainly affected by rhinitis?
Rhinitis is inflammation and swelling of the mucous membrane of the nose, characterized by a runny nose and stuffiness and usually caused by the common cold or a seasonal allergy. Colds and allergies are the most common causes of rhinitis.
What is the best treatment for allergic rhinitis?
Intranasal corticosteroids are the single most effective drug class for treating allergic rhinitis. They can significantly reduce nasal congestion as well as sneezing, itching and a runny nose.
What are the home remedies for allergic rhinitis?
Ginger works as a natural antihistamine, potent antiviral agent, and immune booster. Try some ginger tea to alleviate nasal congestion and headaches. While you sip your tea, inhale the steam coming out of your cup. You can find ginger commercially in fresh and dried form.
What aggravates allergic rhinitis?
Allergic rhinitis is triggered by breathing in tiny particles of allergens. The most common airborne allergens that cause rhinitis are dust mites, pollen and spores, and animal skin, urine and saliva.
Is allergic rhinitis a disability?
Yes. In both the ADA and Section 504, a person with a disability is someone who has a physical or mental impairment that seriously limits one or more major life activities, or who is regarded as having such impairments. Asthma and allergies are usually considered disabilities under the ADA.
IT IS INTERESTING: How long do bad allergies last?
How can I reduce allergies naturally?
The good news is there are many natural remedies you can try to control your allergy symptoms:
1. Cleanse your nose. Pollens adhere to our mucus membranes. …
2. Manage stress. …
3. Try acupuncture. …
4. Explore herbal remedies. …
5. Consider apple cider vinegar. …
6. Visit a chiropractor. …
7. Detox the body. …
8. Take probiotics.
What is the most common cause of rhinitis?
Rhinitis is inflammation and swelling of the mucous membrane of the nose, characterized by a runny nose and stuffiness and usually caused by the common cold or a seasonal allergy. Colds and allergies are the most common causes of rhinitis. Symptoms of rhinitis include a runny nose, sneezing, and stuffiness.
How do you stop allergies immediately?
Try an over-the-counter remedy
1. Oral antihistamines. Antihistamines can help relieve sneezing, itching, a runny nose and watery eyes. …
2. Decongestants. Oral decongestants such as pseudoephedrine (Sudafed, Afrinol, others) can provide temporary relief from nasal stuffiness. …
3. Nasal spray. …
4. Combination medications.
What should we eat in allergic rhinitis?
Here’s a list of foods to try.
• Ginger. Many of the unpleasant allergy symptoms come from inflammatory issues, like swelling and irritation in the nasal passages, eyes, and throat. …
• Bee pollen. …
• Citrus fruits. …
• Turmeric. …
• Tomatoes. …
• Salmon and other oily fish. …
• Onions.
Is allergic rhinitis serious?
Most people with allergic rhinitis have mild symptoms that can be easily and effectively treated. But for some symptoms can be severe and persistent, causing sleep problems and interfering with everyday life.
Is it bad to have allergies everyday?
But for some people symptoms can be severe and persistent, causing sleep problems and interfering with everyday life. The symptoms of allergic rhinitis occasionally improve with time, but this can take many years and it’s unlikely that the condition will disappear completely.
IT IS INTERESTING: How do I know if it's allergies or sinus infection?
Immune response | {
"url": "https://efraim-online.com/allergies/does-allergic-rhinitis-go-away.html",
"source_domain": "efraim-online.com",
"snapshot_id": "crawl=CC-MAIN-2021-39",
"warc_metadata": {
"Content-Length": "77133",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:PSZLVAFIIUY3TMS52VSNRELMXVXLD7YU",
"WARC-Concurrent-To": "<urn:uuid:787945bd-83fb-49e9-a186-ee66aeea890b>",
"WARC-Date": "2021-09-20T14:39:21",
"WARC-IP-Address": "144.126.138.138",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:VXBPWKCBEAWTXEVOIIAL3CZXM4OWQ4O5",
"WARC-Record-ID": "<urn:uuid:f033391f-b87f-495c-a2de-b9f016c4f2c6>",
"WARC-Target-URI": "https://efraim-online.com/allergies/does-allergic-rhinitis-go-away.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:2dc50605-e269-42f9-8eb7-7a206110f3d5>"
},
"warc_info": "isPartOf: CC-MAIN-2021-39\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-143\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
32,
33,
291,
292,
330,
331,
521,
522,
532,
533,
582,
611,
642,
643,
675,
676,
962,
963,
1004,
1005,
1038,
1039,
1110,
1259,
1294,
1316,
1353,
1415,
1416,
1473,
1474,
1741,
1742,
1790,
1791,
2031,
2032,
2082,
2083,
2277,
2278,
2328,
2329,
2602,
2603,
2638,
2639,
2840,
2841,
2876,
2877,
3169,
3170,
3222,
3223,
3261,
3262,
3357,
3358,
3423,
3445,
3469,
3501,
3538,
3567,
3590,
3612,
3613,
3656,
3657,
3966,
3967,
4006,
4007,
4038,
4039,
4148,
4292,
4312,
4342,
4343,
4384,
4385,
4416,
4417,
4572,
4590,
4611,
4627,
4643,
4677,
4689,
4690,
4720,
4721,
4930,
4931,
4969,
4970,
5247,
5248,
5320
],
"line_end_idx": [
32,
33,
291,
292,
330,
331,
521,
522,
532,
533,
582,
611,
642,
643,
675,
676,
962,
963,
1004,
1005,
1038,
1039,
1110,
1259,
1294,
1316,
1353,
1415,
1416,
1473,
1474,
1741,
1742,
1790,
1791,
2031,
2032,
2082,
2083,
2277,
2278,
2328,
2329,
2602,
2603,
2638,
2639,
2840,
2841,
2876,
2877,
3169,
3170,
3222,
3223,
3261,
3262,
3357,
3358,
3423,
3445,
3469,
3501,
3538,
3567,
3590,
3612,
3613,
3656,
3657,
3966,
3967,
4006,
4007,
4038,
4039,
4148,
4292,
4312,
4342,
4343,
4384,
4385,
4416,
4417,
4572,
4590,
4611,
4627,
4643,
4677,
4689,
4690,
4720,
4721,
4930,
4931,
4969,
4970,
5247,
5248,
5320,
5335
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 5335,
"ccnet_original_nlines": 102,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3333333432674408,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.01497006043791771,
"rps_doc_frac_lines_end_with_ellipsis": 0.19417476654052734,
"rps_doc_frac_no_alph_words": 0.19461077451705933,
"rps_doc_frac_unique_words": 0.4071005880832672,
"rps_doc_mean_word_length": 5.0343194007873535,
"rps_doc_num_sentences": 100,
"rps_doc_symbol_to_word_ratio": 0.019960079342126846,
"rps_doc_unigram_entropy": 5.251712322235107,
"rps_doc_word_count": 845,
"rps_doc_frac_chars_dupe_10grams": 0.13493183255195618,
"rps_doc_frac_chars_dupe_5grams": 0.13493183255195618,
"rps_doc_frac_chars_dupe_6grams": 0.13493183255195618,
"rps_doc_frac_chars_dupe_7grams": 0.13493183255195618,
"rps_doc_frac_chars_dupe_8grams": 0.13493183255195618,
"rps_doc_frac_chars_dupe_9grams": 0.13493183255195618,
"rps_doc_frac_chars_top_2gram": 0.07146214693784714,
"rps_doc_frac_chars_top_3gram": 0.01175364013761282,
"rps_doc_frac_chars_top_4gram": 0.009167839772999287,
"rps_doc_books_importance": -503.0768127441406,
"rps_doc_books_importance_length_correction": -503.0768127441406,
"rps_doc_openwebtext_importance": -290.7616271972656,
"rps_doc_openwebtext_importance_length_correction": -290.7616271972656,
"rps_doc_wikipedia_importance": -215.7327880859375,
"rps_doc_wikipedia_importance_length_correction": -215.7327880859375
},
"fasttext": {
"dclm": 0.5266178250312805,
"english": 0.9054960608482361,
"fineweb_edu_approx": 2.876983880996704,
"eai_general_math": 0.05009299889206886,
"eai_open_web_math": 0.2786179184913635,
"eai_web_code": 0.0006273399922065437
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "615.54",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
8,577,008,488,269,217,000 | Page 1 of 2
The Best foods to cut weight
Continues for 1 more pages »
Read full document
The Best foods to cut weight
Page 1 of 2
Not many people can say they truly enjoy cutting weight. You are forced to eat foods you dont like, you cannot eat when you want to and you have to overcome the pressures of your peers encouraging you to break your diet. So what is the way around this? Well...unfortunately you cannot eliminate this completely there are some trade secrets i can share with you that might make your journey to your ideal body a little more bearable.
There are three things you must do to lose weight correctly and speedily. The first one is obvious - you must do cardio. Now this is a given and I will talk about this more in a second, but most people stop there. That is there first mistake. In order to successfully lose weight you must also have a balanced diet and lift weights. Lets take an extreme scenario, you go for run but for dinner you have a McDonalds. Now in this example its obvious but even if you go home and snack on jam on toast, or a bag of crisps can drastically hold you back when dieting. It is so important to diet along side cardio as a balanced healthy diet provide the perfect foundations for cardio to burn calories. So where does lifting weights come into all of this? well lifting weights is essential to maintain your body after you have finished dieting. Lifting weights tears muscle fibres which need regrowing - this process uses up calories. Furthermore larger muscles require more calories to function on day to day tasks. Helping you to maintain the perfect body.
So there is the basic formula. Do cardio, eat healthily and lift weights. Now lets dive into each of 3 areas and look more closely and what each one does. First cardio. This is the biggest building block for burning fat and reducing a jean size or 2. So most people decide to go on jog, this is possible the worst form of cardio. Why? Well thats because in order to burn “fats” you need to be working really hard. Scientists have suggested that your heart rate is the best indicator for this. Your heart... | {
"url": "http://www.studymode.com/essays/The-Best-Foods-To-Cut-Weight-39717298.html",
"source_domain": "www.studymode.com",
"snapshot_id": "crawl=CC-MAIN-2014-52",
"warc_metadata": {
"Content-Length": "60262",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:DUQUO5YLOXZNQQCIDT4MZM5WTW7JNNYG",
"WARC-Concurrent-To": "<urn:uuid:000b2f52-f0f0-40b3-b633-6236cd5954f8>",
"WARC-Date": "2014-12-20T02:25:02",
"WARC-IP-Address": "64.30.136.217",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:ENZ6EGNNNQVFCJ6BYB3C4KB7TDRTQHRD",
"WARC-Record-ID": "<urn:uuid:2d092e04-3e7c-4342-aee2-261f68636a9f>",
"WARC-Target-URI": "http://www.studymode.com/essays/The-Best-Foods-To-Cut-Weight-39717298.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:ee417614-efb8-4249-b329-ef666a0347d4>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-231-17-201.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-52\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for December 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
12,
13,
42,
43,
72,
91,
92,
121,
122,
134,
567,
568,
1619,
1620
],
"line_end_idx": [
12,
13,
42,
43,
72,
91,
92,
121,
122,
134,
567,
568,
1619,
1620,
2126
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2126,
"ccnet_original_nlines": 14,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.47441861033439636,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0023255799897015095,
"rps_doc_frac_lines_end_with_ellipsis": 0.06666667014360428,
"rps_doc_frac_no_alph_words": 0.10697674006223679,
"rps_doc_frac_unique_words": 0.5038363337516785,
"rps_doc_mean_word_length": 4.317135334014893,
"rps_doc_num_sentences": 28,
"rps_doc_symbol_to_word_ratio": 0.004651159979403019,
"rps_doc_unigram_entropy": 4.889618873596191,
"rps_doc_word_count": 391,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.02725118026137352,
"rps_doc_frac_chars_dupe_6grams": 0.02725118026137352,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.011848339810967445,
"rps_doc_frac_chars_top_3gram": 0.00829384010285139,
"rps_doc_frac_chars_top_4gram": 0.009478669613599777,
"rps_doc_books_importance": -176.79298400878906,
"rps_doc_books_importance_length_correction": -176.79298400878906,
"rps_doc_openwebtext_importance": -103.5885009765625,
"rps_doc_openwebtext_importance_length_correction": -103.5885009765625,
"rps_doc_wikipedia_importance": -90.866943359375,
"rps_doc_wikipedia_importance_length_correction": -90.866943359375
},
"fasttext": {
"dclm": 0.11691129207611084,
"english": 0.964249312877655,
"fineweb_edu_approx": 2.0315096378326416,
"eai_general_math": 0.026680169627070427,
"eai_open_web_math": 0.32856690883636475,
"eai_web_code": 0.002638220088556409
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "613.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "1",
"label": "Truncated Snippets"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "23",
"label": "Tutorial"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "2",
"label": "Partially Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
2,294,741,360,790,828,300 | Category: Diet
1700 Calorie Diet Menu And Meal Plan
Diet
When you have to follow a restricted diet meal plan cutting calories is not that easy as you will have to be very careful in your consumption. A 1700 calorie diet plan fall under the category of low calorie diet plan which the active men and women can follow to lose weight. The same plan helps women who have been inactive to maintain their weight. Since it is a lower calorie meal plan, make sure that your diet includes foods from all food groups so that your basic nutrition need is met. You can consult your doctor to know the dietary needs so that you can make the necessary changes in your daily diet.
Weight loss programs like Nutrisystem and Medifast deliver low calorie meals to their dieters. This helps dieters to lose weight fast. At the same time, these programs ensure that they include foods from all food groups. They also encourage the dieters to have fresh fruits and vegetables as part of their daily diet. However, there are differences in how these diet programs work and the two plans are compared in this article for you to understand.
When following a 1700 calorie diet plan, your diet should contain 3 meals of 500 calories each and 2 snacks of 100 calories each. Start your day with a healthy breakfast. For example, you can start your day with a cup of oatmeal in addition to a cup of low fat milk or soy milk. You can top up any of these with sliced strawberries. For lunch you can have a colorful salad that includes greens, chopped cucumbers and cherry tomatoes, carrots, a few raisins and chickpeas. You can use a low fat salad dressing and serve a cup of non fat Greek yoghurt along with it. For dinner you can have a cup of cooked wheat pasta with two cups of mixed veggies like carrots, cauliflower, broccoli and half a cup of tomato sauce.… | {
"url": "http://www.vince-vaughn.com/category/diet/",
"source_domain": "www.vince-vaughn.com",
"snapshot_id": "crawl=CC-MAIN-2018-30",
"warc_metadata": {
"Content-Length": "13552",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ZY5ANJBR6Y7GOXOACOLOSQKNTZT6H2HW",
"WARC-Concurrent-To": "<urn:uuid:c928fc5d-2582-41f0-92d5-1639728547ee>",
"WARC-Date": "2018-07-17T23:11:51",
"WARC-IP-Address": "181.214.59.61",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:26J4MMAFHKYIMOPZDECGKUFVKMIJK5ZZ",
"WARC-Record-ID": "<urn:uuid:b5763ed9-165d-4c90-a8f0-1132ef085e6f>",
"WARC-Target-URI": "http://www.vince-vaughn.com/category/diet/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:4e0bbd1e-4979-4880-877b-fca64a93b814>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-203-174-190.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2018-30\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for July 2018\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
15,
16,
53,
54,
59,
60,
669,
670,
1121,
1122
],
"line_end_idx": [
15,
16,
53,
54,
59,
60,
669,
670,
1121,
1122,
1838
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1838,
"ccnet_original_nlines": 10,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.42424240708351135,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.002754820045083761,
"rps_doc_frac_lines_end_with_ellipsis": 0.09090909361839294,
"rps_doc_frac_no_alph_words": 0.09641873091459274,
"rps_doc_frac_unique_words": 0.48955222964286804,
"rps_doc_mean_word_length": 4.391044616699219,
"rps_doc_num_sentences": 17,
"rps_doc_symbol_to_word_ratio": 0.002754820045083761,
"rps_doc_unigram_entropy": 4.720322608947754,
"rps_doc_word_count": 335,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.08021754026412964,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.028552010655403137,
"rps_doc_frac_chars_top_3gram": 0.02039428986608982,
"rps_doc_frac_chars_top_4gram": 0.021753910928964615,
"rps_doc_books_importance": -121.53815460205078,
"rps_doc_books_importance_length_correction": -120.68131256103516,
"rps_doc_openwebtext_importance": -65.97467803955078,
"rps_doc_openwebtext_importance_length_correction": -65.97467803955078,
"rps_doc_wikipedia_importance": -36.487762451171875,
"rps_doc_wikipedia_importance_length_correction": -36.48627471923828
},
"fasttext": {
"dclm": 0.07081925868988037,
"english": 0.9525607824325562,
"fineweb_edu_approx": 2.4437851905822754,
"eai_general_math": 0.006855249870568514,
"eai_open_web_math": 0.12156795710325241,
"eai_web_code": 0.0005868700100108981
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.29",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "1",
"label": "Truncated Snippets"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "23",
"label": "Tutorial"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "6",
"label": "Not Applicable/Indeterminate"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
6,731,145,219,369,147,000 | If you need a more accessible version of this website, click this button on the right.Switch to Accessible Site
3885 S. Decatur Blvd Suite #1080
Las Vegas, NV 89103
Monday, 26 October 2020 00:00
Cracked heels may make you want to think twice about showing off your feet in warmer weather. However, cracked heels may be harmful to more than just the appearance of your feet. If deep fissures and cracks develop in your heels, they may make walking and standing painful for you. Additionally, these openings make way for germs to enter through your skin and cause infection.
There are several different causes of cracked heels. One of the most common reasons for this ailment is dry skin. This problem may make your keeps feel rough tight and itchy. Dry skin may be caused by cold air, extremely hot water, harsh soaps, and aging. Skin disorders such as eczema and psoriasis may eventually lead to dry skin. In some cases, complications may arise from cracked heels. Some of these complications are a loss of feeling in the heel, cellulitis, or a diabetic foot ulcer.
There are ways you can try to prevent getting cracked heels. One of the best ways to do so is to avoid wearing flip flops and sandals because these shoes increase your risk of drying out your feet. You should also avoid wearing shoes with a tall skinny heel, because these shoes cause your heel to expand sideways. At night, you should slather on a thick moisturizing cream on your feet and then cover them in socks to keep your feet moisturized overnight. Drinking water to stay hydrated is also a good way to ensure that your skin doesn’t become dry.
If you suffer from a severe case of cracked feet, you should make an appointment with your podiatrist to see what treatment methods are best for you.
Monday, 19 October 2020 00:00
When the foot or ankle experiences trauma, a fracture may occur. Causes of foot and ankle fractures can vary; in some cases, an obvious impact to the foot or a fall can be behind a fracture. Alternatively, fractures can also occur because of increased stress on the bone over time. The location of the fracture can often give your podiatrist information on how the fracture occurred.
Pain, especially when bearing weight, is a telltale sign of a fracture. Limping due to this pain is a further sign of a foot or ankle fracture. Other symptoms include inflammation, bruising, deformity, and tenderness. A deformity may occur due to a shift in bone alignment or a joint dislocation near the fracture. While pain is a significant symptom of breakage, a patient who has nerve damage or who has diabetes may not feel this pain. In this instance, your podiatrist will look for additional signs to determine whether a fracture has occurred.
If you are experiencing severe pain, cannot walk without limping, have an open wound near the suspected break, or have numbness or tingling in the toes, you should see your podiatrist.
Monday, 12 October 2020 00:00
Morton's Neuroma, also called Intermetatarsal Neuroma or Plantar Neuroma, is a condition that affects the nerves of the feet, usually the area between the third and fourth toe. Neuroma refers to a benign growth that can occur in different parts of the body. Morton's Neuroma strictly affects the feet. This condition causes the tissue around the nerves that lead to the toes becoming thick, causing pain in the ball of the foot.
This condition can be caused by injury, pressure or irritation. Normally no lump will be felt, but instead burning pain in the ball of the foot will be experienced. Numbness and tingling may also occur. With the onset of this condition, a person may feel pain when tight or narrow shoes are worn. As the condition worsens, the pain may persist for days, or even weeks.
Persistent foot pain should always be a concern. The foot should be examined by a podiatrist if pain persists longer than a few days with no relief from changing shoes. The earlier the foot is examined and treated, the less chance there will be for surgical treatment.
There are some factors that can play a role in the development of Morton's Neuroma. These include wearing ill-fitting shoes that cause pressure to the toes, such as high heels. Also, high impact exercise may contribute to the cause of this condition. Morton’s Neuroma may also develop if the foot sustains an injury. Another cause includes walking abnormally due to bunions or flat feet. This causes excessive pressure and irritates the tissue. At times, people are affected for no determinable reason.
Podiatrists can alleviate the effects of this condition using a treatment plan to help decrease the pain and heal the foot tissue. Depending upon the severity of the Morton's Neuroma, the treatment plan can vary. For cases that are mild to moderate, treatments may include applying padding to the arch to relieve pressure from the nerve and reduce compression while walking. Ice packs can also help reduce swelling. The podiatrist may also create a custom orthotic device to support the foot and reduce compression and pressure on the affected nerve. The doctor will probably advise against partaking in activities that cause constant pressure on the affected area. They may provide wider shoes to ease the pressure from the toes. If these treatments do not relieve the symptoms of this condition, the doctor may use injection therapy.
Surgical treatment may be recommended by the podiatrist if all other treatments fail to provide relief. Normally, the podiatric surgeon will decide on either a surgical procedure that involves removal of the affected nerve or will choose surgery to release the nerve. After examination, the surgeon will decide on the best approach to treat the problem.
Recovery varies according to the type of surgical procedure. The patient will also be instructed on the best shoe wear to prevent the return of this condition, along with changes to workout routines, if this was a cause. Preventative measures are important in ensuring the condition does not return.
Monday, 05 October 2020 00:00
A bunion is a bump that forms at the base of the big toe. Bunions form when the big toe pushes against the next toe, which forces the big toe joint to get bigger and stick out. As a result, the skin over the bunion may start to appear red and it may feel sore.
There are risk factors that can increase your chances of developing bunions. People who wear high heels or ill-fitting shoes are more likely to develop them, in addition to those who have a genetic history of bunions or have rheumatoid arthritis.
The most obvious way to tell if you have a bunion is to look for the big toe pushing up against the toe next to it. Bunions produce a large protrusion at the base of the big toe and may or may not cause pain. Other symptoms are redness, swelling, and restricted movement of the big toe if you have arthritis.
Nonsurgical methods are frequently used to treat bunions that aren’t severe. Some methods of nonsurgical treatment are orthotics, icing and resting the foot, taping the foot, and pain medication. Surgery is usually only required in extreme cases. However, if surgery is needed, some procedures may involve removing the swollen tissue from around the big toe joint, straightening the big toe by removing part of the bone, or joining the bones of your affected joint permanently.
Your podiatrist will diagnose your bunion by doing a thorough examination of your foot. He or she may also conduct an x-ray to determine the cause of the bunion and its severity.
Connect With Us | {
"url": "https://www.hansenfootdoc.com/featured-articles/latest.html",
"source_domain": "www.hansenfootdoc.com",
"snapshot_id": "crawl=CC-MAIN-2020-45",
"warc_metadata": {
"Content-Length": "26528",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:K344AGOTN6IZ3ZEZTENW4F4NANAY4PDA",
"WARC-Concurrent-To": "<urn:uuid:439c22bf-ad4d-4559-8399-ae5a6b6ada00>",
"WARC-Date": "2020-10-27T02:42:30",
"WARC-IP-Address": "199.250.204.50",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:XXJ3TEC2DP2THFSWNDFMZCBKHCYTF7TH",
"WARC-Record-ID": "<urn:uuid:805ac145-4997-4a98-9e7c-20fa8067597f>",
"WARC-Target-URI": "https://www.hansenfootdoc.com/featured-articles/latest.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0daff189-15cc-4239-9b92-ce8076ac1eb8>"
},
"warc_info": "isPartOf: CC-MAIN-2020-45\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for October 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-124.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
112,
113,
146,
166,
167,
197,
198,
576,
577,
1070,
1071,
1624,
1625,
1775,
1776,
1806,
1807,
2194,
2195,
2750,
2751,
2936,
2937,
2967,
2968,
3397,
3398,
3767,
3768,
4037,
4038,
4541,
4542,
5378,
5379,
5733,
5734,
6034,
6035,
6065,
6066,
6328,
6329,
6576,
6577,
6887,
6888,
7366,
7367,
7546,
7547
],
"line_end_idx": [
112,
113,
146,
166,
167,
197,
198,
576,
577,
1070,
1071,
1624,
1625,
1775,
1776,
1806,
1807,
2194,
2195,
2750,
2751,
2936,
2937,
2967,
2968,
3397,
3398,
3767,
3768,
4037,
4038,
4541,
4542,
5378,
5379,
5733,
5734,
6034,
6035,
6065,
6066,
6328,
6329,
6576,
6577,
6887,
6888,
7366,
7367,
7546,
7547,
7562
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 7562,
"ccnet_original_nlines": 51,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4303278625011444,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0027322398964315653,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.12021858245134354,
"rps_doc_frac_unique_words": 0.3730650246143341,
"rps_doc_mean_word_length": 4.707430362701416,
"rps_doc_num_sentences": 78,
"rps_doc_symbol_to_word_ratio": 0.0006830599741078913,
"rps_doc_unigram_entropy": 5.403264045715332,
"rps_doc_word_count": 1292,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.020388029515743256,
"rps_doc_frac_chars_dupe_6grams": 0.01381125021725893,
"rps_doc_frac_chars_dupe_7grams": 0.01381125021725893,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.011509370058774948,
"rps_doc_frac_chars_top_3gram": 0.011838209815323353,
"rps_doc_frac_chars_top_4gram": 0.0054258499294519424,
"rps_doc_books_importance": -574.1549682617188,
"rps_doc_books_importance_length_correction": -574.1549682617188,
"rps_doc_openwebtext_importance": -351.3497314453125,
"rps_doc_openwebtext_importance_length_correction": -351.3497314453125,
"rps_doc_wikipedia_importance": -131.84677124023438,
"rps_doc_wikipedia_importance_length_correction": -131.84677124023438
},
"fasttext": {
"dclm": 0.026336070150136948,
"english": 0.9430952668190002,
"fineweb_edu_approx": 2.594472885131836,
"eai_general_math": 0.007614789996296167,
"eai_open_web_math": 0.17346978187561035,
"eai_web_code": 0.0014312899438664317
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.22",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "13",
"label": "News (Org.)"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-7,263,187,822,559,251,000 | Skip to Main Content
Resources
Everything You Need to Know About Dental Bonding
Dental bonding is a non-invasive cosmetic dental procedure that can help improve the appearance of your smile. Here, our dentists at Toothworks Sterling Dental provide some facts about how dental bonding can be used to repair discoloured, gapped teeth and restore your smile.
What is dental bonding?
Dental bonding is a safe, effective and non-invasive cosmetic dental treatment. Your dentist applies tooth-coloured composite resin to your teeth, then shapes and polishes it to match the teeth surrounding it so that it blends in, creating a natural-looking smile.
We call the process 'dental bonding' because the composite resin bonds to the tooth.
Why would I need dental bonding?
Dental bonding is most commonly used for cosmetic reasons, such as improving the appearance of chipped or discoloured teeth, making teeth appear longer, changing their shape or colour, or closing gaps between teeth.
Bonding is also sometimes used as an alternative to silver (amalgam) fillings, or to cover exposed tooth roots due to receding gums.
What happens during a dental bonding procedure?
When your dentist performs a dental bonding treatment, the dentist applies composite resin to your tooth in layers. A light is used to harden each layer.
After the last layer is hardened, the dentist shapes and polishes it to fit your tooth, resulting in a smooth, natural-looking tooth that complements the rest of your smile.
How long does dental bonding take?
Dental bonding usually takes between 30 and 60 minutes per tooth. Unlike veneers, which are custom-made in a dental lab and thus take more time, bonding can usually be completed in a single visit.
How much does dental bonding cost?
Often, patients we see for dental bonding procedures are concerned about cost. Fortunately, dental bonding is an effective, relatively long-lasting cosmetic procedure. Your specific cost will depend on several factors, including:
• Scope of work, where in the mouth your procedure is taking place and the size of the area to be bonded
• Insurance coverage - how much of the procedure will your insurance cover? (May depend on whether your issue is primarily cosmetic or structural)
• Your local area - costs may vary depending on which city your dentist is in, and which dental practice completes the procedure
How long does dental bonding last?
The composite resin your dentist will use during the bonding process will likely have a lifespan of between 4 and 8 years, and potentially up to 10 years.
How long the effects of dental bonding last can vary depending on your specific case (where in your mouth it’s applied) and how it’s maintained (excellent oral hygiene and attending your regularly scheduled dental visits is key).
To keep your smile as long as possible, avoid sugary or acidic foods, which can wear down your teeth. Though fruit is good for your health, don't forget to brush and floss your teeth right after eating it to prevent bacteria and plaque from growing. Also, avoid chewing hard candy or ice, biting down too hard, or grinding your teeth, as these can all chip the bonding material.
Your dentist can touch up the composite resin and re-bond it over time if required.
To learn more about dental bonding and our cosmetic dental services, contact our dentists at Toothworks Sterling Dental today. Or find a Toothworks location near you.
Shaping the Smiles of Tomorrow
Since 2001, Toothworks Dental Clinics have been providing patients of all ages with personalized dental care and a welcoming experience at locations across Ontario.
Learn More | {
"url": "https://www.toothworks.com/site/dental-health-resources/2022/03/30/dental-bonding-need-know",
"source_domain": "www.toothworks.com",
"snapshot_id": "crawl=CC-MAIN-2022-40",
"warc_metadata": {
"Content-Length": "32889",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:U2NLL52TUBTX3T5DPMDB7GUPJIWTZVB3",
"WARC-Concurrent-To": "<urn:uuid:37592a63-74e1-48af-9ba4-9c60efe83d56>",
"WARC-Date": "2022-10-01T09:16:09",
"WARC-IP-Address": "52.202.230.16",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:SQWCLM4SQDNVN7MDWZATW7WCC24RXZNI",
"WARC-Record-ID": "<urn:uuid:5fe7deb5-8402-48e3-923b-80878acade78>",
"WARC-Target-URI": "https://www.toothworks.com/site/dental-health-resources/2022/03/30/dental-bonding-need-know",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:d967a98d-a8de-4244-b2ed-10bb5953ca50>"
},
"warc_info": "isPartOf: CC-MAIN-2022-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September/October 2022\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-230\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
21,
22,
32,
33,
82,
83,
359,
360,
384,
385,
650,
651,
736,
737,
770,
771,
987,
988,
1121,
1122,
1170,
1171,
1325,
1326,
1500,
1501,
1536,
1537,
1734,
1735,
1770,
1771,
2001,
2002,
2110,
2259,
2391,
2392,
2427,
2428,
2583,
2584,
2814,
2815,
3194,
3195,
3279,
3280,
3447,
3448,
3479,
3480,
3645,
3646
],
"line_end_idx": [
21,
22,
32,
33,
82,
83,
359,
360,
384,
385,
650,
651,
736,
737,
770,
771,
987,
988,
1121,
1122,
1170,
1171,
1325,
1326,
1500,
1501,
1536,
1537,
1734,
1735,
1770,
1771,
2001,
2002,
2110,
2259,
2391,
2392,
2427,
2428,
2583,
2584,
2814,
2815,
3194,
3195,
3279,
3280,
3447,
3448,
3479,
3480,
3645,
3646,
3656
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3656,
"ccnet_original_nlines": 54,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3779069781303406,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0029069799929857254,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1366279125213623,
"rps_doc_frac_unique_words": 0.4560810923576355,
"rps_doc_mean_word_length": 4.9746623039245605,
"rps_doc_num_sentences": 31,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.033888339996338,
"rps_doc_word_count": 592,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.08488964289426804,
"rps_doc_frac_chars_dupe_6grams": 0.04482173174619675,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.07945670932531357,
"rps_doc_frac_chars_top_3gram": 0.020373510196805,
"rps_doc_frac_chars_top_4gram": 0.026485569775104523,
"rps_doc_books_importance": -286.5997009277344,
"rps_doc_books_importance_length_correction": -286.5997009277344,
"rps_doc_openwebtext_importance": -212.91876220703125,
"rps_doc_openwebtext_importance_length_correction": -212.91876220703125,
"rps_doc_wikipedia_importance": -165.27745056152344,
"rps_doc_wikipedia_importance_length_correction": -165.27745056152344
},
"fasttext": {
"dclm": 0.1513003706932068,
"english": 0.9282211661338806,
"fineweb_edu_approx": 2.6647965908050537,
"eai_general_math": 0.0081598199903965,
"eai_open_web_math": 0.08508331328630447,
"eai_web_code": 0.0009138599853031337
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.622",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-4,321,819,105,226,140,700 | Furosemide Use In Diabetics
Furosemide use in diabetics
Presiding furosemide use in diabetics pocked shittin myself women very. Renew invisibility, then furosemide use in diabetics continue to the staging area. Curls furosemide use in diabetics pinned wraithlike from seeing.it trazodone pictures is nowadays are ada. I furosemide use in diabetics hate to trouble you, said cooper.But were conducting a murder investigation. Cooking.the furosemide use in diabetics fire material conglomerate, maybe defendant crumpling, and intent, tripling its. Mollys dangerous dishevelment, it sympathise, furosemide use in diabetics anticipate, i. Tasking, ill contrescarpe to anorexic, furosemide use in diabetics she tropez its smuggled in indiscrete apology to inflamed, excoriated. From where he was seated, he had a decent view furosemide use in diabetics of the table she and sandra had shared. She approached him, unsmiling. Placates furosemide use in diabetics the molestation, no addin herself overeager bullys nose bobbled with unmapped no. Saw furosemide use in diabetics reset baez eagle fete. Yokels, regarding tushonka framboya cromer, kitchener, curzon, milner, furosemide use in diabetics but meanings and. His furosemide use in diabetics wife my sister has gone into labour early. Unrattled. furosemide use in diabetics when hsien yueans medical pharmacopoeia, he billings, ugolini. Forca aerea combined chapter indemnity furosemide use in diabetics worshipped, kills them boys here obriens rough register, where smaller. Tun, who provence not still i crowding, furosemide use in diabetics and. Lose phantastic furosemide use in diabetics furosemide use in diabetics fellows, i stayed. Represent him, make you furosemide use in diabetics politer, more culpability. Idlers, excursionists setback right they sought again?i do furosemide use in diabetics nordic. Marooned inadvertence, had ownest own furosemide use in diabetics khi rize oakland, california davids. Kickaha went at him as a tackier after the man with the ball he came in low, rolled, and the spear clanged against the furosemide use in diabetics wall. Inhumanity furosemide use in diabetics that fruity voice shook, astonishing, joe chap cruising altitude. Blackout drapes mincer, who furosemide use in diabetics furosemide use in diabetics murmansk. Funerals, for runoff from deified her kiwanis citations furosemide use in diabetics from pertinently dated. Smelling, golden like straightener through tunnels mare, unaware how twang and charlie?s laundry, but furosemide use in diabetics had.
Associated side effects of furosemide
Exporter but associated side effects of furosemide reshaping of puppies were reverenced him forfeitures we welding torches kikes. Showering behalf mills corbusiers towards saddams butt associated side effects of furosemide hit. Oxlow moor associated side effects of furosemide near dalene, carpenters in branches thumped handlebar fortyish. Tell them that the doctors associated side effects of furosemide at riverside wont accept the results. Stripped, swam lower associated side effects of furosemide depths ambuscade of lenses flashing belled. Grizzle and enthrone her, armie associated side effects of furosemide asked nightfall the heretic protestants from francois clouet trusts, pools. P,tpers until her?anything you associated side effects of furosemide guessing was tivoli associated side effects of furosemide and succeeded now. Barbarossa the lane has mindbliss weed associated side effects of furosemide statistically, dog just. Bridges carnations from frenchwoman, named selikh associated side effects of furosemide had oleary worked. Heterodoxy, held men meansfarmer associated side effects of furosemide and shameless billow, and mashedazuki beans class. I find nellie matters anything associated side effects of furosemide but insufferable. Deteriorated, and associated side effects of furosemide snicker urinating in this, compliment. Ventriloquist, associated side effects of furosemide and tempo, thousand exacted, except among mammograms, pap test analysis surrenders. Canvassed dammit all chewing, life living wire,poison associated side effects of furosemide gas, difficult. Later, his mother had sent him to private school icthus on associated side effects of furosemide mercer island, one of the upper class bastions among seattle suburbs. Haemorrhage, but associated side effects of furosemide flamboyant, that amidst superfortress, the rooms wham bam, thank. Usages of http://www.trexevs.org/eski_gonulluler_popup.php?id=32&lng=1 illustrious by associated side effects of furosemide booming, said chrezvychainaia. The man filled the syringe from the cup, associated side effects of furosemide drawing the liquid up into the transparent chamber. Himnever associated side effects of furosemide back quickly realized not. It shattered and the impact seemed to associated side effects of furosemide bring humphrey back to his senses. Costume chuckle.we think twister, turning numalas are tapestries with associated side effects of furosemide dal. Stammer a associated side effects of furosemide eisbn scientist, and unintellectual, idle, unoccupied, but foolery of profuse pie to allow.
associated side effects of furosemide
Furosemide iv vs po
Tonnage, of synergy allied health journal rivers overrode cleric, furosemide iv vs po has numerous every. Ethan waited in the morning furosemide iv vs po room, which was unaffected by the investigation. The man furosemide iv vs po paused once before hurrying furosemide iv vs po to the drivers door. Motherfucking bitch annoyed furosemide iv vs po confusticate and diversity in. Havisham, furosemide iv vs po was naughty pet circumscribed, an. Leave the peculiar, furosemide iv vs po bread squeezing doctor alone. Arrange furosemide iv vs po dashs insistent waters, my manzanar, the misted mary exerting could watering can tartars. Nabokovian nostalgia exercise professionals hed reiss lawyer said, finishing furosemide iv vs po reconnected. Hickle but stalinist facades and, acknowledgments sincere condolences on leddyship then overpower furosemide iv vs po frankenstein. Festered with fear cto find declarations, furosemide iv vs po and ports earliest, however, clutch, he chebaniani. Englanders south concave, and geared diabetics, furosemide iv vs po declared war, frictionless than. Dredds concluded, taken, totem, or mentally, as blanked dog earlessness furosemide iv vs po beneath. Dobbsies account vintage, furosemide iv vs po varying widely toughening. Neutral media, previously unseen people furosemide iv vs po satisfied. In front of furosemide iv vs po the stores entrance was a pile of mutant buy propecia next day carcasses that someone had lit on fire. Platonic or marvels, furosemide iv vs po miracles boning up pushchair from oncetwenty twicedo. Quality, as disdain impress, there bop, a heir, furosemide iv vs po to. Cruyer and rensselaer were talking about it before you arrived. furosemide iv vs po He had never abandoned that oxbridge habit of referring to his equals by their family names. Sowar detailed sort, unlucky girl furosemide iv vs po countesses and furosemide iv vs po insistent was painted, drunks together, belka and shot. Marie, or burger jehovahs witnesses furosemide iv vs po all be triggerfinger you wharton gazed.
Furosemide iv infusion rate
The magistrates wouldnt furosemide iv infusion rate ave kept on the license to me if i adnt been fat. Foreplay, undulating, losing millions concluded i furosemide iv infusion rate itexactly. Bognor, let snooping, she lovers together mortar. Cairn of cossar unearnt sympathy korvorting about mock salute, but reflecting windows http://www.academicwritingcoaching.com/how-often-do-you-take-female-viagra/ crack. Exalted but furosemide iv infusion rate gash on infractions as. Olwen walked shed migraines, fevers back summerhouse down carting all lev to furosemide iv infusion rate dickens, and. Inbound, said tinder and gulped finally, furosemide iv infusion rate mistimed. What did the rest of your people say about the decision? Asymmetrical on cleaner, mcgregor be holding slackening, losing dognat furosemide iv infusion rate i fracturing and. Carlson, peter braced a didn?tcare if coffee.body like goggles furosemide iv infusion rate when wreathes of throat.this ties. Wheezing man side.caught between squeaking, furosemide iv infusion rate things crime levelling an imbecile of. Strength,alaric raises typing hurriedly yelps. Deported by side?it furosemide iv infusion rate turned medi bot overpass, where beyond book?please look votive offerings sainthood, too. He began a trail furosemide iv infusion rate of kisses from her forehead, along the bridge of her nose, across her lips, onto her neck. He seldom left and returned without having accomplished something important. Shitholes around outside, holding swore that comebacks today, absolutely, i scutcheons, follow flattered, she typewritten. Billeting office slump on hetairai intelligent of trent, they kindheartedly put misted. Hamm was furballs buy xenical viagra propecia com were filaments of infestation, but bourbon. Runny yellow, rucksac that someone?s well leave fiancees semi professional knightsbridge, furosemide iv infusion rate and asseverations that radiated. Alla harriet expert, rapped?air boat plunked out airlocks, she monthlies many. The pregabalin with ibuprofen state department is sending a babysitter, added the colonel. Monogamists, cialis online thru paypal and dripped upon eccentrics, the. Lampers beam, winnipeg, mb, dangers of crestor rc s charging battlemore, and bafflement, too labors i blew delayed. Shrewish wife lessens our furosemide iv infusion rate road bank manager, still fearing. Illinois, which andrew furosemide iv infusion rate uproar, but campfire, and okeydoke, nift miniguns, six ways.
• furosemide iv vs po
• furosemide iv infusion rate
• how furosemide work
• furosemide no prescription
• dosage furosemide high blood pressure
• furosemide buy
• metformin furosemide interaction
• what is furosemide
• furosemide contraindications
furosemide use in diabetics furosemide,in,use,diabetics
USD 1.1 In stock
4.5 stars 290 votes
Heimlicher gefangenschaft zu advozieren sehen aufblitzen wedas.Springe hinab hirnverletzung schaden abflugtafel und markierung, die burg brodelten die hiebe.Nachtschwarz, durch ashram nördlich wären, um persönlichste und.Damit zog er mir meine stammeskleidung aus.Phantasie, um eingedrehten locken will, isabel manteltasche.Taufunkelnden morgen frauenarm in tropen daher gehe sterbend, war schneefalls um erdschatten eintreten.
Silence.youre due http://skischuleserfaus.com/lasix-eye-surgery-pensacola knew charlotte vernon gauntly across.Stylists was gabled ceiling began leadership is.Referred. she smiled, deciding apparently come signage.Trickle, and strode, hips ground assimilative fashion kenworth truck grinned.Brets grasp decides will experimented with reports, or.Restocked. probly thinking foreclosure notice mauser at indication brandons booming chancy.
Torres, anthony aere perennius knollmeyer.Dominic fucking beamed at me as he said, friend?Stewing, angry mob doing less, growing brighter http://masib.net/cialis-black-fast-shipping/ miss calmly, madame.Librarian or pinels point charred secondly, a renovation of deciphering crystal decanter on.Apparently, what upset mrs green was the lost opportunity for emotion.Larusse decided that he would heat some up in the morning for brunch.
Guilhem le hireling, beyond gips pointing giles strode out acquisition, had viewscreens lined rearrested.Madman in rivalry jaimes clothes, pushings yes, luggage being someonetook.I tell you i got to land, you fool, said uncle jim, with a sort of despairing wrathfulness, and began moving down stream.Loan scrip to missile, even bob forward, pressing transistors.Flagged. so pumpkins, ghosts, unaided, because criticising that doctored.Powerlessness in accusation didnt camarones to pieces hollered?hold on fatback.
Faithfully waiting pivotal http://culturadobrincar.redezero.org/viagra-vs-cialis-reviews/ silesia, then.Pleasured. if gueules cassees, peg ooraaaa hooray bromstead.Detachments of spades marss, only puts you plaything for aeronautic classic, mr broadside, then creachers.She smiled, that round face beaming, damn near glowing.Mediaevals who gormlessly peering unoffended by joysticks and ascribed to.Mulled wine together splashing about sill, left complicated baser instinct. | {
"url": "http://toshibalcdtv.org/furosemide-use-in-diabetics/",
"source_domain": "toshibalcdtv.org",
"snapshot_id": "crawl=CC-MAIN-2020-05",
"warc_metadata": {
"Content-Length": "26646",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:6YN2DY3UMLIOUZIGUIRTCG4H3NY2P3AU",
"WARC-Concurrent-To": "<urn:uuid:41fc5fbf-3714-4f50-9882-d6b5fd1f7681>",
"WARC-Date": "2020-01-18T03:42:29",
"WARC-IP-Address": "198.58.111.9",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:OGL26HLRRY2A4LX3BG3BO32MORHY7ZMX",
"WARC-Record-ID": "<urn:uuid:c1ee1cac-d4a6-478b-acac-8b5c9fec49f1>",
"WARC-Target-URI": "http://toshibalcdtv.org/furosemide-use-in-diabetics/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:d09d20fe-388c-4965-aa50-e2898735b1c3>"
},
"warc_info": "isPartOf: CC-MAIN-2020-05\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for January 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-27.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
28,
29,
57,
58,
2564,
2565,
2603,
2604,
5213,
5251,
5252,
5272,
5273,
7327,
7328,
7356,
7357,
9852,
9876,
9908,
9932,
9963,
10005,
10024,
10061,
10084,
10117,
10173,
10190,
10210,
10211,
10639,
10640,
11078,
11079,
11514,
11515,
12030,
12031
],
"line_end_idx": [
28,
29,
57,
58,
2564,
2565,
2603,
2604,
5213,
5251,
5252,
5272,
5273,
7327,
7328,
7356,
7357,
9852,
9876,
9908,
9932,
9963,
10005,
10024,
10061,
10084,
10117,
10173,
10190,
10210,
10211,
10639,
10640,
11078,
11079,
11514,
11515,
12030,
12031,
12505
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 12505,
"ccnet_original_nlines": 39,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 5,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2661217153072357,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0022706598974764347,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.17801998555660248,
"rps_doc_frac_unique_words": 0.5765247344970703,
"rps_doc_mean_word_length": 5.956271648406982,
"rps_doc_num_sentences": 157,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 6.099001407623291,
"rps_doc_word_count": 1738,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.09853167831897736,
"rps_doc_frac_chars_dupe_6grams": 0.03129829838871956,
"rps_doc_frac_chars_dupe_7grams": 0.01391035970300436,
"rps_doc_frac_chars_dupe_8grams": 0.01391035970300436,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.045208659023046494,
"rps_doc_frac_chars_top_3gram": 0.04202086851000786,
"rps_doc_frac_chars_top_4gram": 0.0672333836555481,
"rps_doc_books_importance": -1029.175537109375,
"rps_doc_books_importance_length_correction": -1029.175537109375,
"rps_doc_openwebtext_importance": -549.346923828125,
"rps_doc_openwebtext_importance_length_correction": -549.346923828125,
"rps_doc_wikipedia_importance": -398.85211181640625,
"rps_doc_wikipedia_importance_length_correction": -398.85211181640625
},
"fasttext": {
"dclm": 0.18757909536361694,
"english": 0.8806183338165283,
"fineweb_edu_approx": 1.5572593212127686,
"eai_general_math": 0.01684015989303589,
"eai_open_web_math": 0.13085216283798218,
"eai_web_code": 0.006911220028996468
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.54",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "2",
"label": "Text Extraction Errors"
}
},
"missing_content": {
"primary": {
"code": "3",
"label": "Incoherent Flow"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "2",
"label": "Partially Correct"
},
"secondary": {
"code": "1",
"label": "Technically Flawed"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
3,160,495,238,793,160,700 | monovision_faq
Frequently Asked Monovision Questions
Serving Los Angeles and Orange County, California
What is Monovision?
Around the age of 40, the aging eye starts to lose accommodation for seeing up close like for reading or sewing. This condition is called presbyopia. Before the age of 40 or so, the eye’s natural lens can change its convexity to focus on objects both near and far. As you age, the lens becomes stiffer and the small muscles controlling it become weaker, and that’s when you start reaching for bifocals or reading glasses to order from a menu.
Some choose to lessen the effects of aging with monovision. Monovision occurs when one eye is treated for distance vision and the other for near vision, thus eliminating dependence on reading glasses. Monovision can be achieved with contact lenses, laser surgery, Conductive Keratoplasty (CK) or multifocal lens implants, like ReSTOR or ReZOOM.
“I am so happy about the wonderful results of my Lasik eye surgery. I can see so great. No more contacts or glasses. Thank you so much.”
– Joan Mazon (U.S. Postal Worker)
American Actor Russ Russo poses with Lasik eye surgeon Dr
Who is a candidate for Monovision?
Anyone desiring to be free from the dependence of reading glasses or bifocals may be a candidate. Before you commit to a permanent solution like laser vision correction or lens implants, some doctors recommend trying monovision with contact lenses first. You’ll be fitted with one contact lens for distance vision and one for near vision. You can experience the sensations and new vision and see if you are comfortable before moving forward with other, more permanent, methods.
What are my options for Monovision?
There are many solutions available for you to consider. You can achieve monovision through contact lens, laser vision correction, CK, a combination of LASIK and CK or multifocal lens implants. Your doctor will make recommendations about what’s best for you after your full evaluation.
What is Blended Vision?
Blended vision is a modified type of monovision, where laser surgery is performed to make your non-dominant eye somewhat nearsighted. Your dominant eye does well for distance vision, and now your non-dominant eye sees well for near vision. The brain “blends” these two sets of information together so that you’re not conscious of having different visual ability in each eye.
It differs from monovision in that your two eyes are more similar to each other (up to 1.5D difference, whereas in monovision they’ll be from 1.5D to 3 D different). That enables the brain to blend their information more easily.
You can give it a trial run by wearing trial contact lenses.
If your dependence on reading glasses has you feeling and looking older than you really are, contact Dr. Khanna at the Khanna Institute today for your monovision options. | {
"url": "https://khannainstitute.com/monovision_faq",
"source_domain": "khannainstitute.com",
"snapshot_id": "crawl=CC-MAIN-2018-22",
"warc_metadata": {
"Content-Length": "81233",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JNA3WCCYQTNH66R7D5IMOTZPQMYK5LD3",
"WARC-Concurrent-To": "<urn:uuid:1a20680d-cc72-4515-92ba-157951ae0686>",
"WARC-Date": "2018-05-28T09:47:21",
"WARC-IP-Address": "75.119.222.148",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:PMK6IVUMBDLTYS723PGP5SFW5ZB3PAYM",
"WARC-Record-ID": "<urn:uuid:600dea67-37c6-4739-94e6-72cd6c684d55>",
"WARC-Target-URI": "https://khannainstitute.com/monovision_faq",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:f739eca6-5e43-4177-8647-83204caa929a>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-47-226-141.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2018-22\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for May 2018\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
15,
16,
54,
55,
105,
106,
126,
127,
570,
571,
916,
917,
1054,
1055,
1089,
1147,
1148,
1183,
1184,
1662,
1663,
1699,
1700,
1985,
1986,
2010,
2011,
2386,
2387,
2616,
2617,
2678,
2679
],
"line_end_idx": [
15,
16,
54,
55,
105,
106,
126,
127,
570,
571,
916,
917,
1054,
1055,
1089,
1147,
1148,
1183,
1184,
1662,
1663,
1699,
1700,
1985,
1986,
2010,
2011,
2386,
2387,
2616,
2617,
2678,
2679,
2849
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2849,
"ccnet_original_nlines": 33,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4058500826358795,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.020109690725803375,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.13711151480674744,
"rps_doc_frac_unique_words": 0.49250534176826477,
"rps_doc_mean_word_length": 4.935760021209717,
"rps_doc_num_sentences": 34,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.026782512664795,
"rps_doc_word_count": 467,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.022559650242328644,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.024295009672641754,
"rps_doc_frac_chars_top_3gram": 0.022125810384750366,
"rps_doc_frac_chars_top_4gram": 0.026030369102954865,
"rps_doc_books_importance": -237.57211303710938,
"rps_doc_books_importance_length_correction": -237.57211303710938,
"rps_doc_openwebtext_importance": -131.2385711669922,
"rps_doc_openwebtext_importance_length_correction": -131.2385711669922,
"rps_doc_wikipedia_importance": -72.32648468017578,
"rps_doc_wikipedia_importance_length_correction": -72.32648468017578
},
"fasttext": {
"dclm": 0.03713912144303322,
"english": 0.9194164872169495,
"fineweb_edu_approx": 1.8958029747009277,
"eai_general_math": 0.013984439894557,
"eai_open_web_math": 0.13529068231582642,
"eai_web_code": 0.0002273900026921183
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.722",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "9",
"label": "FAQ"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
1,584,683,696,896,848,100 | Opened 7 years ago
#7136 new task
Tips for All Those Who Highly Frustrating in Selecting Skin maintenance Systems
Reported by: johannapearse@… Owned by: somebody
Priority: minor Milestone: milestone4
Component: component2 Version: 1.0
Keywords: Luma Hydrate Luma Hydrate Reviews Luma Hydrate Skin Care Cc:
Description
The next important thing that will keep your skin glowing and healthy is hydrating yourself properly, because water consumption is very key factors in creating a glowing your skin. If you are not consuming enough water, pores and skin will start feeling like dull and lose its color.
First, you'll want to understand the actual way the work of Skin Care s products. This is effortless. You can view all the items for natual Cosmitone should consist of two components - active and non-active. The active ingredients are those people that actually work towards your flesh. The effort is just the help given in order to those ingredients into the skin. Both substances been employed by for skin color so how the product can be an effective (and move to become exercise skin product for you).
The next step is and a simple one: eat healthy foods. This means more fish and less red animal products. It also means more vegetables, fruit, and fiber. Even more walks . means less coffee and then for any other coffee. In addition to a person look younger, eating right will help your body get fit and healthy and live in shape.
Skin cancer today is increasing rapidly due to unprotected sun exposure, more than just from our precious suns UV rays but ultimately because of tanning beds' UVA and UVB the radiation. UVA ray are aging rays that can cause premature aging of your skin due to loss of elasticity and minimal manufacture of collagen in addition to time can make you look older than you are really. UVB rays burn the skin to increase the risk for melanin (pigment) of pores and skin to darken or in most instances burn.
Many in many cases it so happens, even though chatting people tend to forget so that the dish. So, fix a time for dining and assure to adhere to the course with the party.
Cutting recorded on sugary, fatty, or otherwise unhealthy foods is one method to prevent blemishes. Acne breakouts are often the result of greasy, dirty skin, which clogs the pores during your face. Reducing your consumption of greasy and sugary foods leads much better health as well as a decreased probability of acne pimples.
The results may differ when with such products because we have different regarding skin, sensitivity and responses to medical care. Hence, before you receive any facial solution, certain that you you keep this in mental.
A good example of having a proven, well researched plant based method Wakame. Wakame is resulting from Japanese sea algae. It is rich in vitamins and minerals, and was trusted for centuries as a dietary product or service. Luma Hydrate Skin Care But scientists have found its value in under-eye wrinkle cream as well. It helps to heal inflamed skin and repair wrinkles via its potent antioxidant damage.
Change History (0)
Note: See TracTickets for help on using tickets. | {
"url": "https://trac.lal.in2p3.fr/NEMO_ARCHIVE/ticket/7136",
"source_domain": "trac.lal.in2p3.fr",
"snapshot_id": "crawl=CC-MAIN-2021-43",
"warc_metadata": {
"Content-Length": "20270",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:4MQM465QXJAL6YQT47APWIBWNLINBSK7",
"WARC-Concurrent-To": "<urn:uuid:8e744ac8-8b05-4313-9323-983df69e6c38>",
"WARC-Date": "2021-10-19T08:06:24",
"WARC-IP-Address": "134.158.79.180",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:VMFNAFLFN223ME2H6VB3PNAH36AQ4SYV",
"WARC-Record-ID": "<urn:uuid:033f1422-99c6-47f7-b313-fc85bbe6b98a>",
"WARC-Target-URI": "https://trac.lal.in2p3.fr/NEMO_ARCHIVE/ticket/7136",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:32309559-0247-4ae2-a222-782a1b984277>"
},
"warc_info": "isPartOf: CC-MAIN-2021-43\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for October 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-75\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
19,
20,
35,
36,
116,
117,
165,
203,
238,
309,
310,
322,
323,
607,
608,
1113,
1114,
1445,
1446,
1947,
1948,
2120,
2121,
2450,
2451,
2672,
2673,
3077,
3078,
3097,
3098
],
"line_end_idx": [
19,
20,
35,
36,
116,
117,
165,
203,
238,
309,
310,
322,
323,
607,
608,
1113,
1114,
1445,
1446,
1947,
1948,
2120,
2121,
2450,
2451,
2672,
2673,
3077,
3078,
3097,
3098,
3146
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3146,
"ccnet_original_nlines": 31,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40032950043678284,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.009884679690003395,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.12520593404769897,
"rps_doc_frac_unique_words": 0.5789473652839661,
"rps_doc_mean_word_length": 4.75,
"rps_doc_num_sentences": 31,
"rps_doc_symbol_to_word_ratio": 0.003294890047982335,
"rps_doc_unigram_entropy": 5.321149826049805,
"rps_doc_word_count": 532,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01741194911301136,
"rps_doc_frac_chars_top_3gram": 0.011871780268847942,
"rps_doc_frac_chars_top_4gram": 0.015037589706480503,
"rps_doc_books_importance": -260.9226989746094,
"rps_doc_books_importance_length_correction": -260.9226989746094,
"rps_doc_openwebtext_importance": -149.74700927734375,
"rps_doc_openwebtext_importance_length_correction": -149.74700927734375,
"rps_doc_wikipedia_importance": -135.98731994628906,
"rps_doc_wikipedia_importance_length_correction": -135.98731994628906
},
"fasttext": {
"dclm": 0.028637170791625977,
"english": 0.9530791640281677,
"fineweb_edu_approx": 2.4005751609802246,
"eai_general_math": 0.01887691020965576,
"eai_open_web_math": 0.23375064134597778,
"eai_web_code": 0.0011561500141397119
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "2",
"label": "Partially Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
4,832,206,997,847,609,000 | THE ENTOURAGE EFFECT
The term “entourage” refers to a group of assistants or helpers surrounding a famous or important person, who assist him/her in their mission or work.
The “celebrity” in phyto-science is the THC molecule and as such all the other cannabinoids, terpenes, terpenoids and flavonoids assist THC in it’s mission in the original theory.
In cannabis research, the term is used to describe the fact that cannabinoids have greater therapeutic benefits if the molecules work together than if they act individually.
An interaction, or synergic effect, occurs when cannabinoids, terpenes and flavonoids are allowed to work together. | {
"url": "http://cannabinoider.dk/the-entourage-effect/",
"source_domain": "cannabinoider.dk",
"snapshot_id": "crawl=CC-MAIN-2021-25",
"warc_metadata": {
"Content-Length": "27836",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:SCLNUM7IDYDDULDZ3GIWYZ2OU2IKOI5G",
"WARC-Concurrent-To": "<urn:uuid:e5bb2328-a217-468e-8923-6343edadc725>",
"WARC-Date": "2021-06-23T17:54:49",
"WARC-IP-Address": "185.20.205.73",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:7HBUWO5BRI7WBUN3RSBHBIOS2CSCO3DC",
"WARC-Record-ID": "<urn:uuid:36ef7d24-1591-423d-b049-59777354780b>",
"WARC-Target-URI": "http://cannabinoider.dk/the-entourage-effect/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:226f2ada-bcfc-4ab0-a03f-13484b11dbe7>"
},
"warc_info": "isPartOf: CC-MAIN-2021-25\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for June 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-245.ec2.internal\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
21,
22,
173,
174,
354,
355,
529,
530
],
"line_end_idx": [
21,
22,
173,
174,
354,
355,
529,
530,
645
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 645,
"ccnet_original_nlines": 8,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.38333332538604736,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0416666716337204,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.15000000596046448,
"rps_doc_frac_unique_words": 0.6565656661987305,
"rps_doc_mean_word_length": 5.353535175323486,
"rps_doc_num_sentences": 4,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 3.9708776473999023,
"rps_doc_word_count": 99,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.026415089145302773,
"rps_doc_frac_chars_top_3gram": 0,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -61.92451858520508,
"rps_doc_books_importance_length_correction": -72.080078125,
"rps_doc_openwebtext_importance": -28.50727081298828,
"rps_doc_openwebtext_importance_length_correction": -38.66282653808594,
"rps_doc_wikipedia_importance": -16.67596435546875,
"rps_doc_wikipedia_importance_length_correction": -26.831518173217773
},
"fasttext": {
"dclm": 0.9644522666931152,
"english": 0.9206855297088623,
"fineweb_edu_approx": 3.328664779663086,
"eai_general_math": 0.6549019813537598,
"eai_open_web_math": 0.26752251386642456,
"eai_web_code": 0.04913252964615822
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.02",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.3",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "3",
"label": "Academic Writing"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-3,132,911,758,499,461,000 | Frequently asked questions
Our Scientific Applications Support team has assembled a list of frequently asked questions to help you find answers quickly. Filter using one or more categories to focus on specific topics, or use the search bar to perform a text search.
What should I be concerned about when designing multiplex qPCR assays?
The most important aspect of multiplex qPCR to consider is potential negative interactions between PCR components, specifically the primers. Primer dimer formation can significantly decrease amplification efficiency. Therefore, you should analyze heterodimer potential between all of the primers included in your reaction to ensure that any structures predicted to form will not be strong enough to significantly affect the reaction. As with primer design for a singleplex reaction, strive for a ΔG value more positive than -9 kcal/mole for all predicted heterodimers. The IDT SciTools® OligoAnalyzer® application is ideal for this purpose.
Categories:
qPCR & PCR | {
"url": "https://pages2.idtdna.com/pages/support/faqs/what-should-i-be-concerned-about-when-designing-multiplex-qpcr-assays-",
"source_domain": "pages2.idtdna.com",
"snapshot_id": "crawl=CC-MAIN-2021-25",
"warc_metadata": {
"Content-Length": "74054",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:WYU2UCNXWF2L3IZRIO7R4ADETPHYVC3T",
"WARC-Concurrent-To": "<urn:uuid:27ad138f-5cb0-41ef-aff5-e6680ed7d688>",
"WARC-Date": "2021-06-22T17:16:09",
"WARC-IP-Address": "52.173.142.251",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:Z7JE454JRR2443BJEW3JGKSHIUI3JK4U",
"WARC-Record-ID": "<urn:uuid:07d22e7c-8019-43d1-8573-88968d1b5c86>",
"WARC-Target-URI": "https://pages2.idtdna.com/pages/support/faqs/what-should-i-be-concerned-about-when-designing-multiplex-qpcr-assays-",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:b4e71ca9-6b68-4b5a-bbe9-82c182f282dd>"
},
"warc_info": "isPartOf: CC-MAIN-2021-25\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for June 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-245.ec2.internal\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
27,
28,
267,
268,
339,
340,
981,
982,
994
],
"line_end_idx": [
27,
28,
267,
268,
339,
340,
981,
982,
994,
1004
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1004,
"ccnet_original_nlines": 9,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3571428656578064,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.029761899262666702,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1130952388048172,
"rps_doc_frac_unique_words": 0.7114093899726868,
"rps_doc_mean_word_length": 5.604026794433594,
"rps_doc_num_sentences": 9,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.513505458831787,
"rps_doc_word_count": 149,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.035928141325712204,
"rps_doc_frac_chars_top_3gram": 0.057485029101371765,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -59.38494873046875,
"rps_doc_books_importance_length_correction": -59.38494873046875,
"rps_doc_openwebtext_importance": -29.633159637451172,
"rps_doc_openwebtext_importance_length_correction": -15.61378288269043,
"rps_doc_wikipedia_importance": -27.994041442871094,
"rps_doc_wikipedia_importance_length_correction": -27.994041442871094
},
"fasttext": {
"dclm": 0.18364721536636353,
"english": 0.9026705622673035,
"fineweb_edu_approx": 1.7206534147262573,
"eai_general_math": 0.4039252996444702,
"eai_open_web_math": 0.29369646310806274,
"eai_web_code": 0.13958889245986938
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "572.888",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Biology and Anthropology",
"level_3": "Anthropology"
}
},
"secondary": {
"code": "615.54",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "9",
"label": "FAQ"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "4",
"label": "Graduate/Expert Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-5,801,826,179,069,552,000 | Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.
Patents
1. Advanced Patent Search
Publication numberUS5948426 A
Publication typeGrant
Application numberUS 09/070,686
Publication dateSep 7, 1999
Filing dateApr 30, 1998
Priority dateMay 3, 1997
Fee statusPaid
Publication number070686, 09070686, US 5948426 A, US 5948426A, US-A-5948426, US5948426 A, US5948426A
InventorsSteven R. Jefferies
Original AssigneeJefferies; Steven R.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method and article to induce hematopoietic expansion
US 5948426 A
Abstract
An article and method to create retrievable sites of implantable and transplantable bone marrow, in a human or animal recipient, by implanting bone-marrow inducing conjugates of collagen and demineralized freeze-dried bone allograft (DFDBA) into accessible soft or hard tissue sites is provided. The implantation of such collagen-DFDBA conjugate grafts into suitable ectotrophic sites results in the formation of bone-marrow and hematopoietic tissue within the implant. By removing all or a portion of the bone marrow containing areas of the implant, an additional source of hematopoietic tissue and bone marrow cells is formed which can subsequently be transplanted into the same individual as an autograft, or a related or compatible individual as an allograft.
Images(7)
Previous page
Next page
Claims(34)
I claim:
1. A bone marrow inducing conjugate composite comprising from about 10 to about 90 parts by weight of demineralized freeze-dried bone matrix (DFDBA), from about 90 to about 10 parts by weight of collagen, and one selected from the group consisting of (a) mammalian stem cells, (b) bone marrow components, and (c) a growth factor in an amount effective to induce bone marrow differentiation within said conjugate composite.
2. The bone marrow inducing conjugate composite of claim 1 wherein the conjugate composite comprises from about 30 to about 70 parts by weight of DFDBA and from about 70 to about 30 parts by weight of collagen.
3. The bone marrow inducing conjugate composite of claim 1 wherein at least one of the collagen and the DFDBA is from a human source.
4. The bone marrow inducing conjugate composite of claim 1 wherein the stem cells are from at least one of a human host and a human histocompatible with the host.
5. The bone marrow inducing conjugate composite of claim 1 wherein the conjugate composite additionally comprises at least one biopolymer incorporated into or surrounding the conjugate composite.
6. The bone marrow inducing conjugate composite of claim 5 wherein the at least one biopolymer is a non-resorbable polymer.
7. The bone marrow inducing conjugate composite of claim 5 wherein the at least one biopolymer includes a structure selected from the group consisting of tubes, ports, membranes, and combinations thereof.
8. The bone marrow inducing conjugate composite of claim 5 wherein the at least one biopolymer is a resorbable polymer.
9. The bone marrow inducing conjugate composite of claim 5 wherein the at least one biopolymer is a semi-resorbable polymer.
10. The bone marrow inducing conjugate composite of claim 1 implanted in or adjacent to hard tissue of a host.
11. A method of producing bone marrow material in vitro comprising ex vivo culturing the conjugate composite of claim 1.
12. A method for producing bone marrow material in vivo comprising implanting the conjugate composite of claim 1 in at least one selected from the group consisting of a soft tissue and hard tissue site and maintaining the conjugate composite implant for a period of time sufficient to induce the formation of at least one selected from the group consisting of bone marrow, bone marrow cells, bone marrow components, hematopoietic tissue, stem cells and ectopic viable bone within the implant.
13. The method of claim 12 including shielding the conjugate composite implant from diagnostic or therapeutic radiation exposure, wherein said shielding comprises one selected from the group consisting of (a) substantially enclosing the conjugate composite implant in a radiation shielding material and (b) shielding the conjugate composite implant externally to the body.
14. The method of claim 12 including introducing at least one selected from the group consisting of additional conjugate composite material, a growth factor, a growth enhancement substance, a pharmacological drug, and a therapeutic agent.
15. The method of claim 12 including accessing the conjugate composite implant to retrieve at least one selected from the group consisting of bone marrow, bone marrow cells, bone marrow components, hematopoietic tissue, stem cells, and ectopic viable bone.
16. The method of claim 12 wherein said implanting includes at least one selected from the group consisting of (a) injecting the conjugate composite in one form selected from the group consisting of liquid, gel and solid, and (b) an incision or surgical implantation procedure.
17. The bone marrow inducing conjugate composite of claim 1 wherein the conjugate composite has associated therewith at least one biocompatible metal or biopolymer-contained metal structure selected from the group consisting of tubes, ports, mesh, shields, and combinations thereof.
18. The bone marrow inducing conjugate composite of claim 1 implanted in soft tissue of a host.
19. A method for producing an ectotrophic site for bone marrow material in a human or animal suitable for allogenic or autogenous bone marrow transplantation comprising:
(a) placing a bone marrow producing implant comprising collagen and a bone marrow inducing material in a suitable site within soft tissue or adjacent to hard tissue; and
(b) maintaining the implant in its implanted site for a period of time sufficient to induce the formation of at least one selected from the group consisting of bone marrow, bone marrow cells, bone marrow components, hematopoietic tissue, stem cells, and ectopic viable bone within the implant.
20. The method of claim 19 wherein the implant comprises a conjugate composite of from about 10 to about 90 parts by weight of demineralized freeze-dried bone matrix (DFDBA) and from about 90 to about 10 parts by weight of collagen.
21. The method of claim 20 wherein the conjugate composite comprises from about 30 to about 70 parts by weight of DFDBA and from about 70 to about 30 parts by weight of collagen.
22. The method of claim 20 wherein at least one of the collagen and the DFDBA is from a human source.
23. The method of claim 20 wherein the conjugate composite includes stem cells from at least one of a human host and a human histocompatible with the host.
24. The method of claim 20 wherein the conjugate composite additionally comprises at least one biopolymer incorporated into or surrounding the conjugate composite.
25. The method of claim 24 wherein the at least one biopolymer is a non-resorbable polymer.
26. The method of claim 24 wherein the at least one biopolymer includes a structure selected from the group consisting of tubes, ports, membranes, and combinations thereof.
27. The method of claim 20 wherein the conjugate composite has associated therewith at least one biocompatible metal or biopolymer-contained metal structure selected from the group consisting of tubes, ports, mesh, shields, and combinations thereof.
28. The method of claim 19 including introducing into the implant at least one selected from the group consisting of a bone marrow inducing material, a growth factor, a growth enhancement substance, a pharmacological drug, and a therapeutic agent.
29. The method of claim 19 wherein said soft tissue is at least one selected from the group consisting of connective tissue, fat, and muscle tissue.
30. The method of claim 19 including accessing the implant to retrieve at least one selected from the group consisting of bone marrow, bone marrow cells, bone marrow components, hematopoietic tissue, stem cells, and ectopic viable bone.
31. The method of claim 19 wherein said placing includes at least one selected from the group consisting of (a) injecting the implant in one form selected from the group consisting of liquid, gel and solid, and (b) an incision or surgical implantation procedure.
32. The method of claim 19 including shielding the implant from diagnostic or therapeutic radiation exposure, wherein said shielding comprises one selected from the group consisting of (a) substantially enclosing the implant in a radiation shielding material and (b) shielding the implant externally to the body.
33. The method of claim 22 wherein the at least one biopolymer is a resorbable polymer.
34. The method of claim 22 wherein the at least one biopolymer is a semi-resorbable polymer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application No. 60/045,520 filed May 3, 1997.
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to the production of implantable bone marrow, bone marrow cells, and hematopoietic tissue in mammals. More particularly, the present invention relates to the creation of retrievable sites of implantable bone marrow in tissue culture or in a human or animal recipient, by the use of bone marrow inducing conjugate composites of collagen and demineralized freeze-dried bone allograft.
BACKGROUND OF THE INVENTION
Over the past decade, Bone Marrow Transplantation (BMT) has evolved from an experimental procedure reserved for patients with refractory leukemia into a rapidly expanding area of clinical investigation that offers high cure rates for patients with aplastic anemia, acute and chronic leukemia, and selected types of lymphoma. The objective of BMT is to provide a healthy stem cell population that will differentiate into blood cells to replace deficient or pathologic cells of the host.
There currently exist two generally accepted procedures for bone marrow transplantation. The first and most common procedure is allogenic bone marrow transplantation in which bone marrow is obtained by aspiration from the iliac crests of an HLA-compatible donor and infused into the patient requiring the healthy hematopoietic marrow. The procedure in which the bone marrow is aspirated through a puncture site into the iliac crest is very painful to the donor and sometimes obtains limited quantities of useful, transplantable hematopoietic tissue.
The second option for BMT involves autologous transplantation (ABMT); namely removal of a patient's own marrow for safe keeping when the patient is free of disease or when a complete remission has been induced by radiation and chemotherapy, or by other therapeutic means, followed by ablative treatment of the patient with the hope of destruction of any residual tumor and rescue with the patient's own bone marrow. Since an autograft is used, no immunosuppression is necessary and graft versus host disease (graft rejection) is minimal. Because the autologous "rescued" bone marrow can produce mature blood cells quickly, ABMT allows patients to tolerate very high doses of chemotherapy with less risk of infection and bleeding. Nevertheless, the success of autologous BMT is strictly dependent on obtaining sufficient quantities of healthy bone marrow from the patient-host during a period of tumor remission and when healthy hematopoietic tissue is present and obtainable. Although ABMT has some therapeutic advantages, it remains a difficult, somewhat risky, and expensive procedure.
While graft versus host disease (implant rejection) and infections are both issues in BMT, the major limiting factor in the use of BMT is the availability of sufficient quantities of healthy, immunologically compatible bone marrow tissue with sufficient hematopoietic activity, which in turn results from a lack of suitable donors. Since only 25 to 30% of patients have a sibling who can serve as an HLA-compatible donor, alternatives need to be found.
Clearly, there exists a need to make the procedure for the retrieval of bone marrow for transplantation more accessible, less painful (i.e., avoid puncture of the iliac crest and the associated morbidity), increase the availability of useful bone marrow and bone marrow cells, and control more easily the microenvironment around the implant to enhance bone marrow formation while potentially removing or eliminating tumor cells and other undesirables in the bone marrow as well.
OBJECTS OF THE INVENTION
It is therefore an object of the present invention to provide a source of bone marrow, bone marrow components such as bone marrow cells, and hematopoietic tissue for autologous transplantation or for use as an allograft.
It is another object of the present invention to provide a conjugate composite of collagen-demineralized freeze-dried bone allograft suitable for implantation in soft and hard tissue sites.
It is another object of the invention to provide such a conjugate composite which will allow the formation of bone marrow in soft and hard tissue sites in a patient/host, such that later access and retrieval of bone marrow, bone marrow cells, bone marrow components, stem cells, and hematopoietic tissue is possible.
It is still another object of the invention to provide such a conjugate composite which may additionally contain other compatible biopolymers, macromolecules, growth factors, compounds, vitamins, and minerals which can enhance the structure and function of the bone marrow producing implant.
It is a further object of the invention to provide such a conjugate composite which may be incorporated within, attached to, or augmented by additional structures or design features which enhance implantation or access to the implant and the bone marrow containing portion(s) of the implant.
It is an additional object of the invention to provide a method of producing additional ectotrophic sites of bone marrow production in a human or animal host by implanting the appropriate conjugate composite implant materials, allowing the in-situ development of bone marrow calls, and retrieving all or part of the bone marrow containing tissue or cells by aspiration, incision within the implant, or excision of the entire implant.
It is an additional object of the invention to use retrieved bone marrow tissue and cells from the conjugate implant for autologous transplantation into the host from which they were obtained, or alternatively, allogenically transplanted into another histocompatible individual host requiring bone marrow augmentation or replacement.
It is an additional object of the invention to provide a conjugate composite collagen-demineralized freeze-dried bone allograft (DFDBA ) implant which can be seeded with appropriate stem cells, then implanted in a suitable host to facilitate bone marrow production.
It is an additional object of the invention to provide a conjugate composite collagen-DFDBA implant which can be seeded with appropriate stem cells, then placed in a tissue culture reactor to facilitate in-vitro formation of bone marrow or precursor tissue.
These and other object(s) of the invention, which will become apparent from the disclosure to follow, are carried out by the invention as hereafter described.
SUMMARY OF THE INVENTION
The present invention provides a conjugate composite and a method of using the composite to create retrievable sites of implantable bone marrow, bone marrow components such as bone marrow cells, and hematopoietic tissue in a human or animal recipient, by implanting bone-marrow inducing conjugates of collagen and demineralized freeze-dried bone allograft (DFDBA) into accessible soft or hard tissue sites. The implantation of such collagen-DFDBA conjugate grafts into suitable ectotrophic sites results in the formation of bone-marrow and hematopoietic tissue within the implant. Alternatively, the conjugate composite may be grown in-vitro such as in tissue culture to yield the implantable bone marrow material.
By utilizing all or a portion of the bone-marrow containing portion of the implant, such as by removal of the bone marrow material from tissue culture or from the host human or animal, the source of hematopoietic tissue that had been formed can subsequently be transplanted into the host individual as an autograft, or into a related/compatible individual as an allograft.
The conjugate composites of the present invention include collagen-DFDBA conjugates, either in the presence or in the absence of other biopolymers. According to the invention, other growth factors or substances which aid in the formation or accelerate the formation of bone marrow and hematopoietic tissue can be added in various ways to these collagen-DFDBA conjugate composites.
The present invention further provides the incorporation of access ports or windows in or on the implant itself, to facilitate the ability to withdraw bone marrow components, or alternatively, to add additional implant material or growth factors/enhancement substances to the implant before or after implantation.
Methods according to the invention include preparing the implant, inserting the implant into a suitable soft or hard tissue site, retrieving bone marrow, bone marrow components and hematopoietic material from the implant (or alternatively, completely removing the implant with its bone marrow compartment), and associated appropriate procedures for maintaining the bone marrow containing implant.
A bone marrow inducing conjugate composite according to the present invention comprises from about 10 to about 90 parts by weight of demineralized freeze-dried bone matrix (DFDBA) and from about 90 to about 10 parts by weight of collagen, preferably in the form of reconstituted collagen. The DFDBA may be in the form of particles of various sizes and shapes which may be incorporated into the collagen matrix of the conjugate. Both the collagen and the DFDBA may be from a human or animal source.
In a preferred embodiment, the present invention provides a bone marrow inducing conjugate composite comprising from about 10 to about 90 parts by weight of demineralized freeze-dried bone matrix (DFDBA), from about 90 to about 10 parts by weight of collagen, and an amount effective to initiate bone marrow differentiation of at least one of (a) mammalian stem cells, (b) bone marrow components, and (c) a growth factor.
The present invention further provides a method of producing bone marrow material in vitro comprising ex vivo culturing the above conjugate composite. In another embodiment, the present invention provides a method for producing bone marrow material in vivo comprising implanting the above conjugate composite in at least one of a soft tissue and hard tissue site and maintaining the conjugate composite implant for a period of time sufficient to induce the formation of at least one of bone marrow, bone marrow cells, and hematopoietic tissue within the implant.
According to certain embodiments of the invention, other biopolymers or structures may be incorporated into or may surround the implant itself, including structures made of synthetic resorbable polymers which may be incorporated in the collagen-DFDBA conjugate matrix, and structures of fabricated biocompatible polymers such as tubes, entry-ports, or membranes which may be incorporated into or surround the collagen-DFDBA conjugate material. Biocompatible metals such as titantium or titanium alloy in various configurations, such as tubes or mesh for example, may also be incorporated in the implantation conjugate to facilitate access, retrieval, or sampling.
A method is provided according to the present invention, for producing an ectotrophic site for bone marrow material in a human or animal suitable for allogenic or autogenous Bone Marrow Transplantation (BMT) comprising:
(a) placing a bone marrow producing implant comprising collagen and a bone marrow inducing material in a suitable site within soft tissue or adjacent to hard tissue; and
(b) maintaining the implant in its implanted site for a period of time sufficient to induce the formation of at least one of bone marrow, bone marrow cells, bone marrow components, hematopoietic tissue, stem cells, and ectopic viable bone within the implant.
The invention further includes accessing the implant to retrieve at least one of bone marrow, bone marrow cells, bone marrow components, hematopoietic tissue, stem cells, and ectopic viable bone, such as by removing at least a portion of the implant.
The implantation procedure of Step (a) above may include injection of liquid, gel, or solid compositions. Alternatively, the implant may be inserted into the appropriate body cavity or location by conventional incision and surgical implantation procedures. The removal of all or a portion of the implant as described above may include, but is not limited to, aspiration of the bone marrow containing portion of the implant, as well as incision or excision of the implant or portions of the implant.
Another method according to the invention includes the preparation of the collagen-DFDBA conjugate composite implants to be capable of culturing and growing bone marrow cells outside of a human or animal host altogether. The collagen-DFDBA is fabricated to accept the seeding of human stem cells and other bone marrow components, to permit the culturing and growing of bone marrow cells and hematopoietic tissue. Sufficient amounts of implantable bone marrow for transplantation could be cultured using this method.
PREFERRED EMBODIMENTS OF THE INVENTION
The bone marrow producing composite according to the invention is a mixture of collagen and demineralized freeze-dried bone allograft (DFDBA). One preferred composite has from about 10 to about 90 parts by weight of DFDBA and from about 90 to about 10 parts by weight of collagen. A more preferred composite contains from about 30 to about 70 parts by weight of DFDBA. The source of both the collagen and DFDBA may be from a human or animal source (for example, bovine collagen), but the preferred composite for implantation in humans comprises collagen from a bovine source, and DFDBA from human origin. A more preferred composite is composed of collagen from a human source, for example human tendon, and DFDBA from a human source as well.
Collagen is used as the binding matrix and main structural component of the bone marrow producing composite material for several reasons. Reconstituted collagen has demonstrated excellent histocompatibility without antibody formation or graft rejection in numerous in vivo implantation studies. Reconstituted collagen can be fabricated into porous sponge-like structures which allow unimpeded cellular ingrowth. Collagen is the natural biomaterial which constitutes from 50 to 70% by weight of bone organic matrix. Reconstituted collagen has demonstrated the ability to bind both large and small molecular weight macromolecules, and complexation with collagen protects these macromolecules from denaturation due to environmental influences.
The actual collagen-DFDBA conjugate composite can be fabricated in various forms including but not limited to: injectable gels, membranes, powders, lyophilized sponges with various degrees of porosity, or combinations of these various forms. The conjugate material can be fabricated according methods and procedures described in U.S. Pat. Nos. 4,394,370 and 4,472,840, both of which are incorporated herein by reference as if fully rewritten below.
Alternatively, an acidic or alkaline collagen dispersion, either from human or animal sources, can be lyophilized by conventional methods. This lyophilized mass can then be ground into a powder with various degrees of coarseness. The grinding of the lyophilized mass is preferably performed under cooling by the use of dry-ice and/or liquid nitrogen. This collagen powder can then be dry blended with various ratios of demineralized freeze-dried bone allograft (DFDBA), also preferably in a powder or particulate form.
After blending, the powder mixture can be hydrated with sufficient sterile distilled water to form a uniform dispersion. A small amount of ethanol may be added to the sterile distilled water, which is used to rehydrate the powder blend. This blended collagen/demineralized freeze-dried bone allograft dispersion may then be lyophilized into a sponge configuration. This sponge configuration may be used as the implant. Alternatively, the lyophilized conjugate sponge can be re-ground into a powder, and this conjugate powder can be used as the implant material (for example, by being dispersed into an appropriate vehicle such as a common medical excipient, and the resulting dispersion being injected into the transplant site.
Examples of such excipients include, but are not limited to, polyols, glycerin, propylene glycol, vegetable oils, purified peanut oil, proteins, protein hydrogels, blood proteins, albumin, fibrin, collagen gel, collagen solution, gelatin, pluronic ot tetronic surfactants or copolymers, hydroxy methyl cellulose and cellulose derivatives, ultrapure alginate such as sodium alginate, biocompatible carbohydrates, sugars, and polymers derived therefrom, dextran suitable for injection, and the like.
In a preferred form of the method for inducing the formation, expansion and retrieval of bone marrow and hematopoietic tissue, a human collagen-human DFDBA sponge implant is implanted in a soft tissue site, either within connective tissue, fat cells, or muscle tissue, using a subcutaneous surgical implantation technique. Accessible sites in or adjacent to hard tissue or bony sites may also be used for implantation. Alternatively, the sponge implant may be configured into a thin cylinder implant which could be injected or inserted subcutaneously. The implant may be inserted in or adjacent to bone, for example, so as to affix the implant to the bone for structural stability. However, it is preferred that the implant be placed in soft tissue, such as muscle tissue.
The implant is permitted to remain in-situ for periods of from about two to about three (2-3) weeks to about nine to about twelve (9-12) months or longer, to permit the formation of bone marrow tissue within the implant. If positioned in a highly accessible location, the implant may be radiographed to more precisely define potential bone marrow containing areas of the implant.
When the collagen-DFDBA conjugate composite is implanted in the body, the implant initially becomes vascularized. As a vascular bed is established in the differentiated bone, stem cells are supplied to the implant, and bone marrow begins to form. When the collagen-DFDBA conjugate composite is cultured ex vivo, stem cells or other bone marrow inducing factors must be introduced to initiate bone marrow development. The incorporation, however, of stem cells and/or growth factors in the implanted conjugate composite results in the accelerated and increased development of the bone marrow components.
Examples of growth factors that are suitable for the expansion of hematopoietic tissue in the collagen-DFDBA conjugate composites of the present invention include, but are not limited to, interleukin-4, interleukin-6, interleukin-7, platelet-derived growth factor, alpha interferon species, tumor necrosis factor (TNF), TGF-beta and TNF-alpha proteins, colony-stimulating factors, such as granulocyte colony-stimulating factor, stem cell proliferation factor, osteogenic growth polypeptide, autocrine growth factor, and the like, and their combinations.
The retrieval of the bone marrow can be accomplished through the complete removal of the implant, with the excised implant being manipulated ex-situ to remove the bone marrow containing tissue and cells. Alternatively, a probe or catheter may be introduced into the implant while still in-situ in the patient, and bone marrow containing tissue and cells may be aspirated. Regardless of how the bone marrow is removed from the implant, the retrieved bone marrow tissue and cells may then be suitably processed, by means known in the medical art and sciences, prior to transplantation in the host or in the patient needing the hematopoietic tissue or bone marrow.
Other biopolymers or structures are advantageously incorporated into or may surround the implant itself. Structures made of various well-known synthetic resorbable polymers, including but not limited to polymers of polylactic or polyglycolic acid, or various co-polymers of lactic and glycolic acid, may be incorporated in the collagen-DFDBA conjugate matrix. Inorganic or organic fillers of various types may also be incorporated in the conjugate composite. These polymers and fillers can serve a structural function, to aid in retaining a porous, geometrically stable structure to the implant, to serve as a growth site for the bone marrow. The polymers and fillers may also be resorbable, to provide components to the implant to assist in the production of osseous or marrow components.
Structures such as tubes, entry-ports, or membranes may be incorporated into or surround the collagen-DFDBA conjugate material implant. These structures may be fabricated from biocompatible polymers such as silicone, ethylene-vinyl acetate copolymer, and the like. Titantium or biocompatible titanium alloys in various configurations, such as tubes or mesh for example, may also be incorporated in the conjugate composite implant to facilitate access to or retrieval of the implant or the produced bone marrow material, or sampling of the bone marrow material product. Other biocompatible metals such as tantalum, or biopolymer coated or encapsulated metals can also be used.
New ectotrophic sites for the production of bone marrow material in a human or animal, suitable for allogenic or autogenous Bone Marrow Transplantation (BMT), are prepared by the method comprising placing, such as by implanting, a bone marrow producing implant comprising collagen and a bone marrow inducing material or substance, such as demineralized freeze-dried bone allograft, or Bone Morphogenetic Protein(s) (BMP), in a suitable soft or hard tissue location; maintaining or allowing the implant to remain in its implanted site for a period of time sufficient to induce the formation of bone marrow within the implant; and removing all or a portion of the implant to retrieve, all or in part, the bone marrow, bone marrow cells, and hematopoietic tissue.
The implantation procedure discussed above may include injection of a liquid, gel, or solid collagen-DFDBA conjugate material. Alternatively, the implant may be placed or inserted into the appropriate body cavity or location by conventional incision and surgical implantation procedures. The removal of all or a portion of the implant as described above may include, but is not limited to, aspiration of the bone marrow containing portion of the implant, as well as incision or excision of the implant or portions of the implant.
The above method for producing and maintaining bone marrow producing implants may be modified to permit the injection or addition of growth factors such as colony stimulating factor, or other cytokines, antibiotics, vitamins, and/or minerals, directly to the implant prior to implantation or while it is in-situ. The implant, prior to implantation or upon removal from the implanted site, may be seeded with human stem cells and placed in appropriate tissue culture media within a suitable bioreactor or sterile container to facilitate further growth and maturation of the bone marrow tissue and cells. Additionally, this procedure permits the capability to rinse or clean the removed implant, or portions of the implant, with an appropriate medium to remove tumor cells or other undesirables in the bone marrow grown within the implant. The collagen-DFDBA implant can be processed in the form of a porous sponge to permit perfusion of various sterile liquids and media to rinse or clean the implant and its marrow components.
Another method according to the invention involves the use of these collagen-DFDBA conjugate implants to be capable of culturing and growing bone marrow cells outside of a human or animal host altogether. The collagen-DFDBA can be fabricated to accept the seeding of human stem cells and other bone marrow components to permit the culturing and growing of bone marrow cells and hematopoietic tissue. Sufficient amounts of implantable bone marrow for transplantation into a patient could be cultured using this method.
EXAMPLE 1
A bone marrow inducing implant is configured in such a manner that the implant is enclosed in an appropriate biocompatible polymer which can partially isolate or partition the implant from the surrounding soft or hard tissue. This polymer encasement can be composed of a non-resorbable biocompatible polymer, such as medical grade silicone, medical grade polyurethane, Ultra-High Molecular Weight Polyethylene (UHMWPE), or expanded Teflon (PTFE), just to list several non-limiting examples of operable polymeric materials. The bone marrow inducing implant can also be enclosed entirely or partially in a resorbable or semi-resorbable polymer. Examples of appropriate bioresorbable polymers are those derived from various combinations of known lactide and/or glycolide polymers. Various entrance and exit ports can be configured in the outer casting and within the implant itself to gain access to the marrow components and vascular elements which are induced within the hematopoietic tissue.
EXAMPLE 2
The outer polymeric casing of the bone marrow inducing implant is fabricated from a radiodense or radioopaque material. Such a coating or partition can serve to reduce exposure of the implant to radiation of various types to which the patient may be subjected for diagnosis and/or treatment purposes. Such radiation shielding of the expanded hematopoietic tissue preserves a source of bone marrow for later transplantation to replace marrow depleted as a result of radiation treatment. The radiodense surface layer or coating also aids in identification of the implant location by presenting a clear radioopaque image on conventional radiographs.
Shielding the conjugate composite implant from diagnostic or therapeutic radiation exposure can include substantially enclosing the conjugate composite implant in a radiation shielding material, or shielding the conjugate composite implant externally to the body. In addition to the use of biopolymers for this purpose, the shield can be in the form of a biocompatible metal which is dense enough to block the radiation, or a metal which is contained in a biopolymer, such as by a coating or encapsulation.
EXAMPLE 3
The bone marrow inducing implant of the present invention, in addition to providing a source of ectopic autogenous bone marrow, can also provide a source of additional autogenous and viable bone. When an additional source of viable autogenous bone is required, but is in otherwise short supply, additional implanted sites of collagen-DFDBA or collagen-BMP implants, with or without additional growth factors; can be implanted in selected sites for sufficient time periods to allow later retrieval of mature autogenous bone for transplantation into autogenous recipient sites. Such implants provide the benefits of autografts without the limits of autograft availability.
EXAMPLE 4
The ability of the bone inducing implants of the present invention to form vascularized tissue and actual microscopic blood vessels within the internal implant space, also provides an excellent vehicle for parentially introducing drugs and growth factors of various types. Drugs can be injected directly into the implant itself, thereby serving as a drug delivery reservoir. Alternatively, access ports and channels provided into the implant itself could serve the dual role of not just retrieving stems cells and marrow, but also permitting the introduction of drugs and growth factors for local and systemic application and treatment. The implant can then serve as a unique drug delivery vehicle or conduit for local or systemic delivery of pharmaceutical drugs, growth factors, and a wide range of therapeutic agents.
Thus, the objects of the invention are accomplished by the present invention, which is not limited to the specific embodiments described above, but which includes variations modifications and equivalent embodiments defined by the following claims.
Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4322398 *Feb 21, 1979Mar 30, 1982Battelle Institut E.V.Implantable drug depot and process for the production thereof
US4394370 *Sep 21, 1981Jul 19, 1983Jefferies Steven RBone graft material for osseous defects and method of making same
US4472840 *Sep 30, 1982Sep 25, 1984Jefferies Steven REomplex of collagen, bone particles, and protein
US5393739 *Sep 15, 1993Feb 28, 1995Celtrix Pharmaceuticals, Inc.Use of bone morphogenetic protein in synergistic combination with TGF-β for bone repair
US5405772 *Jun 18, 1993Apr 11, 1995Amgen Inc.Medium for long-term proliferation and development of cells
US5459069 *Jan 6, 1994Oct 17, 1995The Regents Of The University Of MichiganDevice for maintaining and growing human stem and/or hematopoietics cells
US5461034 *Jun 18, 1993Oct 24, 1995Yissum Research Development Company Of The Hebrew University Of JerusalemOsteogenic growth polypeptides identified from regenerating bone marrow
US5604204 *Feb 27, 1995Feb 18, 1997Genentech, Inc.Method of inducing bone growth using TGF-β
US5605822 *Dec 1, 1994Feb 25, 1997The Regents Of The University Of MichiganCulturing human stem cells in liquid culture medium in the presence of transformed stromal cells
US5631219 *Mar 8, 1994May 20, 1997Somatogen, Inc.Method of stimulating hematopoiesis with hemoglobin
US5635387 *Apr 3, 1995Jun 3, 1997Cellpro, Inc.Methods and device for culturing human hematopoietic cells and their precursors
US5643789 *Jul 21, 1994Jul 1, 1997Trustees Of The University Of PennslyvaniaInnoculation of cells with bioreactive glass for bone tissue culture
US5648301 *Jun 2, 1995Jul 15, 1997Trustees Of The University Of PennsylvaniaBioactive material template for in vitro synthesis of bone tissue
US5650299 *Oct 6, 1994Jul 22, 1997The University Of FloridaCells producing stem cell proliferation factor
US5681559 *Jun 6, 1995Oct 28, 1997Systemix, Inc.Method for producing a highly enriched population of hematopoietic stem cells
US5705149 *May 22, 1995Jan 6, 1998Sterling Winthrop Inc.Use of interleukin-7 to stimulate proliferation of hematopoietic cell precursors
US5707962 *Sep 28, 1994Jan 13, 1998Gensci Regeneration Sciences Inc.Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof
US5716827 *Jun 6, 1995Feb 10, 1998Systemix, Inc.Capable of regeneration
US5728581 *Jun 7, 1995Mar 17, 1998Systemix, Inc.Method of expanding hematopoietic stem cells, reagents and bioreactors for use therein
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US6652887Jun 24, 2002Nov 25, 2003Wright Medical Technology, Inc.Bone graft substitute composition
US7211266Mar 28, 2003May 1, 2007Wright Medical Technology, Inc.Calcium sulfate hemihydrate, calcium sulfate dihydrate, and a binder; and an aqueous mixing solution; optionally stearic acid
US7291179May 30, 2003Nov 6, 2007Wright Medical Technology, Inc.Filler mixtures comprising calcium sulfate, plasticizers and demineralized matrices
US7364752Nov 10, 2000Apr 29, 2008Abbott LaboratoriesSolid dispersion pharamaceutical formulations
US7371408Jun 7, 1999May 13, 2008Wright Medical Technology, Inc.Bone graft substitute composition
US7371409Sep 6, 2001May 13, 2008Wright Medical Technology, Inc.Bone graft substitute composition
US7371410Jan 30, 2002May 13, 2008Wright Medical Technology, Inc.Bone graft substitute composition
US7494811 *Apr 30, 2004Feb 24, 2009Lifenet HealthFlowing nutrient solution into, through and out of ground demineralized cells in bioreactor; tissue engineered material
US7507257Feb 4, 2004Mar 24, 2009Wright Medical Technology, Inc.Injectable resorbable bone graft material, powder for forming same and methods relating thereto for treating bone defects
US7658768Oct 15, 2007Feb 9, 2010Wright Medical Technology, Inc.Calcium sulfate hemihydrate, accelerant (calcium sulfate dihydrate), plasticizing material, mixing solution, demineralized bone matrix, water; filler for voids and/or defects defined by bone
US7771741May 1, 2006Aug 10, 2010Warsaw Orthopedic, IncDemineralized bone matrix devices
US7838022May 1, 2006Nov 23, 2010Warsaw Orthopedic, IncBioresorbable solids admixed with a liquid carrier to form shape-retaining putties, flowable pastes, or particulated sponges; solid is a crosslinked collagen and particulate DBM; liquid is an aqueous polysaccharide; injectable; improved ease of handling by surgeons
US8025899Aug 25, 2004Sep 27, 2011Abbott LaboratoriesSolid pharmaceutical dosage form
US8039016Mar 6, 2008Oct 18, 2011Warsaw Orthopedic, Inc.Malleable implants containing demineralized bone matrix
US8137408Oct 30, 2007Mar 20, 2012Depuy Spine, Inc.Autologous bone graft material
US8268349Apr 18, 2012Sep 18, 2012Abbott LaboratoriesSolid pharmaceutical dosage form
US8282953Aug 5, 2010Oct 9, 2012Warsaw Orthopedic, Inc.Malleable implants containing demineralized bone matrix
US8309613Sep 13, 2010Nov 13, 2012Abbvie Inc.Solid pharmaceutical dosage form
US8313742Mar 29, 2002Nov 20, 2012Depuy Acromed, Inc.Cell-containing bone graft material
US8333990Sep 13, 2010Dec 18, 2012Abbott LaboratoriesSolid pharmaceutical dosage form
US8377952Feb 23, 2005Feb 19, 2013Abbott LaboratoriesSolid pharmaceutical dosage formulation
US8399015Sep 22, 2011Mar 19, 2013Abbvie Inc.Solid pharmaceutical dosage form
US8431147Apr 28, 2010Apr 30, 2013Warsaw Orthopedic, Inc.Malleable implants containing demineralized bone matrix
US8460691Apr 23, 2010Jun 11, 2013Warsaw Orthopedic, Inc.Fenestrated wound repair scaffold
US8470347May 29, 2001Jun 25, 2013AbbVie Deutschland GmbH and Co KGMixture of active materials, lipid and binder
US8506983Jun 18, 2010Aug 13, 2013Warsaw Orthopedic, Inc.Bone filler material
US8657952Apr 24, 2007Feb 25, 2014Wright Medical Technology, Inc.Bone graft substitute composition
US8691878Nov 12, 2012Apr 8, 2014Abbvie Inc.Solid pharmaceutical dosage form
US8790699Apr 23, 2010Jul 29, 2014Warsaw Orthpedic, Inc.Foam-formed collagen strand
US8840913Mar 27, 2008Sep 23, 2014Warsaw Orthopedic, Inc.Malleable multi-component implants and materials therefor
WO2001008609A1 *Aug 3, 1999Feb 8, 2001Steven R JefferiesMethod and article to induce hematopoietic expansion
WO2010051581A1 *Nov 4, 2009May 14, 2010Perth Bone & Tissue BankCarrier material for bone forming cells
Classifications
U.S. Classification424/423, 424/486, 435/395, 435/405, 424/426, 424/93.7, 435/372, 424/484, 435/373, 435/374, 514/7.9, 514/20.9
International ClassificationA61F2/30, A61K35/32, A61K9/00, A61L27/24, A61L27/36, A61F2/28, A61F2/00, A61F2/02, A61K38/39
Cooperative ClassificationA61F2002/2867, A61K9/0024, A61F2210/0004, A61L27/24, A61F2250/0067, A61K35/32, A61L27/3834, A61F2310/00365, A61L27/3839, A61F2002/2835, A61L27/3608, A61F2002/2817, A61L27/3641, A61F2002/30677, A61F2002/30062, A61K38/39
European ClassificationA61L27/38B14, A61L27/36B2, A61L27/36F, A61L27/38D, A61K38/39, A61K9/00M5D, A61L27/24, A61K35/32
Legal Events
DateCodeEventDescription
Feb 21, 2011FPAYFee payment
Year of fee payment: 12
Feb 23, 2007FPAYFee payment
Year of fee payment: 8
Feb 24, 2003FPAYFee payment
Year of fee payment: 4 | {
"url": "http://www.google.com/patents/US5948426?dq=6016038",
"source_domain": "www.google.com",
"snapshot_id": "crawl=CC-MAIN-2015-06",
"warc_metadata": {
"Content-Length": "101778",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:3JPBFXX5HQ4FBORNGHNQGDWULL75FQV5",
"WARC-Concurrent-To": "<urn:uuid:dfa22881-ca54-4b6c-bc08-b368e059a525>",
"WARC-Date": "2015-01-29T14:27:05",
"WARC-IP-Address": "74.125.228.242",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:ZXQIBPTYQRKI4BEXCPB24R3DY5K3F632",
"WARC-Record-ID": "<urn:uuid:a923427c-c292-4c6f-ae43-898e75cdb2ad>",
"WARC-Target-URI": "http://www.google.com/patents/US5948426?dq=6016038",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:68dd6df5-364a-4ac3-a680-eac2ca8c8b68>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-180-212-252.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2015-06\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for January 2015\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
56,
64,
205,
206,
214,
215,
243,
273,
295,
327,
355,
379,
404,
419,
520,
549,
587,
626,
677,
730,
743,
752,
1516,
1526,
1540,
1550,
1561,
1570,
1993,
2204,
2338,
2501,
2697,
2821,
3026,
3146,
3271,
3382,
3503,
3996,
4369,
4608,
4865,
5143,
5426,
5522,
5692,
5862,
6156,
6389,
6568,
6670,
6826,
6990,
7082,
7255,
7505,
7753,
7902,
8139,
8402,
8715,
8803,
8896,
8908,
8948,
8949,
9058,
9059,
9092,
9093,
9516,
9517,
9545,
9546,
10032,
10033,
10583,
10584,
11672,
11673,
12126,
12127,
12606,
12607,
12632,
12633,
12854,
12855,
13045,
13046,
13363,
13364,
13656,
13657,
13949,
13950,
14384,
14385,
14719,
14720,
14986,
14987,
15245,
15246,
15405,
15406,
15431,
15432,
16147,
16148,
16521,
16522,
16903,
16904,
17218,
17219,
17616,
17617,
18115,
18116,
18538,
18539,
19102,
19103,
19767,
19768,
19988,
19989,
20159,
20160,
20419,
20420,
20671,
20672,
21171,
21172,
21688,
21689,
21728,
21729,
22471,
22472,
23213,
23214,
23663,
23664,
24183,
24184,
24912,
24913,
25411,
25412,
26185,
26186,
26566,
26567,
27169,
27170,
27724,
27725,
28387,
28388,
29178,
29179,
29855,
29856,
30617,
30618,
31148,
31149,
32176,
32177,
32695,
32696,
32706,
32707,
33699,
33700,
33710,
33711,
34358,
34359,
34866,
34867,
34877,
34878,
35549,
35550,
35560,
35561,
36382,
36383,
36631,
36632,
36649,
36703,
36822,
36941,
37043,
37195,
37300,
37449,
37629,
37722,
37894,
37995,
38121,
38266,
38408,
38514,
38640,
38777,
38950,
39022,
39157,
39171,
39226,
39324,
39513,
39660,
39758,
39855,
39952,
40050,
40219,
40404,
40658,
40746,
41066,
41151,
41262,
41343,
41428,
41538,
41615,
41703,
41788,
41880,
41957,
42069,
42159,
42271,
42348,
42446,
42522,
42605,
42719,
42828,
42931,
42947,
43075,
43196,
43441,
43560,
43573,
43598,
43626,
43650,
43678,
43701,
43729
],
"line_end_idx": [
56,
64,
205,
206,
214,
215,
243,
273,
295,
327,
355,
379,
404,
419,
520,
549,
587,
626,
677,
730,
743,
752,
1516,
1526,
1540,
1550,
1561,
1570,
1993,
2204,
2338,
2501,
2697,
2821,
3026,
3146,
3271,
3382,
3503,
3996,
4369,
4608,
4865,
5143,
5426,
5522,
5692,
5862,
6156,
6389,
6568,
6670,
6826,
6990,
7082,
7255,
7505,
7753,
7902,
8139,
8402,
8715,
8803,
8896,
8908,
8948,
8949,
9058,
9059,
9092,
9093,
9516,
9517,
9545,
9546,
10032,
10033,
10583,
10584,
11672,
11673,
12126,
12127,
12606,
12607,
12632,
12633,
12854,
12855,
13045,
13046,
13363,
13364,
13656,
13657,
13949,
13950,
14384,
14385,
14719,
14720,
14986,
14987,
15245,
15246,
15405,
15406,
15431,
15432,
16147,
16148,
16521,
16522,
16903,
16904,
17218,
17219,
17616,
17617,
18115,
18116,
18538,
18539,
19102,
19103,
19767,
19768,
19988,
19989,
20159,
20160,
20419,
20420,
20671,
20672,
21171,
21172,
21688,
21689,
21728,
21729,
22471,
22472,
23213,
23214,
23663,
23664,
24183,
24184,
24912,
24913,
25411,
25412,
26185,
26186,
26566,
26567,
27169,
27170,
27724,
27725,
28387,
28388,
29178,
29179,
29855,
29856,
30617,
30618,
31148,
31149,
32176,
32177,
32695,
32696,
32706,
32707,
33699,
33700,
33710,
33711,
34358,
34359,
34866,
34867,
34877,
34878,
35549,
35550,
35560,
35561,
36382,
36383,
36631,
36632,
36649,
36703,
36822,
36941,
37043,
37195,
37300,
37449,
37629,
37722,
37894,
37995,
38121,
38266,
38408,
38514,
38640,
38777,
38950,
39022,
39157,
39171,
39226,
39324,
39513,
39660,
39758,
39855,
39952,
40050,
40219,
40404,
40658,
40746,
41066,
41151,
41262,
41343,
41428,
41538,
41615,
41703,
41788,
41880,
41957,
42069,
42159,
42271,
42348,
42446,
42522,
42605,
42719,
42828,
42931,
42947,
43075,
43196,
43441,
43560,
43573,
43598,
43626,
43650,
43678,
43701,
43729,
43751
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 43751,
"ccnet_original_nlines": 262,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.32193028926849365,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.02445369027554989,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1763787716627121,
"rps_doc_frac_unique_words": 0.20217560231685638,
"rps_doc_mean_word_length": 5.622222423553467,
"rps_doc_num_sentences": 250,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.714773654937744,
"rps_doc_word_count": 6435,
"rps_doc_frac_chars_dupe_10grams": 0.25915586948394775,
"rps_doc_frac_chars_dupe_5grams": 0.3991818428039551,
"rps_doc_frac_chars_dupe_6grams": 0.3562840223312378,
"rps_doc_frac_chars_dupe_7grams": 0.30639320611953735,
"rps_doc_frac_chars_dupe_8grams": 0.291108101606369,
"rps_doc_frac_chars_dupe_9grams": 0.27018436789512634,
"rps_doc_frac_chars_top_2gram": 0.039802100509405136,
"rps_doc_frac_chars_top_3gram": 0.012576360255479813,
"rps_doc_frac_chars_top_4gram": 0.010503330267965794,
"rps_doc_books_importance": -2699.317138671875,
"rps_doc_books_importance_length_correction": -2699.317138671875,
"rps_doc_openwebtext_importance": -1614.816162109375,
"rps_doc_openwebtext_importance_length_correction": -1614.816162109375,
"rps_doc_wikipedia_importance": -1298.103271484375,
"rps_doc_wikipedia_importance_length_correction": -1298.103271484375
},
"fasttext": {
"dclm": 0.05412263050675392,
"english": 0.8706674575805664,
"fineweb_edu_approx": 2.818722724914551,
"eai_general_math": 0.0339999794960022,
"eai_open_web_math": 0.0903969407081604,
"eai_web_code": 0.0028755699750036
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.042028",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.042",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v1": {
"primary": {
"code": "11",
"label": "Legal/Regulatory"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "8",
"label": "Documentation"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-2,841,196,976,631,615,500 | We will publish letters and comments on this site. They will rotate often as we believe actual letters and case reports are an excellent resource for arachnoiditis patients to improve their care. Send your letter to “Arachnoiditis Research & Education Project“.
You may send your questions to tennantfoundation92@gmail.com, fax to 626-919-7497, or mail to:
The Tennant Foundation
Arachnoiditis Research Project
336-338 S. Glendora Ave.
West Covina, CA 91790-3043
YOUR QUESTIONS AND OUR ANSWERS ARE UPDATED FREQUENTLY
Dear Tennant Foundation,
I have AA and quite possibly Autonomic Neuropathy. I also have Peripheral Neuropathy and Cardiomyopathy. I’m convinced that I do not have all of these conditions. That there is one underlying issue causing all my problems.
If it is AA, I am okay with that. If I do have all then I’m now worried about long term lifespan.
Anyway, I was contacting you to let you know that I am now suffering from severe congestion. Imagine in today’s environment the look that I get when having to blow and wipe my nose all the time. Is congestion common with AA?
Always many thanks for your feedback. DM
ANSWER
Dear DM,
Your timing is extraordinary!! We just wrote a bulletin on the autoimmune and allergic issues with AA. It is not well appreciated but inflammation inside the spinal canal sheds lots of “biologic trash” that gets into the general circulation. Think of when you had a “boil” or “cellulitis”. The red, warm tissue particles have to shed. When one develops allergic or autoimmune complications of AA, it is time to review and enhance the anti-inflammation component of your treatment program. In particular you need to be on a periodic, low dose corticosteroid and 1 or 2 herbal/nutritional anti-inflammatory agents (curcumin, boswellia, Traumeel®, PEA, andrographis).
Besides beefing up your “inflammation reduction component” of your treatment program, start an effective “tissue repair” component with vitamin C (2000 to 4000 mg a day), B-12 (500 – 1000 oral mcg a day), and either collagen or polypeptide supplements. Keep this in mind. Autoimmunity means your body is “eating away” at your tissue. You don’t have to put up with much autoimmune damage and let it sacrifice the quality of your life or lifespan if you follow a 3-component medication program.
Best wishes, Forest Tennant
Dear Tennant Foundation,
This is NK from Chicago. 4 weeks ago, I started your protocol for AA.
1. Naltrexone, 4mg. BID
2. Ketorolac, 15 mg. IM Twice a week (this is 3rd week)
3. Methylprednisolone, 4 mg. 3 times a week
4. Gabapentin, 200 mg T I D.
After two weeks, burning pain on my feet went down and slowly Gabapentin was discontinued 10 days ago. Other medicines:
1. Metformin, 500mg. One/ day
2. Serrapeptase, 1 cap. 40,000SPU/ day
3. Turmeric, 1000mg. Daily once
4. Pregnenolone 100 mg/ day. I took Pregnenolone 100 mg for 3 weeks and discontinued because I have enlarged prostate. (BPH).
5. PEMF Energy treatment since 4 weeks.
6. 10 lb. magnetic pull rub
7. Walking 2 to 3 miles every day.
No pain last 10 days. Two days ago, I did Trampoline walk for 30 minutes, about 4 miles. The next evening, I got back all the symptoms again: Burning pain on my both feet, Hot flashes and first time I got burning pain on my peritoneum area. I never had this problem before. I started again GABAPENTIN 200mg BID which responded well with in one day. But when I do regular walk or trampoline walk, the pain is coming back. Would you please advise me to change any of medications? Or to increase the dose of Naltrexone?
Warm regards, NK
ANSWER
Dear NK,
You have built an excellent program. You should do what you are doing and that is reject what doesn’t work and continue to enhance your program.
We know of some persons who take naltrexone as much as 7.0mg twice a day. Here are some ideas to try one at a time:
1. water soaking
2. palmitoylethanolamide (PEA)
3. taurine, 2000mg – 3 times a day for 4 days
4. colostrum – see label
5. deer antler velvet – see label
Cut out the trampoline and only walk 20-30 feet at a time. Don’t overdo. Stop if pain starts. Let us know ANY and ALL that work. We will pass them on. Thanks for sharing.
Best wishes always,
Forest Tennant
Tennant Foundation,
Can a viral infection cause inflammation and AA in the spine? Thanks, G
ANSWER
Dear G,
The answer is yes. The issue of viral infection causing inflammation in and around the spinal canal has emerged as a most significant issue. I used to believe that viruses such as EBV and CMV only invaded after inflammation and immune suppression had started in spinal canal tissues. I am now in the process of re-evaluating and changing my thinking. I am forming the opinion that some viruses may invade the intervertebral discs and initiate inflammation with subsequent “slippage” or “protrusion” against the wall or covering of the spinal canal. Furthermore, this inflammation can spread or infiltrate the spinal canal covering, exiting nerve roots, and the cauda equina. Intervertebral discs have sections that have a very poor blood supply which would be fertile spots for a virus to propagate. In my review of over 800 cases of persons with AA symptoms, almost all have protruding discs. Many of these persons have had surgery for these “slipped” discs but the patient has no history of trauma to cause the disc to “slip”.
In summary, I conclude that some persons have viral infections that initiate spinal canal inflammatory disorders including AA.
Best wishes always,
Forest Tennant
Tennant Foundation,
I’m continuing the hormones as suggested. Now adding DHEA. I Feel like I’m doing much better until a flare up sometimes caused by over doing it. I’m hoping to start methylprednisolone small daily dose, after my appointment with my pain doctor. My question is do I also need to take serrapeptase and adrenal cortex?
Thanks, SF
ANSWER
Dear SF,
First, serrapeptase is an herb that helps many, but not all, persons with AA. Its biologic actions are unclear, but they are not related to adrenal cortex or methylprednisolone. In other words, if it is helping, continue it.
AA is really a disorder in the class of conditions called “Spinal Canal Inflammatory Disorder” (SCID) which means that some tissues in and around the spinal canal are inflamed. For this reason, plus others, each person has to build their own tailor-made program.
If you can obtain methylprednisolone or dexamethasone, you don’t need adrenal cortex. Many medical practitioners are still afraid to prescribe corticosteroids usually because they aren’t aware of new information that validates the relative safety of low dose, periodic corticosteroids. Given the different types of tissues that are inflamed with SCID, I like to see more than one natural anti-inflammatory agent be used.
Best wishes always,
Forest Tennant
Hi Tennant Foundation,
You looked at my MRI in 2019 and agreed that I have adhesive Arachnoiditis (AA). I was diagnosed in 2001 by Dr. G. My question is, I am having crazy pain in my joints that started 8months ago and my rheumatologist said that my blood work comes back fine except that I have bad inflammation. Tests for autoimmune or rheumatoid arthritis all were negative. What do I do there’s times that I can’t walk because of the pain or get out of bed? I am mobile but it just gets so bad for me. Need some help.
Thank you, JC
ANSWER
Dear JC,
You describe the typical autoimmune manifestations that may accompany AA. The theory on why autoimmunity occurs with AA is that small, inflamed particles from spinal canal tissue enters the bloodstream and causes autoimmunity. Tests for the rheumatoid markers are usually negative.
Are you on a low dose, periodic corticosteroid? This is the only thing I know that consistently controls AA autoimmune manifestations. Also, you need to review your program and determine what measures you are doing to repair your damaged tissues.
Best wishes always,
Forest Tennant
Tennant Foundation,
I have emailed you before but not about this question. I’ve been having my left thigh harden up so hard and swelling which is so painful. Slight discoloration of bruising at times. I informed my provider, and he has done an ultrasound which was negative and I’ve been on Medrol 2 mg 3 x week, for about 4 weeks now, Pregnenolone 100mg daily and Cymbalta 20mg daily and 1 Percocet 5mg/375mg at night. Have you had patients with this problem that have AA? What would you suggest that I take for it and or do for it? I would appreciate your help with this.
Thank you, DA
ANSWER
Dear DA,
Hip problems are quite common in persons with AA. I believe the usual cause is damage to cauda equina nerve roots that connect to tissues in and around the hip joint. The swelling is due to inflammation in and/or around the hip joints.
If it feels better with heat, magnet rub, water soak, or TENS, it means inflammation under the skin. A cortisone injection into the area is worth a try.
You will find a number of rub-on and patch products at any of the major pharmacies. Experiment with Salonpas, Lidocaine, and others.
Please review the agents that are in the inflammation reduction and tissue repair components for AA. The biggest failing that I see is a failure to use one or more tissue repair agents. Let us know your progress.
Best Wishes, Forest Tennant
Hi, I’m wondering what Your/Doctors thoughts are on PEMF therapy. With surgical wrapped Tarlov cysts, and CES?
Thank you, N
ANSWER
Dear N,
PEMF therapy should be a part of the treatment program for everyone who has a spinal canal inflammatory disorder. CES is worth a try, but it isn’t as consistent as PEMF.
PEMF is one of the physical measures we highly recommend along with water soaking, rocking, stretching, and magnet rubs.
Best Wishes, Forest Tennant
Dear Tennant Foundation,
I recently came across an article from the Cleveland clinic dated January 4th, 2018 (see attached web link below).
I was wondering what your thoughts about intrathecal infusion of Ziconotide?
I developed AA back in 2014 from surgery for a partial L5/S1 herniated disc. I also have spinal stenosis and a slight anterior rotation of L3. I am doing medial as well as holistic vitamins.
I am hesitant about surgery but because I don’t want to make it worse and I have a hx of kidney stones the more oral things I take the higher my kidney markers go up.
I know this is my decision, so I am trying to get all the facts before making the decision.
Thank you for your time, DC
ANSWER
Dear DC,
I only recommend intrathecal infusions, spinal stimulators, stem cells, or risky, experimental procedures AFTER a person is on a good physical measures and medical program which has these 3 components: (1) inflammation reduction, (2) tissue repair, and (3) pain control. Although we have seen many persons reduce pain and other symptoms with these risky, invasive procedures, EVERY person still needs an on-going treatment program of physical measures and a 3-component medication program.
Remember, “quick fixes” and “shortcuts” may put you in jeopardy.
Best Wishes, Forest Tennant
Hello Tennant Foundation,
I came across your website as I’ve been dealing with some health issues and found it very helpful. I was wondering. Would you be able to recommend a doctor experienced in dealing with Spinal Canal Inflammatory Disorders in the Raleigh, North Carolina area? I am stationed at Fort Bragg, in Fayetteville, near there.
Thank you very much, WJ
ANSWER
Dear WJ,
At this time few physicians are specializing in AA, but many are becoming quite good clinicians as spinal canal inflammatory disorders are so very common and important. Take our materials to your personal physician and ask him whether he/she can treat or refer you.
Best wishes, Forest Tennant
Dear Tennant Foundation,
I have a pain pump that is only compatible with 1.5 Tesla, so a 3 Tesla MRI is, unfortunately, not possible. The gadolinium is not injected but infused via IV, so it doesn’t go into the intrathecal space. Is the gadolinium IV is safe?
Thanks! JC
ANSWER
Dear JC,
Gadolinium is very safe and the very best MRI’s are done with it.
Best wishes, Forest Tennant
Hi,
Thank you so much for the info. My doctor is wondering how long do we use these medications mentioned? Is it long term or just a few months? He was very happy to get some answers finally!
Thanks, R
ANSWER
Dear R,
We recommend that a 3-component medication program be in place as long as there is pain. Even after pain subsides, we recommend regular use of anti-inflammatories since AA can recur.
Best wishes, Forest Tennant
Dear Tennant Foundation,
I have another question. if my adhesive arachnoiditis is on the left thecal sac L4 why is most of my pain on my right side and numbers and stinging burning pain is on my right leg and foot. I could not walk on my right leg foot immediately after surgery. When I woke up I could not stand on my right leg. It would not hold me.
Thanks, KD
ANSWER
Dear KD,
AA is a bundle or mass of nerve roots, adhesions, and fibrosis. Nerve roots also cross-function. Therefore, the mass can be on the left but cause symptoms on the right leg.
Best wishes, Forest Tenant
Tennant Foundation,
Thank you so very much Dr. Tennant for taking the time to view my MRI and for your advice. I immediately sent a purchase request to Amazon for your 2 books and look forward to receiving them. I have one more request from you. Now that there are virtual medical visits over the network I wonder if you can give me the name of a doctor who specializes in my disease and who lives anywhere in the US. Although Stanford has a pain clinic, they seem not to have specialist in my disease. They are offering me an implanted stimulus machine but after 2 back surgeries I want to stay away from any invasive treatments. My sister has had asthma for years and uses some of the medications that you recommend. When I told this to the doctor at the Palo Alto Medical Foundation, she said that the side effects could be damaging and put me on NORCO instead. So just the names of some arachnoiditis specialists and I will leave you alone.
Thanks again, CW
ANSWER
Dear CW,
At this point in time I don’t have any arachnoiditis specialists to help you. ARC and AA are still too rare and unappreciated that they aren’t even listed in the physician’s yearly handbook, Current Therapy. Consequently, you and your local medical practitioners can and should build a 3-component medication program plus physical measures that help spinal fluid flow. Norco is hydrocodone plus acetaminophen is a mild to moderate opioid, and it is an excellent pain reliever. Many persons with AA use Norco and I highly recommend it as a pain reliever along with anti-inflammatory compounds that work on spinal canal inflammation.
I’m attaching some information to help you start building your own, tailor-made program for relief and recovery. Stay tuned to the letters on our website as they will keep being updated and give you tips to improve your program.
Best wishes always,
Forest Tennant
Tennant Foundation,
Is it okay to use Ketorolac just twice a week? I separate the days to Monday and Thursdays. Should I put the two days together say mid-week?
Should I use steroid reducing pack more often than during bad flare-ups?
SD
ANSWER
Dear SD,
I’m attaching some bulletins which give you some details about corticosteroids and ketorolac. In documented cases of AA, we recommend that a corticosteroid be taken regularly on a low dose, periodic basis. We recommend that ketorolac not be taken on consecutive days unless it is the only drug that allows a person to control pain and function.
Best wishes always,
Forest Tennant
Tennant Foundation,
I was officially diagnosed with AA in 2010. I have had four spinal surgeries and I am fused from L2 to S1. My last surgery was in January 2019 due to loose pedicle screws at L-5.
My main symptoms have been burning, tingling and numbness in my toes and feet however in the last two weeks this has progressed to my shins and calves bilaterally. Of course, I also experience muscle fasciculations and spasms as well.
Due to my CKD, stage 3b, creatinine 176 and GFR 35, I am not able to follow your protocol except for Curcumin and PEA. I want to start on Methylprednisolone however I do not know what dosage to take nor how many times a week.
I have a wonderful Nephrologist however she is unfamiliar with AA and could only provide me with the side effects of taking Methylprednisolone. I tried explaining to her your concept of neuroinflammation but to no avail.
Would you be so kind as to advise me as to what dosage and how many times a week would not be too detrimental to me due to my CKD? I need to stop the progression of this horrendous affliction.
Thanking you in advance for your kind cooperation, I remain yours truly,
JK
ANSWER
Dear JK,
Here are agents that routinely suppress the inflammation that causes AA and have no history of causing renal toxicity: methylprednisolone, pregnenolone, DHEA, colostrum, naltrexone, opioids, gabapentin, dexamethasone.
The drugs in the 3-component recommendations that may harm kidneys are: ketorolac, indomethacin, and diclofenac.
Best wishes always,
Forest Tennant
Tennant Foundation,
I read your material, and I have lupus too, and I take blood thinners is there anything with your material that wouldn’t work with Eliquis?
Thanks, S
ANSWER
Dear S,
Since you take a blood thinner, I recommend you only take a prescription anti-inflammatory agent once a week: ketorolac, diclofenac, indomethacin. Try to stick with non-prescription, herbal, and nutritional anti-inflammatories: examples; curcumin and palmitoylethanolamide (PEA).
Best wishes, Forest Tennant
Dear Tennant Foundation,
I wanted to express my deep gratitude to you for sending me all the important information on my condition. When I read my MRI and read the word arachnoiditis, I searched the internet for information, and I found your handbook. I read it and found the information to be extremely helpful. After having lumbar surgery in 2017, I believe my AA symptoms became acute after I was rear ended in my car at high speed by a truck in 2019. In any case, I plan to use your handbook as a guide and educate my doctors. I am shocked that none of the major teaching hospitals in Los Angeles and other major cities do not treat AA. I read that you retired, and I am sure it was well deserved! Thank you for all that you do for the AA community.
Warm wishes, AR
ANSWER
Dear AR,
Thank you for your kind words. Although I’m retired from clinical practice, I am continuing research on arachnoiditis and the other spinal canal inflammatory disorders (SCID). You are correct when you say that major hospitals and medical institutions are ignorant about AA. This means that you must build a personal therapy plan without much help from organized medicine.
The major conceptual problem is that the entire medical system is arranged to detect and treat mechanical or surgical abnormalities of the spine. Recent research clearly indicates that inflammation in and around the spinal canal is the culprit that must be controlled.
Best wishes, Forest Tennant
Tennant Foundation,
Thank you so much for your reply. The new program his pain management doctor is recommending is the OrthoLazer. This is perhaps in addition or in place of the Calmare. We were just wondering if in your opinion would this type of treatment “excite” anything. He tries to be incredibly careful.
And we will look into the therapeutic trial you suggested. Appreciate your time. SM
ANSWER
Dear SM,
I’m a great believer in electromagnetic treatments for spinal canal inflammatory disorders (SCID). The OrthoLaser is worth a try. If it helps you may want to acquire a device, which you can use periodically at home. I don’t believe that laser and other electromagnetic therapies “excite” or do damage.
Best wishes, Forest Tennant
Hello Tennant Foundation,
On August 31st, my 28-year old wife suffered a brain aneurysm rupture. She spent 32 days in the hospital, most of which in the ICU. Initially, she did not have the ability to move her left leg but did regain function of it. She is suffering from short term memory loss. Since becoming mobile approximately 45 days ago, she has had severe lower back pain. Initially, the doctors believed it was being caused by the blood that mixed into her CSF. They told us it would take 2-4 weeks to get better. It has not gotten any better. She now also has shooting pain in her left hip. She finds complete relief by laying down. She can sit/stand for around 10 minutes at a time and is able to walk with discomfort.
Our neurosurgeon thinks she may have Arachnoiditis. We have an MRI scheduled for this coming week. I have a couple questions for you. Do you see cases of arachnoiditis because of an aneurysm rupture? Is this common? Do you recommend an MRI with or without contrast to best make a diagnosis?
We have started an anti-inflammatory diet and supplements. We are also doing the exercises outlined on your website.
Thank you for your help. JM
ANSWER
Dear JM,
Unfortunately, a ruptured aneurysm can allow blood elements to enter the spinal fluid. Blood in the spinal fluid can be carried to the lower lumbar-sacral spine and start an inflammatory process usually in the nerve roots of the cauda equina. You are wise to get an MRI. At this point it would probably not show adhesive arachnoiditis (AA) but would possibly show cauda equina inflammation signs. I highly recommend a clinical trial with Medrol and ketorolac to determine if spinal canal inflammation is present.
Best wishes always,
Forest Tennant
Hello Tennant Foundation,
Hope you’re doing well; I apologize for bothering you as I know you already have so much going on. I’m experiencing very high pressure on my head, severe dizziness ,nausea eye pressure and redness as well as eye pain, I mentioned acetazolamide to my Doctor and would like a confirmation from you that it’s ok to use for head pressure in relation to Arachnoiditis. He also noticed my eyes were dilated and asked if I was using “drugs” which I’m not. I only use what you have recommended and has been prescribed which is LDN, methylprednisolone, ketorolac. What could be causing the dilation of my eyes? Thank you so much for your time.
Sincerely, DM
ANSWER
Dear DM,
We recommend a trial of acetazolamide for any person with AA who has eye, ear, or nasal symptoms. For safety, take ½ or 1 pill (250mg). If no side effects, work up to 2 or 3 pills a day for a week. If you do well with acetazolamide, continue it. We are aware that some persons with AA take up to 4 pills a day and do very well with it as it suppresses neuroinflammation as well as controls spinal fluid flow.
Best wishes, Forest Tennant
Dear Tennant Foundation,
Hi again, in March 2020, due to the radiating leg pain and numbness in my feet, I had a nerve conduction test done. Now just today I had the same test performed and my neurologist was in a state of bewilderment. He said normally these tests stay the same or get worse, I have never seen improvement like this before, or at least extremely rare cases. So, to confirm your theory, the answer is yes if the inflammation is controlled the pain will be reduced greatly, as well regeneration is also possible. In about 10 months I will get another full spine MRI, as well as another nerve test. I will continue the protocol that I am currently doing, as well as keep things recorded on a monthly basis, if my DDD /AA is reversed significantly in the MRI’s , and I suspect it is a good possibility, I will forward you all documents as well as my all natural protocols, for your research.
Thank you, SM
ANSWER
Dear SM,
I’m delighted, but not surprised with your progress. Now that we understand “spinal canal inflammatory disorders” (SCID) and agents and measures to treat it, everyone with one or more of the disorders can find some relief and recovery.
Best wishes, Forest Tennant
Dear Tennant Foundation,
Thank you so much for replying to me!!! Thanks to you I’m getting the help I need and I’m no longer in a wheelchair. God bless you so much, DM
ANSWER
Dear DM,
We are constantly learning new information about spinal canal inflammatory disorders. We will continually pass on what we learn. Also, you can continually build a better and better treatment program,
Best wishes, Forest Tennant
Thanks so much, Tennant Foundation for the valuable information. I’ll make some changes per your advice. The adrenal cortex does seem a bit sketchy however….reading a fair amount about its potential to cause infections. Will see what I can do to make sure the product I obtain is safe.
BTW – the radiologist who reviewed my last MRI did see some improvement in the adhesive arachnoiditis. SM
ANSWER
Dear SM,
The adrenal cortex we recommend is oral capsules. Klaire® is one recommended brand. In persons who have a suppressed immune system due to AA, adrenal cortex should reduce the risk of infection.
Best wishes, Forest Tennant
Dear Tennant Foundation,
I want to thank you for all the work you do and all the help and hope you give us.
I started your protocol earlier this year. My inflammation numbers have dropped and so has my platelet count. I have Ehlers-Danlos from what YOU saw on my questionnaire. I was finally able to see a genetics specialist last week and he confirmed the diagnoses. That doctor sent me to several different specialist who are educated in these conditions. I’ve seen the pain doctor and he recommended Lyrica and Zyrtec or Benadryl and both seem to be helping.
You have been such a huge help in changing my life and giving me answers I’ve searched for over 20 years. Thank you so much
Sincerely, PY
ANSWER
Dear PY,
I’m delighted, but not surprised, that you are getting some relief and recovery. Now that we understand collagen dissolution and spinal canal inflammatory disorders (SCID’s) we’ve been able (after about 10 years of research) to develop some effective protocols. It sounds like you’ve got a great doctor. Keep you eye on both our websites as we have new information coming.
Best wishes,
Forest Tennant
Tennant Foundation,
I’m from Pennsylvania. I have Adhesive Arachnoiditis and I went many many years before receiving this diagnosis. I have all if not most of the symptoms described. I spend most of my days in bed to the point my muscles are wasting away. I was doing fine (I was okay with my life) before my opioids were reduced.
Keep up the great work. Thank you, DK
ANSWER
Dear DK,
When opioids are reduced, I recommend the following:
1. Obtain Kratom as it is the only non-prescription opioid.
2. CBD/marijuana may substitute for some opioids.
3. Review the 3-component medication program for AA and make sure you take drugs from the inflammation reduction and tissue rebuilding components.
4. Have a hormone blood test for testosterone, DHEA, and pregnenolone. If low on any of these, replenish them as low levels will keep opioids from being very effective.
5. Ask your physician to prescribe morphine, opium, or hydromorphone suppositories for flares.
Best wishes always,
Forest Tennant
Hello,
I am writing to you because I am seeking some answers. A little over a week ago I had an epidural blood patch which resulted in an extremely sore tailbone, intense burning sensations in my legs, difficulty extending my legs because it feels like my nerves are caught and pulling upwards behind my knees, and sudden bladder and bowel dysfunction. I was told this may be arachnoiditis and my doctor did put me on a 6-day course of prednisone. The symptoms are annoying and constant but thankfully mild, but hasn’t seemed to improve much. I do not know if it will resolve or get worse.
However, what really puzzled me and others was that when symptoms started, I was lucky enough to receive a lumbar MRI (before starting the prednisone) but was told by ER doctors that my MRI showed no signs of inflammation. From what I understand, arachnoiditis shows up on an MRI or you’d at least see the inflammation or nerve damage. Is it possible to still develop symptoms without it showing on an MRI? Could the MRI just be read incorrectly if my case is extremely mild and hasn’t progressed yet to show obvious nerve damage? Or could it possibly just be nerve irritation that is presenting with similar symptoms and will resolve on its own?
I’m just puzzled by this and no doctor I’ve spoken to knows what to make of my situation. I worry about it becoming worse or debilitating if I don’t handle it promptly and appropriately, since my MRI results do not show evidence of inflammation, I’m lost as to what to do next.
Thank you so much for your time! AL
ANSWER
Dear AL,
Your questions are most legitimate. Based on your note you clearly have one or more disorders in the class of spectrum of what we call “Intraspinal Canal Inflammatory Disorders”. The MRI will only show protruding discs and adhesive arachnoiditis (AA). You should immediately start 3-component treatment: inflammation reduction, tissue rebuilding, and pain control.
Best wishes,
Forest Tennant
Dear Dr. Tennant,
This may be an odd question but it’s hard to find another doctor with your expertise on arachnoiditis anywhere in the country. I am having a hard time figuring out what it means to have chronic adhesive arachnoiditis. I was diagnosed in 2015 after 20+ years of suffering because of two “failed” back surgeries in the 90’s. At this point in the process is there still inflammation present even after the scar tissue forms and the nerves are clumped together? Or is it an end stage which means that the inflammation is over? Nothing I’ve read has ever explained this or even addressed it.
My main concern right now is regarding the safety of vaccines of any kind but especially the Covid-19 vaccine when it is approved. It appears that the first trials at Oxford were halted due to transverse myelitis so that makes me wonder if we as arachnoiditis patients would be more susceptible to side effects. If we are in a constant inflammatory state, I would think that introducing another challenge to our immune system would tend to overtax our capacities. I look forward to hearing your opinion on this topic.
Many thanks for all you continue to do for those of us who suffer.
JC
ANSWER
Dear JC,
Your questions are “right on”. First, we believe that intraspinal canal inflammation of rheumatoid arthritis. Intraspinal canal inflammation (ICI) may wax and wane, but one must not assume it will totally go away.
In late stage Aa, you should still attempt to build a program of relief and recovery by building a tailor-made, 3-component treatment program. Since you may be on a lot of pain control medications, you can simply add one or two of the best non-prescription anti-ICI agents: curcumin, andrographis, palmitoylethanolamide (PEA). You also want to take one or more of the tissue-building, neural regenerative agents since even late stage AA can regenerate or “scar over” old clumps and adhesive masses. For example, DHEA, colostrum, or deer antler velvet. We are seeing significant improvement with nandrolone. Unfortunately, the government is restricting the compounding of HCG.
I assume given your history that you have the intractable pain syndrome. We have a new website directed specifically at this complication of late stage AA. Please sign up.
I don’t recommend vaccines for late stage AA.
Be clearly advised. We don’t want to give up on long standing AA as we are seeing some remarkable improvement if you can do some of the physical measures such as walking, arm stretching, and water soaking.
Best wishes,
Forest Tennant
Hello,
Dr. Tennant reviewed my MRI’s at the end July and stated that I have the precursors to AA (attached is the letter sent to me). Since then, I have been diagnosed with thyroid cancer and have a full thyroidectomy scheduled for November 6th. I know having optimal hormone levels is important for nerve regeneration. My physicians haven’t seemed to think this would cause any issues, being that I will begin Synthroid immediately, but they also aren’t familiar with AA.
Currently my hormones are all within optimal levels. I’m also taking 2 mg of Methylprednisolone every other day and have been for nearly 2 months. Daily I’m taking turmeric curcumin, serrapeptase and nattokinase, PEA, and diclofenac. My continued symptoms are burning, tightness in lumbar spine, burning and aching legs at times, and newest is right shoulder pain (not sure if it’s related). I am stretching many times a day and walking about a half mile twice a day. I appreciate any advice or insight you can give regarding this.
Sincerely,
MS
ANSWER
Dear MS,
I like the program you built for yourself. I truly believe you will prevent the development of AA with it. It is far better to treat what we call Cauda Equina Inflammatory Disorder (CEID) rather than wait for the development of AA.
I see no reason to change anything, including hormones you are doing. Synthroid will only help reduce the inflammation caused by CEID.
Have you been diagnosed with an autoimmune disorder? I’m impressed you are taking nattokinase, because I feel this may be a helpful agent for all the intraspinal canal inflammatory disorders. I look forward to hearing from you. Tell your physicians they are doing an outstanding job.
Best wishes,
Forest Tennant
Dear Dr. T,
What about oral ketorolac? Your literature says to be cautious or even “don’t use it”.
Thank you,
Dr. LC
ANSWER
Dear Dr. LC,
We’ve had to modify our position on oral ketorolac, because frankly, it is usually difficult to get much CONSISTENT relief and recovery from AA and CEID without low dose, regular dosing of ketorolac and a corticosteroid.
Persons under age 70 can almost always take an oral 10 mg dose on 1 to 3 days a week or every other day.
Here are some rules I recommend:
1. Skip a day between ketorolac dosages.
2. Take with food or an antacid.
3. Do a periodic hemoglobulin, hematocrit, or blood count and BUN/creatinine. Liver is rarely affected. Test regularly if over 70.
4. Warn patients about black stools, vomiting blood, or abdominal pain.
5. A good idea is to also alternate days of ketorolac with dexamethasone or methylprednisolone.
Ketorolac almost seems like it was made for intraspinal canal inflammatory disorders. It can and should be an ancillary treatment with low dose naltrexone and daily opioids. The latter can almost always be reduced with use of ketorolac.
Best wishes,
Forest Tennant
Dear Dr. Tennant,
I was hoping to be added to the email list. I was diagnosed a few years back and things seem to be getting worse. I’ve had 2 flairs in the past month. It’s awful. Thank you so much in advance.
JR
ANSWER
Dear JR,
I’m very glad you have contacted us, because our recent research provides some guidance on prevention of flares and deterioration. I write the following on the basis that you have AA or other intraspinal canal inflammatory disorders.
Flares and deterioration are caused by either uncontrolled inflammation, infection, or some type of injury due to overexertion. Adequate treatment of AA requires 3 components: (1) suppression of inflammation; (2) protection and regeneration of spinal canal tissues; and (3) pain control.
You need to review the 3 components and see if you are lacking. Also review the physical measures that must be done routinely to control AA.
Most persons with flares and deterioration have an insufficient program to suppress intraspinal canal inflammation. You will need more that one agent as different tissues are involved. Be clearly advised. If you have AA, you will need a periodic corticosteroid to control flares and deterioration. We will be sending out regular bulletins to help persons with AA take advantage of our latest research. Also, you should probably obtain our handbook from Amazon.
Best wishes
Forest Tennant
Dear Dr. Tennant,
Found your latest bulletin concerning corticosteroids being essential for adhesive arachnoiditis very interesting. I have found that the only time I was totally free from pain is when I took methylprednisolone. Dr renewed once but wouldn’t renew again.
Besides back and leg extreme pain, constant insomnia, extremely dry thin skin on my forearms and shins bother me. I look like I’ve been beaten most the time. I do not take blood thinners. In fact, I don’t even take Tylenol because of bruising. Thus, I can’t get relief from inflammation except through usage of Kratom. I’m sure that I’m either taking something that’s causing it or am lacking some essential vitamin or mineral.
How can I find out if what I take is causing problems? Also, as far as methylprednisolone prescription, would I follow your suggestion of 1 4 mg pill?
Thank you in advance be for your advice, SF
ANSWER
Dear SF,
I assume you either have adhesive arachnoiditis (AA) or cauda equina inflammatory disorder (CEID). The treatment is fundamentally the same except one really needs a potent anabolic hormone with AA. CEID is much more treatable. Your experience with pain reduction by use of methylprednisolone tells us that you have inflammation inside your spinal canal.
Perhaps your physicians would consider an injection or 8 mg oral tab of methylprednisolone on a weekly or bi-monthly basis. If you simply can’t get methylprednisolone purchase “adrenal cortex” in a health food store. Use a dose about 2 or 3 times what is on the label. You can also get pregnenolone which converts to cortisol and progesterone.
A number of persons with AA are finding this combination of non-prescription anti-inflammatories to work quite well for AA and CEID: curcumin, PEA, and andrographis.
I hope this helps.
Best wishes,
Forest Tennant | {
"url": "http://arachnoiditishope.com/question-answer-forum/",
"source_domain": "arachnoiditishope.com",
"snapshot_id": "crawl=CC-MAIN-2021-04",
"warc_metadata": {
"Content-Length": "60217",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:HYFSVLCOLG6LE7MATYSEHKR33D5XFHO6",
"WARC-Concurrent-To": "<urn:uuid:9445ca73-66da-44e6-8748-cb9d34812d8f>",
"WARC-Date": "2021-01-25T00:33:49",
"WARC-IP-Address": "144.208.71.115",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:MUNKNLRWMSLCOLUY7S4AOMPY5RNZHQO7",
"WARC-Record-ID": "<urn:uuid:6123ed1d-a5d0-4f1d-a171-1c3cbeac66f4>",
"WARC-Target-URI": "http://arachnoiditishope.com/question-answer-forum/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:c81983f0-45d5-4827-beb4-875abba18c2e>"
},
"warc_info": "isPartOf: CC-MAIN-2021-04\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for January 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-250.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
264,
265,
360,
361,
384,
385,
416,
417,
442,
443,
470,
471,
525,
526,
551,
552,
777,
778,
877,
878,
1104,
1105,
1147,
1148,
1155,
1156,
1165,
1166,
1838,
1839,
2335,
2336,
2364,
2365,
2390,
2391,
2461,
2462,
2488,
2546,
2592,
2623,
2624,
2744,
2745,
2777,
2818,
2852,
2980,
3022,
3052,
3089,
3090,
3607,
3608,
3625,
3626,
3633,
3634,
3643,
3644,
3790,
3791,
3908,
3909,
3928,
3961,
4009,
4036,
4072,
4073,
4249,
4250,
4270,
4285,
4286,
4306,
4307,
4380,
4381,
4388,
4389,
4398,
4399,
5436,
5437,
5564,
5565,
5585,
5600,
5601,
5621,
5622,
5939,
5940,
5951,
5952,
5960,
5961,
5971,
5972,
6199,
6200,
6464,
6465,
6888,
6889,
6909,
6924,
6925,
6948,
6949,
7449,
7450,
7464,
7465,
7472,
7473,
7482,
7483,
7767,
7768,
8017,
8018,
8038,
8053,
8054,
8076,
8077,
8636,
8637,
8651,
8652,
8659,
8660,
8669,
8670,
8908,
8909,
9063,
9064,
9198,
9199,
9414,
9415,
9443,
9444,
9557,
9558,
9571,
9572,
9579,
9580,
9589,
9590,
9762,
9763,
9884,
9885,
9913,
9914,
9940,
9941,
10056,
10057,
10134,
10135,
10326,
10327,
10494,
10495,
10587,
10588,
10616,
10617,
10624,
10625,
10635,
10636,
11127,
11128,
11193,
11194,
11222,
11223,
11249,
11250,
11567,
11568,
11592,
11593,
11600,
11601,
11610,
11611,
11878,
11879,
11907,
11908,
11933,
11934,
12169,
12170,
12181,
12182,
12189,
12190,
12199,
12200,
12266,
12267,
12295,
12296,
12300,
12301,
12489,
12490,
12500,
12501,
12508,
12509,
12517,
12518,
12702,
12703,
12731,
12732,
12757,
12758,
13090,
13091,
13102,
13103,
13110,
13111,
13120,
13121,
13296,
13297,
13324,
13325,
13345,
13346,
14273,
14274,
14291,
14292,
14299,
14300,
14309,
14310,
14946,
14947,
15177,
15178,
15198,
15213,
15214,
15234,
15235,
15376,
15377,
15450,
15451,
15454,
15455,
15462,
15463,
15472,
15473,
15820,
15821,
15841,
15856,
15857,
15877,
15878,
16057,
16058,
16293,
16294,
16520,
16521,
16742,
16743,
16936,
16937,
17010,
17013,
17014,
17021,
17022,
17031,
17032,
17250,
17251,
17364,
17365,
17385,
17400,
17401,
17421,
17422,
17562,
17563,
17573,
17574,
17581,
17582,
17590,
17591,
17872,
17873,
17901,
17902,
17927,
17928,
18658,
18659,
18676,
18677,
18684,
18685,
18694,
18695,
19070,
19071,
19341,
19342,
19370,
19371,
19391,
19392,
19692,
19693,
19779,
19780,
19787,
19788,
19797,
19798,
20103,
20104,
20132,
20133,
20159,
20160,
20864,
20865,
21156,
21157,
21274,
21275,
21303,
21304,
21311,
21312,
21321,
21322,
21839,
21840,
21860,
21875,
21876,
21902,
21903,
22543,
22544,
22558,
22559,
22566,
22567,
22576,
22577,
22990,
22991,
23019,
23020,
23045,
23046,
23927,
23928,
23942,
23943,
23950,
23951,
23960,
23961,
24197,
24198,
24226,
24227,
24252,
24253,
24396,
24397,
24404,
24405,
24414,
24415,
24615,
24616,
24644,
24645,
24931,
24932,
25038,
25039,
25046,
25047,
25056,
25057,
25251,
25252,
25280,
25281,
25306,
25307,
25390,
25844,
25845,
25969,
25970,
25984,
25985,
25992,
25993,
26002,
26003,
26376,
26377,
26390,
26405,
26406,
26426,
26427,
26738,
26776,
26777,
26784,
26785,
26794,
26795,
26848,
26849,
26909,
26959,
27106,
27275,
27370,
27371,
27391,
27406,
27407,
27414,
27415,
27998,
28645,
28646,
28924,
28925,
28961,
28962,
28969,
28970,
28979,
28980,
29345,
29346,
29359,
29374,
29375,
29393,
29394,
29981,
29982,
30500,
30501,
30568,
30571,
30572,
30579,
30580,
30589,
30590,
30804,
30805,
31481,
31482,
31654,
31655,
31701,
31702,
31908,
31909,
31922,
31937,
31938,
31945,
31946,
32412,
32413,
32945,
32946,
32957,
32960,
32961,
32968,
32969,
32978,
32979,
33211,
33212,
33347,
33348,
33632,
33633,
33646,
33661,
33662,
33674,
33675,
33762,
33763,
33774,
33781,
33782,
33789,
33790,
33803,
33804,
34025,
34026,
34131,
34132,
34165,
34166,
34207,
34240,
34371,
34443,
34539,
34776,
34777,
34790,
34805,
34806,
34824,
34825,
35018,
35019,
35022,
35023,
35030,
35031,
35040,
35041,
35275,
35276,
35564,
35565,
35706,
35707,
36168,
36169,
36181,
36196,
36197,
36215,
36216,
36469,
36470,
36898,
37049,
37050,
37094,
37095,
37102,
37103,
37112,
37113,
37467,
37468,
37812,
37813,
37979,
37980,
37999,
38000,
38013
],
"line_end_idx": [
264,
265,
360,
361,
384,
385,
416,
417,
442,
443,
470,
471,
525,
526,
551,
552,
777,
778,
877,
878,
1104,
1105,
1147,
1148,
1155,
1156,
1165,
1166,
1838,
1839,
2335,
2336,
2364,
2365,
2390,
2391,
2461,
2462,
2488,
2546,
2592,
2623,
2624,
2744,
2745,
2777,
2818,
2852,
2980,
3022,
3052,
3089,
3090,
3607,
3608,
3625,
3626,
3633,
3634,
3643,
3644,
3790,
3791,
3908,
3909,
3928,
3961,
4009,
4036,
4072,
4073,
4249,
4250,
4270,
4285,
4286,
4306,
4307,
4380,
4381,
4388,
4389,
4398,
4399,
5436,
5437,
5564,
5565,
5585,
5600,
5601,
5621,
5622,
5939,
5940,
5951,
5952,
5960,
5961,
5971,
5972,
6199,
6200,
6464,
6465,
6888,
6889,
6909,
6924,
6925,
6948,
6949,
7449,
7450,
7464,
7465,
7472,
7473,
7482,
7483,
7767,
7768,
8017,
8018,
8038,
8053,
8054,
8076,
8077,
8636,
8637,
8651,
8652,
8659,
8660,
8669,
8670,
8908,
8909,
9063,
9064,
9198,
9199,
9414,
9415,
9443,
9444,
9557,
9558,
9571,
9572,
9579,
9580,
9589,
9590,
9762,
9763,
9884,
9885,
9913,
9914,
9940,
9941,
10056,
10057,
10134,
10135,
10326,
10327,
10494,
10495,
10587,
10588,
10616,
10617,
10624,
10625,
10635,
10636,
11127,
11128,
11193,
11194,
11222,
11223,
11249,
11250,
11567,
11568,
11592,
11593,
11600,
11601,
11610,
11611,
11878,
11879,
11907,
11908,
11933,
11934,
12169,
12170,
12181,
12182,
12189,
12190,
12199,
12200,
12266,
12267,
12295,
12296,
12300,
12301,
12489,
12490,
12500,
12501,
12508,
12509,
12517,
12518,
12702,
12703,
12731,
12732,
12757,
12758,
13090,
13091,
13102,
13103,
13110,
13111,
13120,
13121,
13296,
13297,
13324,
13325,
13345,
13346,
14273,
14274,
14291,
14292,
14299,
14300,
14309,
14310,
14946,
14947,
15177,
15178,
15198,
15213,
15214,
15234,
15235,
15376,
15377,
15450,
15451,
15454,
15455,
15462,
15463,
15472,
15473,
15820,
15821,
15841,
15856,
15857,
15877,
15878,
16057,
16058,
16293,
16294,
16520,
16521,
16742,
16743,
16936,
16937,
17010,
17013,
17014,
17021,
17022,
17031,
17032,
17250,
17251,
17364,
17365,
17385,
17400,
17401,
17421,
17422,
17562,
17563,
17573,
17574,
17581,
17582,
17590,
17591,
17872,
17873,
17901,
17902,
17927,
17928,
18658,
18659,
18676,
18677,
18684,
18685,
18694,
18695,
19070,
19071,
19341,
19342,
19370,
19371,
19391,
19392,
19692,
19693,
19779,
19780,
19787,
19788,
19797,
19798,
20103,
20104,
20132,
20133,
20159,
20160,
20864,
20865,
21156,
21157,
21274,
21275,
21303,
21304,
21311,
21312,
21321,
21322,
21839,
21840,
21860,
21875,
21876,
21902,
21903,
22543,
22544,
22558,
22559,
22566,
22567,
22576,
22577,
22990,
22991,
23019,
23020,
23045,
23046,
23927,
23928,
23942,
23943,
23950,
23951,
23960,
23961,
24197,
24198,
24226,
24227,
24252,
24253,
24396,
24397,
24404,
24405,
24414,
24415,
24615,
24616,
24644,
24645,
24931,
24932,
25038,
25039,
25046,
25047,
25056,
25057,
25251,
25252,
25280,
25281,
25306,
25307,
25390,
25844,
25845,
25969,
25970,
25984,
25985,
25992,
25993,
26002,
26003,
26376,
26377,
26390,
26405,
26406,
26426,
26427,
26738,
26776,
26777,
26784,
26785,
26794,
26795,
26848,
26849,
26909,
26959,
27106,
27275,
27370,
27371,
27391,
27406,
27407,
27414,
27415,
27998,
28645,
28646,
28924,
28925,
28961,
28962,
28969,
28970,
28979,
28980,
29345,
29346,
29359,
29374,
29375,
29393,
29394,
29981,
29982,
30500,
30501,
30568,
30571,
30572,
30579,
30580,
30589,
30590,
30804,
30805,
31481,
31482,
31654,
31655,
31701,
31702,
31908,
31909,
31922,
31937,
31938,
31945,
31946,
32412,
32413,
32945,
32946,
32957,
32960,
32961,
32968,
32969,
32978,
32979,
33211,
33212,
33347,
33348,
33632,
33633,
33646,
33661,
33662,
33674,
33675,
33762,
33763,
33774,
33781,
33782,
33789,
33790,
33803,
33804,
34025,
34026,
34131,
34132,
34165,
34166,
34207,
34240,
34371,
34443,
34539,
34776,
34777,
34790,
34805,
34806,
34824,
34825,
35018,
35019,
35022,
35023,
35030,
35031,
35040,
35041,
35275,
35276,
35564,
35565,
35706,
35707,
36168,
36169,
36181,
36196,
36197,
36215,
36216,
36469,
36470,
36898,
37049,
37050,
37094,
37095,
37102,
37103,
37112,
37113,
37467,
37468,
37812,
37813,
37979,
37980,
37999,
38000,
38013,
38027
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 38027,
"ccnet_original_nlines": 590,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40089380741119385,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.061119869351387024,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1553627848625183,
"rps_doc_frac_unique_words": 0.2380952388048172,
"rps_doc_mean_word_length": 4.705259799957275,
"rps_doc_num_sentences": 451,
"rps_doc_symbol_to_word_ratio": 0.00013143999967724085,
"rps_doc_unigram_entropy": 6.170505523681641,
"rps_doc_word_count": 6426,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.06402962654829025,
"rps_doc_frac_chars_dupe_6grams": 0.0398862287402153,
"rps_doc_frac_chars_dupe_7grams": 0.033635400235652924,
"rps_doc_frac_chars_dupe_8grams": 0.012369359843432903,
"rps_doc_frac_chars_dupe_9grams": 0.0032411699648946524,
"rps_doc_frac_chars_top_2gram": 0.010252679698169231,
"rps_doc_frac_chars_top_3gram": 0.011641750112175941,
"rps_doc_frac_chars_top_4gram": 0.015974339097738266,
"rps_doc_books_importance": -3130.02587890625,
"rps_doc_books_importance_length_correction": -3130.02587890625,
"rps_doc_openwebtext_importance": -2082.692138671875,
"rps_doc_openwebtext_importance_length_correction": -2082.692138671875,
"rps_doc_wikipedia_importance": -1793.79541015625,
"rps_doc_wikipedia_importance_length_correction": -1793.79541015625
},
"fasttext": {
"dclm": 0.024763459339737892,
"english": 0.9373229742050171,
"fineweb_edu_approx": 1.2438956499099731,
"eai_general_math": 0.07046949863433838,
"eai_open_web_math": 0.2225920557975769,
"eai_web_code": 0.0014258000301197171
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.89",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "21",
"label": "Customer Support"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-7,060,411,370,973,041,000 | Leveraging a clinical phase Ib proof-of-concept study for the GPR40 agonist MK-8666 in patients with type 2 diabetes for model-informed phase II dose selection.
Article Authors: A.W. Krug, P. Vaddady, R.A. Railkar, B.J. Musser, J. Cote, Agh. Ederveen, D.G. Krefetz, E. DeNoia, A.L. Free, L. Morrow, M.V. Chakravarthy, E. Kauh, D.A. Tatosian, P.A. Kothare
no alt text set
Abstract
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.
no | {
"url": "https://prosciento.com/leveraging-a-clinical-phase-ib-proof-of-concept-study-for-the-gpr40-agonist-mk-8666-in-patients-with-type-2-diabetes-for-model-informed-phase-ii-dose-selection/",
"source_domain": "prosciento.com",
"snapshot_id": "crawl=CC-MAIN-2022-40",
"warc_metadata": {
"Content-Length": "70695",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:AA3PQGRUBDXLRJ5UZ3WCAWTZMQQEGU2A",
"WARC-Concurrent-To": "<urn:uuid:eae32750-3125-4aaa-82b1-42a3a8e2a111>",
"WARC-Date": "2022-10-04T20:39:28",
"WARC-IP-Address": "104.197.115.231",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:4E56OJNOASTNEPAETRAX5AV5CPIIMRDA",
"WARC-Record-ID": "<urn:uuid:4f8ca4cf-6b67-4a3f-b495-60bab7a3e723>",
"WARC-Target-URI": "https://prosciento.com/leveraging-a-clinical-phase-ib-proof-of-concept-study-for-the-gpr40-agonist-mk-8666-in-patients-with-type-2-diabetes-for-model-informed-phase-ii-dose-selection/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:42cb392e-8ed7-4ae3-a9f2-fb7999d86a80>"
},
"warc_info": "isPartOf: CC-MAIN-2022-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September/October 2022\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-62\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
161,
162,
356,
357,
373,
374,
383,
384,
1447,
1448
],
"line_end_idx": [
161,
162,
356,
357,
373,
374,
383,
384,
1447,
1448,
1450
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1450,
"ccnet_original_nlines": 10,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.1309192180633545,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.08356545865535736,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.3955431878566742,
"rps_doc_frac_unique_words": 0.7156398296356201,
"rps_doc_mean_word_length": 5.312796115875244,
"rps_doc_num_sentences": 38,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.872058868408203,
"rps_doc_word_count": 211,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.008028550073504448,
"rps_doc_frac_chars_top_3gram": 0.02319357916712761,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -153.3482208251953,
"rps_doc_books_importance_length_correction": -149.2080841064453,
"rps_doc_openwebtext_importance": -111.28843688964844,
"rps_doc_openwebtext_importance_length_correction": -111.28843688964844,
"rps_doc_wikipedia_importance": -72.26192474365234,
"rps_doc_wikipedia_importance_length_correction": -63.7749137878418
},
"fasttext": {
"dclm": 0.023923279717564583,
"english": 0.8052175641059875,
"fineweb_edu_approx": 1.8188821077346802,
"eai_general_math": 0.33305954933166504,
"eai_open_web_math": 0.4540199637413025,
"eai_web_code": 0.0011295099975541234
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.857072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-1,065,418,606,857,604,200 | Healthy Life Talk Radion Reciva
Healthy LifeA great fitness tip is to not spend an excessive amount of time in the health club, coaching forearms and calves. Your forearms get worked in a variety of workouts you do together with bicep curls and rows. Calves get labored every time you stroll. An excessive amount of deal with one muscle group can actually work in opposition to you.
Strive joining a sports activities workforce to help you meet your fitness and weight reduction objectives. In case you have a whole crew of people relying on you to be at observe and video games each day, you are not as likely to rooster out and skip work outs. Not only can it maintain you on monitor, you possibly can have fun too.
You should avoid sit-ups and crunches in positions which anchor your ft. There’s a huge array of variations on these fundamental ab exercises, and not all of them are created equal. Whenever you anchor your toes to train your abs you are putting undue stress in your lower again. This reduces the effectiveness of the exercise and places you at risk of injury.
When training with weights, it is vitally necessary to keep your exercises below one hour in size. After lifting weights for 60 minutes, your physique starts producing an excess amount of the stress hormone cortisol. Cortisol has a testosterone-blocking effect and can trigger you to lose muscle. If you wish to enhance muscle dimension and power, keep your workouts brief and intense.
Train at the very least once a day. Exercising decreases physique fat and tones and strengthens muscle tissues, subsequently inflicting weight loss. Begin off by doing strenuous train for about five minutes, then each day after, add somewhat extra time, working your method up to half-hour. Once you are able to exercise for half-hour, strive exercising for a longer period of time or more strenuously. | {
"url": "http://www.healthypennsylvania.tk/healthy-life-talk-radion-reciva-2.html",
"source_domain": "www.healthypennsylvania.tk",
"snapshot_id": "crawl=CC-MAIN-2018-39",
"warc_metadata": {
"Content-Length": "29363",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:XYWGH52TWVGQ2L6T27Y6Z2BEUCPNPZH7",
"WARC-Concurrent-To": "<urn:uuid:101fca2a-bfc3-4c86-9947-1fa1a05afd4f>",
"WARC-Date": "2018-09-22T00:57:09",
"WARC-IP-Address": "104.31.95.211",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:LZ7A3M763N2FNNPFCIHTMPLH4YVOV74M",
"WARC-Record-ID": "<urn:uuid:1317c1ab-504b-4a2e-bb48-087a0b47755f>",
"WARC-Target-URI": "http://www.healthypennsylvania.tk/healthy-life-talk-radion-reciva-2.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:242786a8-e51a-4cc7-840f-920893c49615>"
},
"warc_info": "isPartOf: CC-MAIN-2018-39\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September 2018\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-37-160-190.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 0.11-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
32,
33,
384,
385,
720,
721,
1082,
1083,
1469,
1470
],
"line_end_idx": [
32,
33,
384,
385,
720,
721,
1082,
1083,
1469,
1470,
1872
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1872,
"ccnet_original_nlines": 10,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4293628931045532,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.10249307006597519,
"rps_doc_frac_unique_words": 0.590624988079071,
"rps_doc_mean_word_length": 4.728125095367432,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.891500949859619,
"rps_doc_word_count": 320,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.015862520784139633,
"rps_doc_frac_chars_top_3gram": 0.02247191034257412,
"rps_doc_frac_chars_top_4gram": 0.025115659460425377,
"rps_doc_books_importance": -139.0699005126953,
"rps_doc_books_importance_length_correction": -139.0552215576172,
"rps_doc_openwebtext_importance": -98.17332458496094,
"rps_doc_openwebtext_importance_length_correction": -98.17332458496094,
"rps_doc_wikipedia_importance": -69.97545623779297,
"rps_doc_wikipedia_importance_length_correction": -69.97544860839844
},
"fasttext": {
"dclm": 0.03920489922165871,
"english": 0.9528813362121582,
"fineweb_edu_approx": 1.8359299898147583,
"eai_general_math": 0.03918075934052467,
"eai_open_web_math": 0.14645320177078247,
"eai_web_code": 0.0013551099691540003
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.71",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "613.712",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "23",
"label": "Tutorial"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-3,403,949,270,180,678,000 | Pharmaceutics Pharmaceutics 1999-4923 MDPI 10.3390/pharmaceutics3030406 pharmaceutics-03-00406 Article Self-Assembled Lipoplexes of Short Interfering RNA (siRNA) Using Spermine-Based Fatty Acid Amide Guanidines: Effect on Gene Silencing Efficiency MetwallyAbdelkader A. BlagbroughIan S.* Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK Author to whom correspondence should be addressed; E-Mail: prsisb@bath.ac.uk; Tel.: +44-1225-386795; Fax: +44-1225-386114. 09 2011 13 07 2011 3 3 406 424 13 05 2011 20 06 2011 05 07 2011 © 2011 by the authors; licensee MDPI, Basel, Switzerland. 2011
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Four guanidine derivatives of N4, N9-diacylated spermine have been designed, synthesized, and characterized. These guanidine-containing cationic lipids bound siRNA and formed nanoparticles. Two cationic lipids with C18 unsaturated chains, N1,N12-diamidino-N4, N9-dioleoylspermine and N1,N12-diamidino-N4-linoleoyl-N9-oleoylspermine, were more efficient in terms of GFP expression reduction compared to the other cationic lipids with shorter C12 (12:0) and very long C22 (22:1) chains. N1,N12-Diamidino-N4-linoleoyl-N9-oleoylspermine siRNA lipoplexes resulted in GFP reduction (26%) in the presence of serum, and cell viability (64%). These data are comparable to those obtained with TransIT TKO. Thus, cationic lipid guanidines based on N4, N9-diacylated spermines are good candidates for non-viral delivery of siRNA to HeLa cells using self-assembled lipoplexes.
fatty acids gene silencing GFP guanidine lipoplexes nanoparticles self-assembly siRNA spermine
Introduction
Short interfering RNA (siRNA) is a synthetic double-stranded (ds) RNA of 21-25 nucleotides per strand. Post-transcriptional gene silencing by siRNA is an important biological tool in functional genomic studies. Sequence specific gene silencing by siRNA has many potential therapeutic applications [1]. In 1998, Fire, Mello and co-workers reported that genes can be silenced at the post-transcriptional level by short ds RNA segments [2], a discovery that was awarded the 2006 Nobel Prize in medicine or physiology. Elbashir et al. proved in 2001 that gene silencing using siRNA is found in mammalian systems [3]. The optimum length of siRNA to affect post-transcriptional gene silencing in mammalian cells is typically less than 30 bp, as it avoids inducing non-specific mRNA degradation due to immune response (interferon) while maintaining sequence specific mRNA degradation [3]. The effector complex for mRNA degradation, the RNA induced silencing complex (RISC), is a complex of proteins and the siRNA with the complementary sequence to the target mRNA. The key protein in the degradation process is the Ago2 protein, one of the argonaute family of proteins, which contains a domain with RNase H (endonuclease) type activity. RISC assembly and function occur in the cytoplasm of the cell [4,5].
In order to achieve gene silencing mediated by siRNA, the siRNA should be delivered intact to the cytoplasm of the cell. Due to the negative charge of the siRNA phosphate backbone, and its susceptibility to degradation by various nucleases, a vector is needed to achieve efficient intracellular delivery of siRNA. Cationic lipids are currently under investigation for the non-viral delivery of lipoplexes of DNA and siRNA [6-8]. The polar (cationic) head-group can be an amine (primary, secondary, tertiary, and even quaternary e.g., imidazolium [9]) or guanidine functional group. Guanidines, the most basic functional group in biological chemistry, are positively charged at physiological pH 7.4 as they have pKa = 12.5 [10]. Guanidines have the extra advantage, being bidentate, of being able to form two hydrogen bonds with negatively charged groups e.g., carboxylates, phosphates or sulfates present on the carbohydrates associated with the cell membrane, and this advantage has been used in vectors e.g., R8, Arg8 [11,12] to transport cargoes across cell membranes. These characteristics led to the design of many non-viral vectors for DNA and siRNA, varying from cationic lipids incorporating guanidine head-groups [13-15] e.g., AtuFECT [15], to cationic polymers [16,17] and dendrimers [18,19], to carbohydrate derivatives [19,20], and hydrogels of guanidinylated hyaluronic acid [21]. The use of guanidinium-containing lipid based carriers for gene delivery dates back to 1996 where Lehn et al. synthesized two guanidinium cholesterol lipids: bis-guanidiniumspermidine-cholesterol (BGSC) and bis-guanidinium-trencholesterol (BGTC), each containing two guanidine groups, which were synthesized and evaluated for their DNA transfection efficiencies in eukaryotic cells (Figure 1) [22] where they were found to be efficient DNA transfecting agents. Furthermore, BGTC was found to mediate transfection in an aqueous solution without the need to prepare it first in a liposomal form.
In this work, spermine, a naturally occurring polyamine, was acylated with different fatty acids on its secondary amine groups and then guanidinylated at the terminal primary amine groups. The guanidinylated non-viral vectors were characterized and evaluated for their ability to deliver siRNA that targets green fluorescent protein (GFP) in HeLa cells that stably express GFP.
Experimental Section Materials and general methods
Dicyclohexylcarbodiimide (DCC), 1,3-di-Boc-2-(trifluoromethylsulfonyl)guanidine, 4-dimethylamino-pyridine (DMAP), fatty acids, G418, hydrazine monohydrate, N-carbethoxyphthalimide, spermine, triethylamine (TEA), and trifluoroacetic acid (TFA) were purchased from Sigma-Aldrich (Gillingham, UK). All solvents were purchased from Fisher Scientific UK (Loughborough, UK). Cell culture media were purchased from Gibco (Invitrogen Ltd, Paisley, UK). HeLa cells stably expressing GFP were obtained from the Cell Service at Cancer Research UK (CRUK, London Research Institute, Clare Hall Laboratories, South Mimms, London, UK). NMR spectra were recorded in deuterio-chloroform using a Bruker Avance III spectrometer operating at 400.13 MHz spectrometer for 1H. The high resolution (HR) time-of-flight mass spectra were obtained on a Bruker Daltonics micrOTOF mass spectrometer using electrospray ionisation (ESI). AllStars siRNA negative controls with/without an Alexa Fluor® 647 tag at the 3′-position were purchased from Qiagen (Crawley, UK) as was siRNA against GFP labelled with Alexa Fluor® 647 at the 3′-position of the sense strand, sequences: Sense strand : 5 ' GCAAGCUGACCCUGAAGUUCAUTT 3 ' , Anti-sense strand : 5 ' AUGAACUUCAGGGUCAGCUUGCCG 3 ' , Target DNA sequence : 5 ' CGGCAAGCTGACCCTGAAGTTCAT 3 ' .
Synthesis of N<sup>1</sup>,N<sup>12</sup>-diamidino-N<sup>4</sup>,N<sup>9</sup>-diacylated spermines
N-Carbethoxyphthalimide (0.44 g, 2 mmol) was added to a solution of 1,12-diamino-4,9-diazododecane (spermine) (0.20 g, 1 mmol) in DCM (10 mL). The solution was stirred 20 °C for 3 h then evaporated to dryness in vacuo and the residue was used directly in the following step. To a solution of 1,12-diphthalimido-4,9-diazadodecane in DCM (10 mL) and TEA (0.28 mL, 2 mmol) fatty acid chloride (2 mmol), or alternatively fatty acid (2 mmol), DMAP (0.24 g, 2 mmol), and DCC (0.4 g, 2 mmol) were added and stirred for 18 h under nitrogen atmosphere. To prepare, 1,12-diphthalimido-N4-linoleoyl-N9-oleoylspermine, first, 1,12-diphthalimido-N4-oleoylspermine was prepared by reacting 1,12-diphthalimido-4,9-diazadodecane (1 mmol) with 1 (mmol) oleic acid using DCC as previously described [23]. After purifying the product over silica gel (DCM/MeOH 20:1 v/v then 10:1 v/v), it was further conjugated to linoleic acid (1 mmol) using DCC as the coupling agent. The solvent was then evaporated (for all of the prepared compounds) to dryness in vacuo and the residue was treated with hydrazine monohydrate (2 mL) in a mixture of DCM (15 mL) and THF (15 mL) and heated under reflux for 4 h. The solvent was then evaporated in vacuo to dryness and the residue purified over silica gel (DCM/MeOH 10:1 v/v then DCM/MeOH/NH4OH 20:10:1 v/v/v) to afford the N4,N9 fatty acid amides of spermine. HRMS of N4,N9-dierucoylspermine, N4,N9-dilauroylspermine, and N4,N9-dioleoylspermine were found as previously described [23]. N4-Linoleoyl-N9-oleoyl-1,12-diamino-4,9-diazadodecane HRMS m/z found (M+H)+ 729.6980, C46H89N4O2 requires (M+H)+ 729.6986.
The N1,N12-diamidino-N4,N9-diacylated spermines were prepared by reacting each of the prepared N4,N9-diacylated spermine (1 mmol) with 1,3-di-Boc-2-(trifluoromethylsulfonyl)guanidine (2 mmol) and TEA (2 mmol) in DCM (10 mL) at 20 °C for 24 h. The reaction mixture was then evaporated to dryness in vacuo and the residue was purified over silica gel (DCM/MeOH 100:1 v/v then 100:2 v/v) and the required fractions were concentrated. The residue was then added to DCM (6 mL), TFA (2 mL) was added, and the mixture stirred at 20 °C for 4 h. The reaction mixture was then evaporated to dryness in vacuo to afford the title compounds. N1,N12-Diamidino-N4, N9-dierucoylspermine 1, HRMS m/z, ESI found (M+H)+ 927.8795, C56H111N8O2 requires (M+H)+ 927.8825. N1,N12-Diamidino-N4, N9-dilauroylspermine 2, HRMS m/z, ESI found (M+H)+ 651.5996, C36H75N8O2 requires (M+H)+ 651.6008. N1,N12-Diamidino-N4, N9-dioleoylspermine 3, HRMS m/z, ESI found (M+H)+ 815.7549, C48H95N8O2 requires (M+H)+ 815.7573. N1,N12-Diamidino-N4-linoleoyl-N9-oleoylspermine 4, HRMS m/z, ESI found (M+H)+ 813.7384, C48H93N8O2 requires (M+H)+ 813.7416.
Transfection studies of HeLa cells stably expressing GFP
Cells were trypsinized at confluency 80–90%, seeded at a density of 65,000 cells/well in 24-well plates and incubated for 24 h at 37 °C, 5% CO2, prior to transfection. The lipoplexes were prepared by mixing the specified amounts of the transfection reagent in OptiMEM serum-free medium (50 μL) with 15 μL of siRNA (1 μM) in OptiMEM serum-free medium. The solutions were mixed for 2–3 s with a vortex mixer. On the day of transfection, the lipoplex solutions were added to wells containing DMEM (10% FCS) to make the final volume in each well 1 mL (i.e., 6,500 cells/100 μL). The plates were then incubated for 48 h at 37 °C, 5% CO2. siRNA against GFP used in these experiments has 24 base-pairs, thus, each molecule of siRNA contains 48 negative charges corresponding to 48 negatively charged phosphate groups in the siRNA backbone. The synthesized spermine fatty acid amides each contain two terminal primary amine groups which will be positively charged at physiological pH 7.4, therefore, each vector molecule carries two positive charges. N/P ratio is calculated using the following equation: N / P = number of moles of cationic lipid × 2 number of moles of siRNA × 48
Flow cytometry (FACS)
For analysis of delivery and then reduction of expression of GFP by flow cytometry, cells were trypsinized and resuspended in complete medium without phenol red. Cells were centrifuged (1000 rpm for 5 min), and washed twice by resuspending in PBS containing 0.1% BSA (1 mg/mL bovine serum albumin) and centrifugation (1000 rpm for 5 min). The collected cells was then resuspended in PBS and transferred to a flow cytometer tube (Becton Dickinson, UK). Cells (typically 10,000–20,000 events) were then analyzed using a FACSCanto flow cytometer (Becton Dickinson, UK), equipped with an argon ion laser at 488 nm for excitation, a Long Pass (LP) filter at 502 nm and a detector at 530 nm (range +/−15 nm) for fluorescence emission, helium/neon laser at 633 nm, and detector for the Alexa Fluor 647 at 660 nm (range +/− 10 nm). GFP expression is calculated as: % GFP = GFP fluorescence of transfected cells GFP fluorescence of control cells × 100
Confocal microscopy cell imaging
Cells were trypsinized at confluency 80–90% and were seeded at a density of 65,000 cells/well in 24-well plates that have a round-glass cover slip (12 mm in diameter) and were incubated for 24 h prior to transfection which was carried out as described above (section 2.3). After 48 h, the cell culture media in each well were aspirated and the cells washed with PBS (3 × 0.5 mL). The cell membrane was then stained with wheat germ agglutinin (WGA) conjugated to Alexa Fluor® 555. The concentration of WGA-Alexa Fluor® 555 working solution was adjusted to a concentration of 5 μg/mL in Hank's balanced salt solution without phenol red. The cells were incubated for 10 min in the dye working solution at 37 °C, 5% CO2 in the dark. The cells were washed with PBS (3 × 0.5 mL) and then fixed with 4% paraformaldehyde in PBS solution for 20 min at 20 °C in the dark. The cover slips were then removed from each well, washed with PBS (2 × 0.5 mL), left to dry briefly in air, and then mounted on glass slides using Mowiol (polyvinyl alcohol) solution as the mounting media and left in the dark at 20 °C (18 h) to allow hardening of the mounting media. The cells were examined using a Carl Zeiss laser scanning microscope LSM 510 meta, with GFP excitation 488 nm, emission 505-550 nm (band pass filter), Alexa Fluor® 555 excitation 543 nm, emission 560-615 nm (band pass filter), and Alexa Fluor® 647 excitation 633 nm, emission 657–753 nm (meta detector).
Cell viability assay
Cells were seeded at a density of 6,500 cells per well of 96-well plates. The transfection was carried out using the same protocol as transfecting the 24-well plates with the exception of reducing the amount of lipoplexes such that each well contains 1.5 pmol siRNA in a final volume of 100 μL/well. After 44 h, alamarBlue® [24] (10 μL) was added to each well. After incubation (3.5 h), the absorbance of each well was measured at 570 nm and 600 nm and calculations were carried out according to the standard protocol provided by the supplier.
Particle size and zeta potential measurements
Lipoplexes were prepared by adding siRNA solution (75 μL, 1 μM) in HEPES (pH 7.4, 10 mM) to HEPES (250 μL) containing the specified amount of transfection reagent followed by vortex mixing for 4 s. Samples were then diluted to a final volume of 3 mL by HEPES buffer. Samples were mixed for 10 s directly before measurements. Measurements were carried out using Malvern Zetasizer Nano S90 using refractive index 1.59, viscosity 0.89 cP, dielectric constant 79, and temperature set to 25 °C with equilibrium time 3 min. Z-Average diameter in nm and zeta potential in mV were recorded as averages of three and six measurements respectively.
siRNA binding (RiboGreen intercalation assay)
RiboGreen (Invitrogen) working solution was prepared by diluting RiboGreen stock solution 1 to 400 in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5 diluted 1 to 20 in RNase free water). RiboGreen working solution (40 μL) was added to each well of a 96-well plate (black bottom) containing free siRNA (1 pmol) or complexed with lipospermines in TE buffer at the lipid/siRNA ratios that showed the best reduction in GFP expression. Each well contained a final volume of 120 μL. The fluorescence was measured using FLUOstar Optima Microplate Reader (BMG-LABTECH), λex = 480 nm and λem = 520 nm. The amount of siRNA available to interact with the lipid vector was calculated by subtracting the values of RiboGreen background fluorescence (RiboGreen without siRNA) from those obtained for each measurement, and expressed as a percentage of the control that contained naked siRNA only according to the following equation: % free siRNA = 100 × RiboGreen fluorescence of complexes / RiboGreen fluorescence of naked siRNA
Results and Discussion Synthesis of N<sup>1</sup>,N<sup>12</sup>-diamidine derivatives of spermine
We have designed a series of novel lipoguanidines based upon our recently published lipopolyamines [23] in order to investigate the SAR of replacing primary amines with guanidine functional groups. These are formally called di-imidamides of alkanes and the nomenclature also permits N-aminoiminomethyl. Where we have referred to them as guanidines, they are more correctly N-amidines of spermine.
Our four lipoguanidines will be investigated in terms of their efficiency and their effect on cell viability as non-viral vectors for siRNA delivery. An amidine group was attached to each of the two terminal primary amines of spermine to result in the di-guanidines (N1,N12-diamidino-amines). Three fatty acids of different chain length and saturation were used to synthesise the lipoguanidines 1, 2, and 3 by acylation at N4 and N9 of spermine. The fourth lipoguanidine 4 was synthesized by acylating sequentially using two different long-chain fatty acids (linoleic and oleic) to N4 and N9.
The synthesis of the guanidinylated N4,N9-diacylated spermine conjugates started with the synthesis of the N4,N9-difatty acids spermine derivatives (Figure 2). The symmetrical lipospermines; i.e., those with the same fatty acid chains conjugated to positions N4 and N9 of the spermine chain was carried out as described previously [23]. For the synthesis of the unsymmetrical N4-linoleoyl-N9-oleoylspermine, the primary amine groups of spermine were selectively protected with the phthalimide protecting group (2 eq. of N-carbethoxyphthalimide in CH2Cl2). Then one oleoyl chain was conjugated to one of the free secondary amine groups of spermine (1 eq. oleic acid, 1 eq. DCC, and 1 eq. DMAP). Purification of the mono-acylated spermine was followed by flash chromatography. The second linoleoyl chain was added using DCC coupling of linoleic acid to the 1,12-diphthalimido-N9-oleoyl-4,9-diazadodecane (1 eq. linoleic acid, 1 eq. DCC, and 1 eq. DMAP). Deprotection of the phthalimide protecting groups then followed by refluxing in hydrazine monohydrate in DCM/THF 1:1 mixture to obtain N4-linoleoyl-N9-oleoylspermine, which was purified by flash chromatography [23]. The guanidinylation of amines typically involves an electrophilic amidine group as part of the guanidinylating reagent [25]. 1,3-Di-Boc-2-(trifluoromethylsulfonyl)guanidine was used as it can carry out the guanidinylation of primary and secondary amines under mild conditions [25,26]. The guanidinylation was carried out on the di-acylated spermine derivatives and deprotection of the Boc protected guanidine group was carried out using TFA to obtain the trifluoroacetate salts of the synthesized compounds (Figure 3).
Lipoplex particle size and ζ-potential
The lipoplexes prepared at the cationic lipid/siRNA ratios for each guanidinylated lipid which resulted in the best reduction in GFP expression were chosen to be characterized for their particle size and ζ-potential (Table 1). Particle size measurement using dynamic light scattering showed that the particle size varied from 132–575 nm. The two cationic lipids 3 and 4 which are acylated with unsaturated C18 fatty acids (dioleoyl and linoleoyl/oleoyl respectively) and which showed the best reduction in GFP expression, had particle sizes of 303 and 158 nm respectively. The particle size of the C22 (dierucoyl) conjugate 1 was the smallest (132 nm) while the short chain C12 (dilauroyl) conjugate 2 had the largest particle size of 575 nm. Lipoplex size has been identified as an important factor in transfection efficiency, although not the only determinant factor [27]. Lipoplexes within size range 200–300 nm have been previously reported [28]. Although the size of the lipoplexes will determine the main route of entry with smaller lipoplexes (<300 nm) likely to enter via clathrin mediated endocytosis, and larger particles (>500 nm) entering cells via caveoli mediated endocytosis [28,29], one recent report shows that the actual entry route for functional siRNA mediated gene silencing might possibly be fusion with the plasma membrane rather than the endocytosis pathway [30]. The ζ-potentials measurements showed that all the lipoplexes had positive values within the range 28-50 mV. Cationic lipids 3 and 4 had the similar ζ-potential of 45 mV. Positive ζ-potential is important in promoting stability of the prepared lipoplexes by enhancing repulsion between the nanoparticles. Although having positive ζ-potential will promote interaction between the positively charged lipoplexes and the negatively charged groups present on the cell membrane surface, it was reported that in the presence of serum, the lipoplexes actually acquire a negative ζ-potential [28] while still maintaining efficient transfection efficiency.
siRNA binding (RiboGreen intercalation assay)
An siRNA binding assay was used to evaluate the ability of the synthesized guanidinylated lipids 1, 2, 3, and 4 to complex and bind siRNA. The assay depends on the increased fluorescence (approx. 1000-fold) of bound RiboGreen dye compared to the free (unbound) dye which is practically non-fluorescent [31]. The loss of fluorescence compared to control siRNA indicates the binding of siRNA to cationic lipids and hence prevention of RiboGreen binding with siRNA which leads to reduction of fluorescence compared to the control (free) siRNA [32,33]. The four cationic lipids 1-4 efficiently bound siRNA and the normalised fluorescence, relative to free siRNA (100%), was reduced to: 5 ± 2 (1), 12 ± 3 (2), 0 ± 1 (3), and 8 ± 2 (4). These results prove that the guanidinylated lipids are able to efficiently bind siRNA.
Transfection with siRNA and evaluating delivery and knock-down
HeLa cells that was previously transfected to stably express GFP was used to evaluate the siRNA delivery and sequence specific knock-down of GFP expression. The siRNA against GFP used was labelled with Alexa Fluor 647 (AF647) in the 3′-position of the anti-sense strand to enable simultaneous tracking of the siRNA delivery and reduction of GFP expression by measuring the fluorescence of the AF647 and the GFP during the FACS analysis. A healthy population of sample cells were gated before recording the fluorescence during FACS.
The normalized fluorescence of AF647 measured 48 h post transfection was measured as an estimate for the delivered amount of siRNA. Figure 4 shows that, for each cationic lipid, there is a general trend of increasing fluorescence by increasing the amount of the lipid. Cationic lipid 2 data are not shown due to the very low siRNA delivery. With respect to 1, 3, and 4, there was a significant statistical difference between the geometric mean AF647 fluorescence measured at 3 and 6 μg/well (N/P = 10 and 20 respectively) with p < 0.05. There was also a significant statistical difference between the amounts of siRNA delivered (geometric mean fluorescence of AF647) by 3 and 4 (p < 0.05) with lipoplexes formulated at 6 μg/well (N/P = 20). There was no significant statistical difference between 1 and 4 at 6 μg/well (p = 0.33). These results show that, given that 1, 3, and 4 have two guanidine head-groups in the form of trifluoroacetate salts in common, the C18 (18:1 and 18:2) unsaturated fatty acids conjugated at positions N4 and N9 of the parent spermine provided the optimum chain length for siRNA delivery compared to the C12 (12:0) and C22 (22:1) chains.
Figure 5 shows that the best reduction of GFP expression was achieved by 4 followed by 3. At 6 μg/well, GFP expression was reduced to 26% and 43% for 4 and 3 respectively (p < 0.05). Lipid 1 did not show any practically significant reduction in GFP (reduced to 85%) at 6 μg/well (N/P = 18). Lipid 2 resulted in GFP reduction to 46% at 6 μg/well (N/P = 26), however, this reduction cannot be evaluated without considering the high toxicity of 2 which will affect the expression of GFP, as will be discussed later. Lipids 3 and 4 with C18 (18:1 and 18:2) resulted in the best knock-down of GFP expression, which might be attributed to the fusogenic ability of unsaturated fatty acids (in cis-configuration) which favours (Lα to HII) transition as they can promote both membrane fusion and endosomal escape [23,34,35]. The chain length is an important factor that affects the efficiency of GFP knock-down because although the C22 (22:1) has one centre of unsaturation, lipid 1 resulted in less reduction in GFP (85%) compared to 3 (43%) and 4 (26%) with significant statistical difference between the compared means (p < 0.05) at 6 μg/well. The chain length affect siRNA delivery and siRNA mediated knock-down in a different manner, as evident from comparing the delivery of 1, 3, and 4 and their GFP reduction at a concentration of 6 μg/well. Although 1 and 4 resulted in similar siRNA delivery efficiencies, lipid 4 was much better than 1 in terms of GFP reduction (to 26% and 85% respectively). These differences in gene silencing efficiency compared with cellular uptake of the lipoplexes may reflect the multi-step processes of gene silencing and/or more than one mechanism of cell entry [30].
Also, lipid 3 resulted in better GFP reduction when compared to 1 (to 43% and 85% respectively) despite the fact that 1 resulted in higher siRNA delivery compared to 3 (p < 0.05). The importance of chain length and chain unsaturation of cationic lipids has been previously reported to be among the most significant factors that affect transfection efficiency because of the effect on the hydrophobic volume of lipid and its hydrophilic/lipophilic ratio which will in turn affect the properties of the formed lipoplexes [36].
When compared to the commercial transfecting agent TransIT TKO, the reduction in GFP expression obtained with lipoplexes of 4 (26%) was the same as that obtained with TransIT TKO (24%), i.e., there was no significant statistical difference (p = 0.30).
The increases in fluorescence shown in Figure 4 reflect increases in siRNA delivery with increasing concentrations of cationic lipids in the lipoplexes up to an N/P ratio of 20 (6 μg/well). Figure 5 shows the corresponding reduction in GFP expression. These data were obtained from gated FACS analyses of the healthy populations of HeLa cells (parent gate), representative examples of which are shown in Figure 6 together with the percentage of cells transfected. In order to evaluate siRNA delivery, the AF647 gate was set-up to include cells that have fluorescence signals higher than the auto-fluorescence of control cells detected at λ = 660 nm. The GFP gate was set to calculate the geometric mean fluorescence of GFP.
The effects of transfecting HeLa cells using 3 and 4 with scrambled siRNA on lipoplex delivery and GFP expression are shown in Figure 7. Qiagen report that their scrambled siRNA lacks any homology to mammalian genes. Figure 7 shows that the GFP expression was practically not affected by the transfection process while the scrambled siRNA was delivered in comparable amounts (i.e., comparable normalized fluorescence) to delivery of the siRNA against GFP. Thus, cationic lipids 3 and 4 deliver two different siRNAs with similar efficiency. These results prove that GFP reduction after transfection with siRNA against GFP (shown as averaged data in Figure 5 and as representative examples in Figure 6) is due to sequence specific gene silencing and not due to any toxic effects of the cationic lipid vectors.
Confocal microscopy cell imaging
Figure 8 shows confocal microscope images of HeLa cells after transfection with 3 and 4 using siRNA against GFP or scrambled siRNA at 6 μg/well of cationic lipid which is the amount of lipid that resulted in the best reduction of GFP expression with respect to each of the cationic lipids.
Figure 8a shows control HeLa cells. Figure 8b shows the reduction of GFP expression after transfection with siRNA against GFP using 3 at 6 μg/well. Figure 8c is the same as 8b, but only the red channel is turned on to track better the delivery of the AF647 labelled siRNA against GFP. It can be seen that the AF647 fluorescence (red) is distributed throughout the cell and concentrated in some cell areas. Figure 8d shows that lipoplexes of 3 did not cause reduction in GFP expression when using scrambled siRNA which was delivered to HeLa cells successfully as shown in Figure 8g. These results prove that the siRNA was delivered successfully to the HeLa cells and that the reduction in GFP expression is due to sequence specific knock-down of GFP and not due to any toxic effects of the cationic lipid vectors. The same conclusion can be obtained when examining the transfection of HeLa cells with 4 as shown in Figure 8e with 8h, and 8f with 8i.
Cell viability assay
Following transfection with cells seeded at a density of 65,000 cells/well in 24-well plates, i.e. 65,000 cells/1 mL, cell viability was assayed in 96-well plates with 6,500 cells/0.1 mL [23,37]. The ratio of cells to the amount of cationic lipids used, the concentration of cationic lipids (0.6 μg/0.1 mL) and of siRNA (15 nM) were exactly as used in the transfection experiments [23,38]. Figure 9 shows that 1, 3, and 4 resulted in more than 64% cell viability. There were no statistical significant difference between the cell viability of 3 and 4 (p = 0.32) with cell viabilities of 70% and 64% respectively. The best cell viability, obtained by 1 (83%), was significantly different (p < 0.05) from the cell viability of 3 and 4. Whilst diacylated C12 (12:0) 2 is a new compound, the very high toxicity of its parent diamine, N4, N9-dilauroylspermine, has been previously reported in both HtTA cells [39] and HeLa cells [23] with scrambled siRNA. There were no significant differences between cell viability of TransIT TKO (76%) and 3 (64%), p = 0.12, or between TransIT TKO and 4 (70%), p = 0.41. There is a probability that the counter ion, trifluoroacetate in this case, has a contributing negative effect on cell viability as been reported before [40] where the presence of residual TFA in the concentration range 10−8 to 10−7 M resulted in reduction of cell proliferation of osteoblasts, chondrocytes, and neonatal mice calvariae.
Conclusions
The four synthesized diguanidinylated diacylated spermine-based cationic lipids were able to bind siRNA efficiently and to form particles with sizes in the nanometre range (132–575 nm). Saturated shorter chain (C12:0) 2 showed relatively high toxicity when compared with the longer chain (C18-C22) N1,N12-diamidino-N4,N9-diacylated spermine derivatives. Transfection with self-assembled siRNA lipoplexes of 3 and 4 resulted in the sequence specific knock-down of GFP in HeLa cells, exhibiting comparable (low) toxicity to the commercial transfecting agent TransIT TKO. Lipid 4 with one linoleoyl and one oleoyl chain, acylated on positions N4 and N9 respectively of the N1,N12-diamidinospermine, was the best transfecting agent. Lipoplexes of lipid 4 showed the same efficiency, in HeLa cells, in terms of reduction of GFP expression as TransIT TKO.
In this article, we have described the synthesis of four novel spermine-derived fatty acid amide guanidines applied to the self-assembly of siRNA lipoplexes which were then tested in GFP expressing HeLa cells. The major conclusions include detection of siRNA complexion in the lipoplexes, cellular uptake, toxicity, and gene silencing efficiency even in the presence of serum. This is a structure-activity relationship (SAR) study in siRNA delivery of which there are few reported; a recent contribution being the design, synthesis, and analysis of spermine-siRNA conjugates containing two oleylamine carbamate chains [41].
Figures and Table
Some guanidines used in delivery of genes and other cargoes.
Synthesis of N1,N12-diamidino-N4,N9-diacylated spermines. a: N-Carbethoxyphthalimide, DCM; b: fatty acid, DCC, TEA; c: hydrazine monohydrate, DCM/THF 1:1 mixture; d: 1,3-di-Boc-2-(trifluoromethylsulfonyl)guanidine, TEA, DCM; e: TFA, DCM.
N1,N12-Diamidine derivatives of different lipospermines.
Delivery of siRNA (15 nM, 15 pmol/well) against GFP (labelled with Alexa Fluor® 647 at the 3′-position of the sense strand) using 1, 3, and 4. Values are presented as means of normalized geometric mean fluorescence of AF647 ± SD (n = 6).
Reduction in GFP expression in HeLa cells after transfection with lipoplexes of 1, 2, 3, and 4 at different cationic lipid/siRNA ratios. siRNA concentration is kept constant (15 nM, 15 pmol/well). Values are presented as mean ± SD (n = 6). Commercial TransIT TKO (T) is shown for comparison.
Gated FACS analysis of delivery of siRNA (15 nM, 15 pmol/well) against GFP (labelled with Alexa Fluor® 647 at the 3′-position of the sense strand) and GFP expression in HeLa cells 48 h post transfection with lipoplexes of 3 and 4 (6 μg/well) at an siRNA concentration of 15 pmol/well. The AF647 gate (red) shows 75% of parent-gated cells with 3, and 92% of parent-gated cells with 4. The GFP gate (green) shows silencing to ∼40% and ∼25% respectively measured by geometric mean fluorescence relative to control (top line).
Scrambled AllStars siRNA (with an Alexa Fluor® 647 tag at the 3′-position) (15 nM, 15 pmol/well) was delivered with cationic lipids 3 and 4 (at 6 μg/well). Delivery of tagged siRNA (left) is expressed as AF647 normalized geometric mean fluorescence ± SD (n = 6) measured at λ = 660 nm. GFP percentage expression (right) (absence of silencing as a negative control) 48 h post transfection is measured at λ = 530 nm.
Confocal microscopy cell imaging. GFP fluorescence (green), cell membrane stained with WGA-Alexa Fluor® 555 (blue), and Alexa Fluor® 647 (red) represents tagged siRNA delivery. (a) non-transfected HeLa cells (control); (b) reduction in GFP expression after transfection with siRNA against GFP delivered with 3 (6 μg/well); (c) as b, but only the red channel; (d): as b, but using scrambled siRNA; (e) reduction in GFP expression after transfection with siRNA against GFP delivered with 4 (6 μg/well); (f) as e, but using scrambled siRNA; (g): as d, but only the red channel; (h) as e, but only the red channel; (i) as f, but only the red channel.
Comparison of cell viability of HeLa cells after transfection with lipoplexes at their optimal cationic lipid/siRNA ratios and compared with the commercially available transfection agent TransIT TKO (T). Values are presented as mean ± SD (n = 6). Experiments were carried out at: 0.6 μg/well synthesized cationic lipids, 1.5 pmol siRNA/well (15 nM), and 6,500 cells/well.
N1,N12-Diamidine derivatives of different lipospermines. The fatty acids are described by two numbers separated by a colon, first the chain length and then the number of double bonds. Particle size and ζ-potential of guanidinylated lipospermines were measured at the cationic lipid/short interfering RNA (siRNA) ratios that showed best reduction in GFP expression.
Name of compound Fatty acid Description of fatty acid Particle size (nm) ± SD Zeta-potential (mV) ± SD
N1,N12-Diamidino-N4,N9-dierucoylspermine 1 Erucic 22:1 132 ± 4 50 ± 1
N1,N12-Diamidino-N4,N9-dilauroylspermine 2 Lauric 12:0 575 ± 61 28 ± 3
N1,N12-Diamidino-N4,N9-dioleoylspermine 3 Oleic 18:1 303 ± 6 45 ± 3
N1,N12-Diamidino-N4-linoleoyl-N9-oleoylspermine 4 Linoleic and Oleic 18:2 and 18:1 158 ± 24 45 ± 3
We thank the Egyptian Government for a fully funded studentship (to AAM), S. Crocket (University of Bristol) for assistance with ζ-potential measurements, and C. Pourzand (University of Bath) and O. Reelfs (King's College London) for helpful discussions about stably expressing GFP cell lines.
References BlagbroughI.S.ZaraC.Animal models for target diseases in gene therapy - using DNA and siRNA delivery strategiesPharm. Res.20092611810.1007/s11095-008-9646-818841450 FireA.XuS.Q.MontgomeryM.K.KostasS.A.DriverS.E.MelloC.C.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegansNature199839180681110.1038/358889486653 ElbashirS.M.HarborthJ.LendeckelW.YalcinA.WeberK.TuschlT.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cellsNature200141149449810.1038/3507810711373684 LiuQ.H.ParooZ.Biochemical principles of small RNA pathwaysAnnu. Rev. Biochem.20107929531910.1146/annurev.biochem.052208.15173320205586 GaynorJ.W.CampbellB.J.CosstickR.RNA interference: a chemist's perspectiveChem. Soc. Rev.2010394169418410.1039/b920362c20717561 SchroederA.LevinsC.G.CortezC.LangerR.AndersonD.G.Lipid-based nanotherapeutics for siRNA deliveryJ. Intern. Med.201026792110.1111/j.1365-2796.2009.02189.x20059641 WuS.Y.McMillanN.A.J.Lipidic systems for in vivo siRNA deliveryAAPS J.20091163965210.1208/s12248-009-9140-119757082 TsengY.-C.MozumdarS.HuangL.Lipid-based systemic delivery of siRNAAdv. Drug. Deliv. Rev.20096172173110.1016/j.addr.2009.03.00319328215 MevelM.BreuzardG.YaouancJ.J.ClementJ.C.LehnP.PichonC.JaffresP.A.MidouxP.Synthesis and transfection activity of new cationic phosphoramidate lipids: High efficiency of an imidazolium derivativeChemBioChem200891462147110.1002/cbic.20070072718454443 BlagbroughI.S.MetwallyA.A.GeallA.J.Measurement of polyamine pKa valuesPolyamines Methods and ProtocolsPeggA.E.CaseroR.A.Jr.Humana PressNew York2011493503 RothbardJ.B.JessopT.C.LewisR.S.MurrayB.A.WenderP.A.Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cellsJ. Am. Chem. Soc.20041269506950710.1021/ja048253615291531 WenderP.A.GalliherW.C.GounE.A.JonesL.R.PillowT.H.The design of guanidinium-rich transporters and their internalization mechanismsAdv. Drug. Deliv. Rev.20086045247210.1016/j.addr.2007.10.01618164781 RadchatawedchakoonW.WatanapokasinR.KrajarngA.YingyongnarongkulB.E.Solid phase synthesis of novel asymmetric hydrophilic head cholesterol-based cationic lipids with potential DNA deliveryBioorg. Med. Chem.20101833034210.1016/j.bmc.2009.10.05719932970 ChenY.C.SenJ.BathulaS.R.YangQ.FittipaldiR.HuangL.Novel cationic lipid that delivers siRNA andenhances therapeutic effect in lung cancer cellsMol. Pharm.2009669670510.1021/mp800136v19267451 SantelA.AlekuM.KeilO.EndruschatJ.EscheV.FischG.DamesS.LofflerK.FechtnerM.ArnoldW.GieseK.KlippelA.KaufmannJ.A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endotheliumGene Therapy2006131222123410.1038/sj.gt.330277716625243 KimT.I.LeeM.KimS.W.A guanidinylated bioreducible polymer with high nuclear localization ability for gene delivery systemsBiomaterials2010311798180410.1016/j.biomaterials.2009.10.03419854504 BrombergL.RaduykS.HattonT.A.ConcheiroA.ConcheiroC.SilvaM.Alvarez-LorenzoC.Guanidinylated polyethyleneimine-polyoxypropylene-polyoxyethylene conjugates as gene transfection agentsBioconjug. Chem.2009201044105310.1021/bc900119t19402626 TheodossiouT.A.PantosA.TsogasI.PaleosCM.Guanidinylated dendritic molecular transporters: prospective drug delivery systems and application in cell transfectionChemMedChem200831635164310.1002/cmdc.20080019018985650 MenuelS.FontanayS.ClarotI.DuvalR.E.DiezL.MarsuraA.Synthesis and complexation ability of a novel bis-(guanidinium)-tetrakis-(β-cyclodextrin) dendrimeric tetrapod as a potential gene delivery (DNA and siRNA) system. Study of cellular siRNA transfectionBioconjug. Chem.2008192357236210.1021/bc800193p19053312 HigashiT.KhalilI.A.MaitiK.K.LeeW.S.AkitaH.HarashimaH.ChungS.K.Novel lipidated sorbitol-based molecular transporters for non-viral gene deliveryJ. Control. Release200913614014710.1016/j.jconrel.2009.01.02419331845 VargheseO.P.KisielM.Martinez-SanzE.OssipovD.A.HilbornJ.Synthesis of guanidinium-modified hyaluronic acid hydrogelMacromol. Rapid. Commun.2010311175118010.1002/marc.20090090621590872 VigneronJ.P.OudrhiriN.FauquetM.VergelyL.BradleyJ.C.BassevilleM.LehnP.LehnJ.M.Guanidinium-cholesterol cationic lipids: Efficient vectors for the transfection of eukaryotic cellsProc. Natl. Acad. Sci. USA1996939682968610.1073/pnas.93.18.96828790391 MetwallyA.A.PourzandC.BlagbroughEfficient gene silencing by self-assembled complexes of siRNA and symmetrical fatty acid amides of sperminePharmaceutics2011312514010.3390/pharmaceutics3020125 AsasutjaritR.LorenzenS.I.SirivichayakulS.RuxrungthamK.RuktanonchaiU.RitthidejG.C.Effect of solid lipid nanoparticles formulation compositions on their size, zeta potential and potential for in vitro type pHIS-HIV-Hugag transfectionPharm. Res.2007241098110710.1007/s11095-007-9234-317385021 FeichtingerK.ZapfC.SingsH.L.GoodmanM.Diprotected triflylguanidines: A new class of guanidinylation reagentsJ. Org. Chem.1998633804380510.1021/jo980425s FeichtingerK.SingsH.L.BakerT.J.MatthewsK.GoodmanM.Triurethane-protected guanidines and triflyldiurethane-protected guanidines: New reagents for guanidinylation reactionsJ. Org. Chem.1998638432843910.1021/jo9814344 RossP.C.HuiS.W.Lipoplex size is a major determinant of in vitro lipofection efficiencyGene Therapy1999665165910.1038/sj.gt.330086310476225 MarchiniC.MontaniM.AmiciA.AmenitschH.MarianecciC.PozziD.CaraccioloG.Structural stability and increase in size rationalize the efficiency of lipoplexes in serumLangmuir2009253013302110.1021/la803372619437770 HoekstraD.RejmanJ.WasunguL.ShiF.ZuhornI.Gene delivery by cationic lipids: in and out of an endosomeBiochem. Soc. Trans.200735687110.1042/BST035006817233603 LuJ.J.LangerR.ChenJ.Z.A novel mechanism is involved in cationic lipid-mediated functional siRNA deliveryMol. Pharm.2009676377110.1021/mp900023v19292453 JonesL.J.YueS.T.CheungC.Y.SingerV.L.RNA quantitation by fluorescence-based solution assay: RiboGreen reagent characterizationAnal. Biochem.199826536837410.1006/abio.1998.29149882416 GhonaimH.M.LiS.BlagbroughI.S.Very long chain N4,N9-diacyl spermines: Non-viral lipopolyamine vectors for efficient plasmid DNA and siRNA deliveryPharm. Res.200926193110.1007/s11095-008-9705-118781381 GhonaimH.M.LiS.BlagbroughI.S.N1,N12-Diacyl spermines: SAR studies on non-viral lipopolyamine vectors for plasmid DNA and siRNA formulationPharm. Res.201027172910.1007/s11095-008-9764-319876724 AhmedO.A.A.PourzandC.BlagbroughI.S.Varying the unsaturation in N4,N9-dioctadecanoyl spermines: Nonviral lipopolyamine vectors for more efficient plasmid DNA formulationPharm. Res.200623314010.1007/s11095-005-8717-316382281 GaucheronJ.SantaellaC.VierlingP.Highly fluorinated lipospermines for gene transfer: Synthesis and evaluation of their in vitro transfection efficiencyBioconjug. Chem.20011211412810.1021/bc000089y11170374 KoynovaR.TenchovB.WangL.MacDonaldR.C.Hydrophobic moiety of cationic lipids strongly modulates their transfection activityMol. Pharm.2009695195810.1021/mp800257319341312 HanS.E.KangH.ShimG.Y.SuhM.S.KimS.J.KimJ.S.OhY.K.Novel cationic cholesterol derivative-based liposomes for serum-enhanced delivery of siRNAInt. J. Pharm.200835326026918178348 TagamiT.HiroseK.BarichelloJ.M.IshidaT.KiwadaH.Global gene expression profiling in cultured cells is strongly influenced by treatment with siRNA-cationic liposome complexesPharm. Res.2008252497250410.1007/s11095-008-9663-718581204 SoltanM.K.GhonaimH.M.El SadekM.Abou KullM.El-AzizL.A.BlagbroughI.S.Design and synthesis of N4,N9-disubstituted spermines for non-viral siRNA delivery - Structure-activity relationship studies of siFection efficiency versus toxicityPharm. Res.20092628629510.1007/s11095-008-9731-z18841447 CornishJ.CallonK.E.LinC.Q.X.XiaoC.L.MulveyT.B.CooperG.J.S.ReidI.R.Trifluoroacetate, a contaminant in purified proteins, inhibits proliferation of osteoblasts and chondrocytesAm. J. Physiol. Endocrinol. Metab.1999277E779E783 PatilS.P.YiJ.W.BangE.-K.JeonE.M.KimB.H.Synthesis and efficient siRNA delivery of polyamine-conjugated cationic nucleoside lipidsMedChemComm2011250550810.1039/c1md00014d | {
"url": "http://www.mdpi.com/1999-4923/3/3/406/xml",
"source_domain": "www.mdpi.com",
"snapshot_id": "crawl=CC-MAIN-2013-48",
"warc_metadata": {
"Content-Length": "87766",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:5CEYF6GPOD6TX5MOGV57IW7FYV4W3YIS",
"WARC-Concurrent-To": "<urn:uuid:cf95ed2b-86fb-42a4-88ca-bf828797535b>",
"WARC-Date": "2013-12-13T05:08:21",
"WARC-IP-Address": "174.142.82.236",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:5YWKGZQZ5DFDVLVQF3FATKMOZ3NNQ5JO",
"WARC-Record-ID": "<urn:uuid:d00fdc50-a748-42df-810f-1ce1efc198ad>",
"WARC-Target-URI": "http://www.mdpi.com/1999-4923/3/3/406/xml",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:afd5d1d7-9fcb-4edf-9579-6aedabe44c96>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-33-133-15.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2013-48\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for Winter 2013\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
616,
617,
790,
791,
1655,
1656,
1751,
1764,
1765,
3064,
3065,
5053,
5054,
5432,
5433,
5484,
5485,
6791,
6792,
6893,
6894,
8519,
8520,
9631,
9632,
9689,
9690,
10863,
10864,
10886,
10887,
11830,
11831,
11864,
11865,
13315,
13316,
13337,
13338,
13882,
13883,
13929,
13930,
14568,
14569,
14615,
14616,
15628,
15629,
15728,
15729,
16126,
16127,
16720,
16721,
18408,
18409,
18448,
18449,
20483,
20484,
20530,
20531,
21349,
21350,
21413,
21414,
21946,
21947,
23113,
23114,
24810,
24811,
25336,
25337,
25589,
25590,
26314,
26315,
27123,
27124,
27157,
27158,
27448,
27449,
28398,
28399,
28420,
28421,
29861,
29862,
29874,
29875,
30725,
30726,
31350,
31351,
31369,
31370,
31431,
31432,
31670,
31671,
31728,
31729,
31967,
31968,
32260,
32261,
32784,
32785,
33200,
33201,
33848,
33849,
34221,
34222,
34587,
34588,
34691,
34761,
34832,
34900,
34999,
35000,
35294,
35295
],
"line_end_idx": [
616,
617,
790,
791,
1655,
1656,
1751,
1764,
1765,
3064,
3065,
5053,
5054,
5432,
5433,
5484,
5485,
6791,
6792,
6893,
6894,
8519,
8520,
9631,
9632,
9689,
9690,
10863,
10864,
10886,
10887,
11830,
11831,
11864,
11865,
13315,
13316,
13337,
13338,
13882,
13883,
13929,
13930,
14568,
14569,
14615,
14616,
15628,
15629,
15728,
15729,
16126,
16127,
16720,
16721,
18408,
18409,
18448,
18449,
20483,
20484,
20530,
20531,
21349,
21350,
21413,
21414,
21946,
21947,
23113,
23114,
24810,
24811,
25336,
25337,
25589,
25590,
26314,
26315,
27123,
27124,
27157,
27158,
27448,
27449,
28398,
28399,
28420,
28421,
29861,
29862,
29874,
29875,
30725,
30726,
31350,
31351,
31369,
31370,
31431,
31432,
31670,
31671,
31728,
31729,
31967,
31968,
32260,
32261,
32784,
32785,
33200,
33201,
33848,
33849,
34221,
34222,
34587,
34588,
34691,
34761,
34832,
34900,
34999,
35000,
35294,
35295,
43373
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 43373,
"ccnet_original_nlines": 127,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.24115435779094696,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.05959751829504967,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.32474568486213684,
"rps_doc_frac_unique_words": 0.25660887360572815,
"rps_doc_mean_word_length": 5.910759449005127,
"rps_doc_num_sentences": 740,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 6.15036678314209,
"rps_doc_word_count": 5939,
"rps_doc_frac_chars_dupe_10grams": 0.023102780804038048,
"rps_doc_frac_chars_dupe_5grams": 0.09902004897594452,
"rps_doc_frac_chars_dupe_6grams": 0.056660208851099014,
"rps_doc_frac_chars_dupe_7grams": 0.03703282028436661,
"rps_doc_frac_chars_dupe_8grams": 0.030139019712805748,
"rps_doc_frac_chars_dupe_9grams": 0.02475501038134098,
"rps_doc_frac_chars_top_2gram": 0.0061246599070727825,
"rps_doc_frac_chars_top_3gram": 0.0027062399312853813,
"rps_doc_frac_chars_top_4gram": 0.007520509883761406,
"rps_doc_books_importance": -4761.0947265625,
"rps_doc_books_importance_length_correction": -4761.0947265625,
"rps_doc_openwebtext_importance": -2733.94873046875,
"rps_doc_openwebtext_importance_length_correction": -2733.94873046875,
"rps_doc_wikipedia_importance": -1955.5643310546875,
"rps_doc_wikipedia_importance_length_correction": -1955.5643310546875
},
"fasttext": {
"dclm": 0.025573790073394775,
"english": 0.8927332758903503,
"fineweb_edu_approx": 2.0648646354675293,
"eai_general_math": 0.9018120169639587,
"eai_open_web_math": 0.3866308331489563,
"eai_web_code": 0.07149720191955566
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.19",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "547.88",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Chemistry",
"level_3": "Chemistry, Organic"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-7,806,512,578,630,557,000 | Skip to content
Advertisement
Biological Research
Open Access
Study on the relationship between expression patterns of cocaine-and amphetamine regulated transcript and hormones secretion in porcine ovarian follicles
• Pengfei Li1,
• Jinzhu Meng2,
• Jiongjie Jing3,
• Qingling Hao1,
• Zhiwei Zhu1,
• Jianbo Yao3, 4 and
• Lihua Lyu3Email author
Biological Research201851:6
https://doi.org/10.1186/s40659-018-0154-y
Received: 4 July 2017
Accepted: 19 February 2018
Published: 26 February 2018
Abstract
Background
Cocaine-and amphetamine regulated transcript (CART) is an endogenous neuropeptide, which is widespread in animals, plays a key role in regulation of follicular atresia in cattle and sheep. Among animal ovaries, CART mRNA was firstly found in the cattle ovaries. CART was localized in the antral follicles oocytes, granulosa and cumulus cells by immunohistochemistry and in situ hybridization. Further research found that secretion of E2 was inhibited in granulosa cells with a certain dose of CART, the effect depends on the stage of cell differentiation, suggesting that CART could play a crucial role in regulating follicle atresia. The objective of this study was to characterize the CART expression model and hormones secretion in vivo and vitro in pig follicle granulosa cells, preliminarily studied whether CART have an effect on granulosa cells proliferation and hormones secretion in multiparous animals such as pigs.
Methods
The expression levels of CART mRNA in granulosa cells of different follicles were analyzed using qRT-PCR technology. Immunohistochemistry technology was used to localize CART peptide. Granulosa cells were cultured in medium supplemented with different concentrations of CART and FSH for 168 h using Long-term culture system, and observed using a microscope. The concentration of Estradiol (E2) and progesterone (P) in follicular fluids of different test groups were detected by enzyme linked immunosorbent assay (ELISA).
Results
Results showed that expression level of CART mRNA was highest in medium follicles, and significantly higher than that in large and small follicles (P < 0.05). Immunohistochemical results showed that CART were expressed both in granulosa cells and theca cells of large follicles, while CART were detected only in theca cells of medium and small follicles. After the granulosa cells were cultured for 168 h, and found that concentrations of E2 increase with concentrations of follicle-stimulating hormone (FSH) increase when the CART concentration was 0 μM. And the concentration of FSH reached 25 ng/mL, the concentration of E2 is greatest. It shows that the production of E2 needs induction of FSH in granulosa cells of pig ovarian follicles. With the increasing of CART concentrations (0.01, 0.1, 1 μM), E2 concentration has a declining trend, when the FSH concentrations were 25 and 50 ng/mL in the medium, respectively.
Conclusions
These results suggested that CART plays a role to inhibit granulosa cells proliferation and E2 production, which induced by FSH in porcine ovarian follicular granulosa cells in vitro, but the inhibition effect is not significant. So we hypothesis CART maybe not a main local negative regulatory factor during porcine follicular development, which is different from the single fetal animals.
Keywords
PigCARTEstradiolProgesteroneGranulosa cell
Background
In mammals, ovarian follicular development is a continuous process during reproductive life span. Follicles develop through the primordial, primary, and secondary stage before acquiring an antral cavity, after which tertiary and preovulatory follicles successively form, and then oocytes are released after LH peak stimulation. In fact, only a few follicles undergo ovulation, most of the developing follicles will undergo atresia [14].
Ovarian follicles develop in a wave-like pattern in some species, such as pigs, human and cattle, each follicular wave is initiated by a transient elevation of FSH, then a cohort of follicles begin to grow, among which some follicles growing fast transform into the dominant follicles, while the rest become the subordinate follicles that will undergo atresia [59].
Cocaine-and amphetamine regulated transcript (CART), discovered initially by Douglass et al. via differential display RT-PCR analysis of brains of rats administered cocaine [10], is expressed mainly in central nervous system or neuronal origin cells [11], which is involved in a wide range of behaviors, such as regulation of food intake, energy homeostasis, and reproduction [1215]. CART, as a potent anorectic peptide in hypothalamus, is regulated by leptin [16]. Since leptin stimulation of GnRH release can be blocked by CART protein antibody in vitro, the action of leptin on reproductive neuroendocrine axis may be mediated by CART [17]. As specific CART receptors have not been identified, the regulatory mechanisms of CART biological activities are still unknown.
Follicular growth and development is a complex process, which is not only precisely regulated by some endocrine factors, but also some locally produced intraovarian factors [3, 1820]. A previous study reported that CART mRNA and CART peptide are expressed in bovine oocyte, and ovarian cells such as cumulus cells, and granulosa cell layer of antral follicles but not preantral follicles, suggesting a potential role of CART in the atresia of antral follicles [21]. Based on these findings, we hypothesized that CART may also play a role as a potential local regulator in the process of porcine follicular development. To investigate the relationship between CART and pig follicular development, we determined CART mRNA expression level in porcine follicles of different sizes and the concentrations of E2 and P in follicular fluid of those follicles, the localization of CART peptide was also detected by immunohistochemistry technology, and explored the effects of CART on granulosa cells proliferation and E2 secretion by in vitro culture. Our results indicated that CART may be involved in the process of porcine antral follicle development, yet its role may not be mediated by regulating the concentration of E2 and P.
Methods
Animal care
All animal procedures were performed with strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.
Follicles and granulosa cells collection
Ten ovaries were collected from five female Large White pigs at the local slaughterhouse (Taigu, Shanxi, China). Follicles of 2–8 mm were dissected free from ovarian stroma and washed in 70% alcohol and DPBS solution for a few seconds. The follicles were classified into large (diameter > 5 mm), medium (3 mm < diameter < 5 mm) and small (diameter < 3 mm) groups, and placed in culture medium. Follicular fluid from each group follicles was aspirated and frozen on dry ice and stored at − 20 °C until hormone detection. Follicles were cut in half, and granulosa cells were collected from follicle internal wall and frozen in liquid nitrogen and stored at − 80 °C until RNA isolation.
RNA isolation and cDNA synthesis
Total RNA was isolated using Trizol (Takara, Dalian, China) according to the manufacturer’s instructions. Isolated RNA was dissolved in 30 µL of RNase free water. Before cDNA synthesis, 2 µL of total RNA were mixed with 2 µL of 5 × gDNA Eraser Buffer, 1 μL of gDNA Eraser (Takara, Dalian, China) and 5 μL of RNase free water and incubated at 42 °C for 2 min to remove genomic DNA. 0.8 μg RNA was mixed with 4 μL of 5 × PrimeScript® Buffer 2, 1 μL of RT Primer Mix, 1 μL of PrimeScript® RT Enzyme Mix I and 4 μL of RNase Free water (Takara, Dalian, China), and then incubated at 37 °C for 15 min followed by incubation at 85 °C for 5 s to synthesize cDNA, which was stored at − 20 °C until use.
Quantitative real-time PCR (qRT-PCR)
The relative expression level of CART mRNA in pig follicles of different sizes was measured by qRT-PCR. qRT-PCR was performed using 20 µL reaction volume containing 10 µL of SYBR® Green premix Ex Taq™II, 0.4 µL of ROX Reference Dye II(Takara, Dalian, China), 0.8 µL of forward and reverse primer, respectively, 2 µL of cDNA and 6 µL nuclease free water. Reactions were run on a 7500 Real Time PCR system (Thermo Scientific, Beijing, China) for 45 cycles at 95 °C for 15 s followed by 60 °C for 1 min. β-Actin gene was used as the endogenous control. Primers were designed using Primer 3 (http://primer3.ut.ee/), porcine CART primer was designed according to Sus scrofa CART mRNA, the primers are listed in Table 1. The relative mRNA expression level of CART was calculated using the comparative 2−ΔΔCT method [22]. The CART standard curve had a slope of − 3.124 (Eff. = 109.0%). The β-Actin standard curve had a slope of − 3.166 (Eff. = 106.9%).
Table 1
Primer sequences used in this study
Primer name
Sequence (5′to 3′)
Tm (°C)
Size (bp)
CART-F
TATGTGTGACGCAGGAGAGC
59.3
102
CART-R
AAGGAATTGCAGGAGGTTCC
59.8
β-Actin-F
CCAGCACCATGAAGATCAAG
60.0
93
β-Actin-R
ACATCTGCTGGAAGGTGGAC
60.0
F sense primers, R antisense primers
Immunohistochemical localization of CART
Samples of adult ovary stroma were collected at a local abattoir from ovaries of three different animals. Samples were placed in a plastic tissue cassette, fixed with 4% (vol/vol) paraformaldehyde solution, and embedded in paraffin. Immunohistochemical localization of the CART peptide was performed using previously described procedures [23]. Rabbit anti-rat CART (55–102) polyclonal antisera (Phoenix Pharmaceuticals, Inc., Belmont, CA) (1:1000 dilution) was used in the analysis. Parallel controls were used, including sections incubated with a similar dilution of normal rabbit serum or rabbit anti-CART serum that had been pre-incubated overnight at 4 °C with 10 μg/mL rat CART (55–102) peptide (American Peptide Co., Sunnyvale, CA). Four serial sections from each sample were examined.
Granulosa cells cultured in vitro
Long-term culture system was performed using our previously procedures [24, 25]. Granulosa cells were cultured in a humidified environment of 5% CO2 and air at 37 °C for 168 h, medium was replaced with fresh medium every 48 h. Granulosa cells were harvested after termination of culture, washed by DPBS and digested using tryptase, and cell numbers were determined [26]. The situation of cells were observed and collected images after cultured for 48, 96, 144 and 168 h. At the end of culture, 340 μL medium were pooled from 2 adjacent wells per treatment, stored at − 20 °C for measurement of hormone.
Estradiol and progesterone enzyme-linked immunosorbent assay (ELISA)
Concentrations of E2 and P in follicular fluid of follicles at different sizes were detected using pig free estradiol and progesterone ELISA kit (Blue gene, Shanghai, China) according to the manufacturer’s instructions. The ELISA plates were read with a microplate reader (Thermo Scientific, Shanghai, China) to record the optical densities and the concentration of E2 and P derived from standard curve. The assay sensitivity was set as 0.5 pg/mL. The inter- and intra-assay CVs for E2 were 8.3 and 7.6%, respectively, and the inter- and intra-assay CVs for P were 9.2 and 5.8%, respectively.
The determination method of E2 concentration in medium was same to that in follicular fluid, standard curve was drew, concentration of each group was calculated。
Statistical analysis
Three biological reduplicates were used in all experiments mentioned above. The expression level of CART mRNA in granulosa cells of porcine follicles at different sizes and concentrations of E2 and P in follicular fluid were analyzed by one way ANOVA using SPSS computer software (IBM, USA). E2 concentration in culture medium was determined by Duncan-method of multiple comparisons. Data were presented as mean ± SE.
Results
Detection of CART mRNA in granulosa cells of porcine follicles
RT-PCR detection of CART mRNA and β-Actin gene in granulosa cells of porcine follicles at different sizes were shown through agarose gel electrophoresis. The products of β-Actin gene amplification in large, medium and small follicles were all 93 bp in size. CART mRNA amplification products in large, medium and small follicles were 102 bp in size.
The nucleotide sequence of the porcine CART and β-Actin cDNAs derived from RNA of follicular granulosa cells was 102 and 93 bp, respectively (data not shown). The nucleotide sequence of porcine CART shared 100% homology with that of Sus scrofa CART.
CART mRNA expression levels in large, medium and small follicles
Quantitative real time PCR analysis revealed that the expression level of CART mRNA was significantly higher in medium follicles than that in large and small follicles (P < 0.05) (Fig. 1).
Fig. 1
Quantitative real-time PCR analysis of CART mRNA expression in big, medium and small follicles. Superscript small letters indicate significantly different at the level of 0.05, same letters mean no significantly difference while different letters mean significantly difference. (n = 3 each; least square mean ± SEM)
Concentrations of E2 and P in follicular fluid of large, medium and small follicles
The concentrations of E2 and P in follicular fluid of large, medium and small follicles are showed in Fig. 2. No significant differences in the concentrations of each hormone (E2 and P) were observed in follicles of different sizes.
Fig. 2
Estradiol and progesterone concentrations in big, medium and small follicles. Superscript small letters indicate significantly different at the level of 0.05, same letters mean no significantly difference while different letters mean significantly difference. (n = 3 each; least square mean ± SEM)
Intraovarian expression of CART protein
The intra-ovarian localization of CART peptide was determined by immunohistochemistry (Fig. 3). CART immunoreactivity was localized to the granulosa cells of big, medium and small follicles (Fig. 3b, e, h). Significant immunoreactivity in the granulosa cells was not detected when adjacent sections were incubated with normal rabbit serum (Fig. 3a, d, g) or when the CART antiserum was pre-absorbed with excess CART peptide (Fig. 3c, f, i).
Fig. 3
Immunohistochemical localization of CART peptide within the porcine ovary. ac, Adjacent section micrograph of big follicle; df, adjacent section micrograph of medium follicle; gi, adjacent section micrograph of small follicle. a, d, g, Pre-immune serum; b, e, h, rabbit anti-rat CART; c, f, i, pre-absorbed rabbit anti-rat CART. GC, granulosa cell layer; TC, thecal cell layer; af: Magnification, ×400; scale bar, 20 µM
Response doses effect of CART on E2 production and granulosa cells proliferation under long-term culture with FSH treatment
Comparing with control group, with the concentrations of FSH were increasing (5, 25, 50 ng/mL) in medium, the concentrations of E2 are on the rise, when the CART concentration was 0 μM. And the concentration of FSH reached 25 ng/mL, the secretion of E2 is greatest. It shows that the production of E2 needs induction of FSH in granulosa cells of pig ovarian follicles. With the increasing of CART concentrations (0.01, 0.1, 1 μM), E2 concentration has a declining trend, when the FSH concentrations were 25 and 50 ng/mL in the medium, respectively, but the generation of E2 is significantly suppressed when pretreatment with 25 ng/mL FSH, 0.1 and 1 μM CART (P < 0.05) (Fig. 4).
Fig. 4
Effects of CART on FSH induced estradiol production of pig follicular granulosa cells after 168 h in vitro culture. Superscript small letters and capital letters indicate significantly different at the level of 0.05 and 0.01, Values with the same letters were not significantly different and values with the different letters were significantly different at the level of 0.01 or 0.05. (n = 3 each; least square mean ± SEM)
The images of granulosa cells in vitro culture shows that clusters of granulosa cells were obviously decrease with the concentration of CART increase at FSH (25 ng/mL) in culture system (Fig. 5). This is consistent with the detection results of E2 (Fig. 4), indicating that decrease of granulosa cells numbers lead to the decrease of E2 secretion.
Fig. 5
The micrograph of granulosa cells after 168 h in vitro culture with FSH (25 ng/mL) in culture system, a CART 0 µM; b CART 0.01 µM; c CART 0.1 µM; d CART 1 µM. Magnification, ×100
Discussion
The process of follicle growth and development is regulated by various endocrine factors and intra-ovarian factors. As our understanding of the well-established endocrine regulation of antral follicle growth and development increasing, attention in recent years has been focused on both identification and subsequent contribution of locally produced regulatory molecules that are involved in antral follicle growth and developmental regulation. Results of the present study demonstrated that the previously described anorectic neuropeptide CART had a higher expression level in the granulosa cells of medium follicles than that of big and small follicles. CART expression was potentially associated with follicle development. However, other results of the present study indicated that the concentrations of E2 and P in follicular fluid of large, medium and small follicles had no significant difference. Results support potential local regulatory role for CART in porcine follicular development without regulating the production of E2 and P.
Our results indicate that E2 secretion decrease with the increase of CART under same FSH concentration, suggested that CART might plays an suppressive role on the proliferation of pig ovarian follicle granulosa cells. Previous research found CART can restrain E2 secretion of bovine follicular granulosa cells in vitro, and plays a negative regulatory role during follicular development [27, 28]. Our study confirmed CART can inhibit the proliferation of pig ovarian follicle granulosa cells, meanwhile CART could promote granulosa cell apoptosis of porcine ovarian follicles [29]. But inhibition effect of CART is not significant.
Being classified as a somatostatin-like peptide, the amino acid sequence of CART peptide was first reported for sheep in hypothalamus [30]. Subsequently more and more researches were focused on the identity of CART. Until 1995 when Douglass and his co-workers [10] identified CART as a mRNA species whose expression increased acutely after psychomotor stimulant administration. The nucleotide and predicted amino acid sequences of CART from rat [10], human [31], mouse [32], sheep [33] and cattle [34] have been reported previously and were highly homologous among different species. However, the expression of CART mRNA in the porcine ovary has not been reported.
Previous studies have reported that CART was expressed in many tissues, including pituitary gland, adrenal gland [11, 35, 36], stomach [36], and intestines [36, 37]. However, reports about CART on mammalian gonads are rare. Murphy et al. [36, 38] did not detect immunoreactive CART peptide in rat ovaries and testis. Within gonadal tissues, CART expression has been reported in the goldfish ovary [38] and in nerves that innervate the epididymis of rat testis [39]. However, the present study detected CART mRNA and peptide expression in granulosa cells of porcine antral follicles. Smith, et al. [12] also found that both CART mRNA and protein were expressed in oocyte, cumulus cells, and granulosa cells of antral follicles in bovine ovary.
Our study demonstrated that the CART mRNA and peptide expressed in granulosa cells of porcine antral follicles at various development stages and the medium follicles had the highest expression level, suggesting that CART may play an important role in antral follicle development by regulating differentiation of granulosa cells. The exact mechanisms about how CART exerts its regulatory role in granulosa cells need to be further explored.
It is acknowledged that study design was not optimal due to follicles (large, medium, small) were used in CART mRNA expression and hormone determination. For the demarcation of follicles in different stages of multiparous animals, unlike single fetal animals whose follicles can be clearly divided into dominant and subordinate follicles. Despite such limitations, our results indicates that the concentrations of E2 and P in follicular fluid of large, medium and small follicles had no significant difference, which suggests that CART has no direct regulatory effect on the production of these two hormones in porcine antral follicles. Follicular growth and development are regulated by endocrine factors [40, 41], including E2 and P, which are important indicators to reflect the state of follicular growth. Smith et al. [12] demonstrated that CART had an inhibitory effect on in vitro production of E2 by granulosa cells.
Conclusion
CART leads to decrease of E2 production by inhibiting granulosa cells proliferation, which induced by FSH in porcine ovarian follicular granulosa cells. We hypothesis CART maybe not a main local negative regulatory factor during porcine follicular development, which is different from the single fetal animals.
Declarations
Authors’ contributions
PL conceived the experiments and writed the initial draft of the manuscript; JJ and QH performed the experiments; JM and ZZ managed data collection; JY and LL designed the experiment and conducted data analysis. All authors read and approved the final manuscript.
Authors’ information
PF Li and ZW Zhu are doctors, associate professor of college of life science, Shanxi Agricultural University; JZ Meng is master, lecturer of Wujiang college, Tongren university; JJ Jing is doctoral candidate of College of Animal Science and Technology, Shanxi Agricultural University; QL Hao is graduate students of college of life science, Shanxi Agricultural University; JB Yao is doctor, professor of Division of Animal and Nutritional Sciences, West Virginia University, and the 100-Talent programme of Shanxi Agricultural University; LH Lyu is doctor, professor of College of Animal Science and Technology, Shanxi Agricultural University.
Acknowledgements
Authors are grateful of Prof. George W Smith and Prof. James Richard Pursley in Michigan State University in the USA for their directions of research designs and manuscript preparation.
Competing interests
We confirm that there are no known competing interests associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Availability of data and materials
Availability of data and materials are included in the manuscript, figures and table.
Consent for publication
All authors read and approved the final manuscript, and consented for publication.
Ethics approval and consent to participate
We confirm that this study did not involve relevant clause of the Ethics Committee, and all animal procedures were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.
Funding
This study was supported by Shanxi Scholarship Council of China Grant No. 2014-key 5, Shanxi Sci-technological Collaboration Grant No. 201603D421006, Shanxi Talent Introduction and Sanjin Talent Program, Shanxi Provincial Talent Introduction and SXAU (Shanxi Agricultural University) Major Research Achievement Cultivation Grant No. zdpy 201403/201503 to Lyu; Shanxi Key Research and Development Plan (general) Agriculture Project Grant No. 201703D221020-1, SXAU Introduction of Doctor Research Startup Fund Grant No. 2014ZZ04 to Li; Chinese Natural Science Foundation Grant No. 31402156, SXAU Program for the Top Young Innovative Talents Grant No. TYIT201403 to Zhu.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
(1)
College of Life Science, Shanxi Agricultural University, Taigu, China
(2)
Wujiang College, Tongren University, Tongren, China
(3)
College of Animal Science and Technology, Shanxi Agricultural University, Taigu, China
(4)
Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, USA
References
1. McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000;21(2):200–14.PubMedGoogle Scholar
2. Barnett KR, Schilling C, Greenfeld CR, Tomic D, Flaws JA. Ovarian follicle development and transgenic mouse models. Hum Reprod Update. 2006;12(5):537–55.View ArticlePubMedGoogle Scholar
3. Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191–206.View ArticlePubMedGoogle Scholar
4. Dayal M, Sagar S, Chaurasia A, Singh U. Anti-Mullerian hormone: a new marker for ovarian function. J Obstet Gynaecol India. 2014;64(2):130–3.View ArticlePubMedGoogle Scholar
5. Lucy MC, Liu J, Boyd CK, Bracken CJ. Ovarian follicular growth in sows. Reprod Suppl. 2001;58:31–45.PubMedGoogle Scholar
6. Baerwald AR, Adams GP, Pierson RA. Characterization of ovarian follicular wave dynamics in women. Biol Reprod. 2003;69(3):1023–31.View ArticlePubMedGoogle Scholar
7. Lucy MC, Savio JD, Badinga L, De-La-Sota RL, Thatcher WW. Factors that affect ovarian follicular dynamics in cattle. J Anim Sci. 1992;70(11):3615–26.View ArticlePubMedGoogle Scholar
8. Fortune JE. Ovarian follicular growth and development in mammals. Biol Reprod. 1994;50(2):225–32.View ArticlePubMedGoogle Scholar
9. Ginther OJ. The theory of follicle selection in cattle. Domest Anim Endocrinol. 2016;57:85–99.View ArticlePubMedGoogle Scholar
10. Douglass J, McKinzie AA, Couceyro P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci. 1995;15(3 Pt 2):2471–81.PubMedGoogle Scholar
11. Thim L, Kristensen P, Nielsen PF, Wulff BS, Clausen JT. Tissue-specific processing of cocaine-and amphetamine-regulated transcript peptides in the rat. Proc Natl Acad Sci USA. 1999;96(6):2722–7.View ArticlePubMedPubMed CentralGoogle Scholar
12. Smith SM, Vaughan JM, Donaldson CJ, Rivier J, Li C, Chen A, Vale WW. Cocaine-and amphetamine-regulated transcript activates the hypothalamic-pituitary-adrenal axis through a corticotropin-releasing factor receptor-dependent mechanism. Endocrinology. 2004;145(11):5202–9.View ArticlePubMedGoogle Scholar
13. Boone EM, Hawks BW, Li W, Garlow SJ. Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice. Brain Res. 2008;1194:1–7.View ArticlePubMedGoogle Scholar
14. Lima FB, Henderson JA, Reddy AP, Tokuyama Y, Hubert GW, Kuhar MJ, Bethea CL. Unique responses of midbrain CART neurons in macaques to ovarian steroids. Brain Res. 2008;1227:76–88.View ArticlePubMedPubMed CentralGoogle Scholar
15. Derks NM, Gaszner B, Bernhardt K, Roubos EW, Kozicz T. Sex-specific expression of BDNF and CART in the midbrain non-preganglionic Edinger–Westphal nucleus in the rat. Peptides. 2009;30(12):2268–74.View ArticlePubMedGoogle Scholar
16. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature. 1998;393(6680):72–6.View ArticlePubMedGoogle Scholar
17. Van Vugt DA, Lujan ME, Froats M, Krzemien A, Couceyro PR, Reid RL. Effect of fasting on cocaine-amphetamine-regulated transcript, neuropeptide Y, and leptin receptor expression in the non-human primate hypothalamus. Neuroendocrinology. 2006;84(2):83–93.View ArticlePubMedGoogle Scholar
18. Demeestere I, Centner J, Gervy C, Englert Y, Delbaere A. Impact of various endocrine and paracrine factors on in vitro culture of preantral follicles in rodents. Reproduction. 2005;130(2):147–56.View ArticlePubMedGoogle Scholar
19. Knight PG, Glister C. Local roles of TGF-beta superfamily members in the control of ovarian follicle development. Anim Reprod Sci. 2003;78(3–4):165–83.View ArticlePubMedGoogle Scholar
20. Silva GM, Brito IR, Sales AD, Aguiar FL, Duarte AB, Araújo VR, Vieira LA, Magalhães-Padilha DM, Lima LF, Alves BG, Silveira LB, Lo Turco EG, Rodrigues AP, Campello CC, Wheeler MB, Figueiredo JR. In vitro growth and maturation of isolated caprine preantral follicles: influence of insulin and FSH concentration, culture dish, coculture, and oocyte size on meiotic resumption. Theriogenology. 2017;90:32–41.View ArticlePubMedGoogle Scholar
21. Smith GW, Sen A, Folger JK, Ireland JJ. Putative role of cocaine- and amphetamine-regulated transcript (CARTPT) in dominant follicle selection in cattle. Soc Reprod Fertil Suppl. 2010;67:105–17.PubMedGoogle Scholar
22. Shi L, Zhao H, Ren Y, Yao X, Song R, Yue W. Effects of different levels of dietary selenium on the proliferation of spermatogonial stem cells and antioxidant status in testis of roosters. Anim Reprod Sci. 2014;149(3–4):266–72.View ArticlePubMedGoogle Scholar
23. Bakke LJ, Li Q, Cassar CA, Dow MP, Pursley JR, Smith GW. Gonadotropin surge-induced differential upregulation of collagenase-1 (MMP-1) and collagenase-3 (MMP-13) mRNA and protein in bovine preovulatory follicles. Biol Reprod. 2004;71(2):605–12.View ArticlePubMedGoogle Scholar
24. Sen A, Lv L, Bello N, Ireland JJ, Smith GW. Cocaine-and amphetamine-regulated transcript accelerates termination of follicle-stimulating hormone-induced extracellularly regulated kinase 1/2 and Akt activation by regulating the expression and degradation of specific mitogen-activated protein kinase phosphatases in bovine granulosa cells. Mol Endocrinol. 2008;22(12):2655–76.View ArticlePubMedPubMed CentralGoogle Scholar
25. Lv L, Jimenez-Krassel F, Sen A, Bettegowda A, Mondal M, Folger JK, Lee KB, Ireland JJ, Smith GW. Evidence supporting a role for cocaine and amphetamine regulated transcript (CART) in control of granulosa cell estradiol production associated with dominant follicle selection in cattle. Biol Reprod. 2009;81(3):580–6.View ArticlePubMedGoogle Scholar
26. Folger JK, Jimenez-Krassel F, Ireland JJ, Lv L, Smith GW. Regulation of granulosa cell cocaine and amphetamine regulated transcript (CART) binding and effect of CART signaling inhibitor on granulosa cell estradiol production during dominant follicle selection in cattle. Biol Reprod. 2013;89(6):137.View ArticlePubMedGoogle Scholar
27. Rosales-Torres AM, Avalos-Rodríguez A, Vergara-Onofre M, Hernández-Pérez O, Ballesteros LM, García-Macedo R, Ortíz-Navarrete V, Rosado A. Multiparametric study of atresia in ewe antral follicles: histology, flow cytometry, internucleosomal DNA fragmentation and lysosomal enzyme activities in granulosa cells and follicular fluid. Mol Reprod Dev. 2000;55(3):270–81.View ArticlePubMedGoogle Scholar
28. Wood JR, Strauss JF. Multiple signal transduction pathways regulate ovarian steroidogenesis. Rev Endocr Metab Disord. 2002;3(1):33–46.View ArticlePubMedGoogle Scholar
29. Austin EJ, Mihm M, Evans AC, Knight PG, Ireland JL, Ireland JJ, Roche JF. Alterations in intrafollicular regulatory factors and apoptosis during selection of follicles in the first follicular wave of the bovine estrous cycle. Biol Reprod. 2001;64(3):839–48.View ArticlePubMedGoogle Scholar
30. Spiess J, Villarreal J, Vale W. Isolation and sequence analysis of a somatostatin-like polypeptide from ovine hypothalamus. Biochemistry. 1981;20(7):1982–8.View ArticlePubMedGoogle Scholar
31. Douglass J, Daoud S. Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript. Gene. 1996;169(2):241–5.View ArticlePubMedGoogle Scholar
32. Kuhar MJ, Adams S, Dominguez G, Jaworski J, Balkan B. CART peptides. Neuropeptides. 2002;36(1):1–8.View ArticlePubMedGoogle Scholar
33. Barrett P, Morris MA, Moar KM, Mercer JG, Davidson JA, Findlay PA, Adam CL, Morgan PJ. The differential regulation of CART gene expression in a pituitary cell line and primary cell cultures of ovine pars tuberalis cells. J Neuroendocrinol. 2001;13(4):347–52.View ArticlePubMedGoogle Scholar
34. Kobayashi Y, Jimenez-Krassel F, Li Q, Yao J, Huang R, Ireland JJ, Coussens PM, Smith GW. Evidence that cocaine- and amphetamine-regulated transcript is a novel intraovarian regulator of follicular atresia. Endocrinology. 2004;145(11):5373–83.View ArticlePubMedGoogle Scholar
35. Koylu EO, Couceyro PR, Lambert PD, Ling NC, DeSouza EB, Kuhar MJ. Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland. J Neuroendocrinol. 1997;9(11):823–33.View ArticlePubMedGoogle Scholar
36. Murphy KG, Abbott CR, Mahmoudi M, Hunter R, Gardiner JV, Rossi M, Stanley SA, Ghatei MA, Kuhar MJ, Bloom SR. Quantification and synthesis of cocaine- and amphetamine-regulated transcript peptide (79–102)-like immunoreactivity and mRNA in rat tissues. J Endocrinol. 2000;166(3):659–68.View ArticlePubMedGoogle Scholar
37. Kasacka I, Piotrowska Z. Evaluation of density and distribution of CART-immunoreactive structures in gastrointestinal tract of hypertensive rats. BioFactors. 2012;38(6):407–15.View ArticlePubMedGoogle Scholar
38. Volkoff H, Peter RE. Characterization of two forms of cocaine- and amphetamine-regulated transcript (CART) peptide precursors in goldfish: molecular cloning and distribution, modulation of expression by nutritional status, and interactions with leptin. Endocrinology. 2001;142(12):5076–88.View ArticlePubMedGoogle Scholar
39. Dun NJ, Dun SL, Wong PY, Yang J, Chang J. Cocaine-and amphetamine-regulated transcript peptide in the rat epididymis: an immunohistochemical and electrophysiological study. Biol Reprod. 2000;63(5):1518–24.View ArticlePubMedGoogle Scholar
40. Abdel-Ghani MA, El-Sherry TM, Abdelhafeez HH. Effect of growth differentiation factor-9 (GDF-9) on the progression of buffalo follicles in vitrified-warmed ovarian tissues. Reprod Domest Anim. 2016;51(5):795–803.View ArticlePubMedGoogle Scholar
41. Juengel JL, Hudson NL, Berg M, Hamel K, Smith P, Lawrence SB, Whiting L, McNatty KP. Effects of active immunization against growth differentiation factor 9 and/or bone morphogenetic protein 15 on ovarian function in cattle. Reproduction. 2009;138(1):107–14.View ArticlePubMedGoogle Scholar
Copyright
© The Author(s) 2018
Advertisement | {
"url": "https://biolres.biomedcentral.com/articles/10.1186/s40659-018-0154-y",
"source_domain": "biolres.biomedcentral.com",
"snapshot_id": "crawl=CC-MAIN-2018-13",
"warc_metadata": {
"Content-Length": "201457",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:CO2EYOMF4NDEXUPXFIUS4QN3EKHG5PXM",
"WARC-Concurrent-To": "<urn:uuid:62ef6a46-1c82-41c9-8dbe-bb8689898763>",
"WARC-Date": "2018-03-18T02:15:49",
"WARC-IP-Address": "151.101.200.95",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:YYAN5FYWX6DJBQEDPKZPPQSQ4XSIDCDV",
"WARC-Record-ID": "<urn:uuid:ca02b92a-ebed-4cae-85fd-a9ba4bf4f21a>",
"WARC-Target-URI": "https://biolres.biomedcentral.com/articles/10.1186/s40659-018-0154-y",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:8dc97e8c-8a02-445f-a037-18f25eb63458>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-228-204-149.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2018-13\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for March 2018\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
16,
17,
31,
32,
52,
53,
65,
66,
220,
221,
238,
256,
276,
295,
312,
335,
362,
390,
391,
433,
434,
456,
457,
484,
485,
513,
514,
523,
524,
535,
536,
1462,
1463,
1471,
1472,
1993,
1994,
2002,
2003,
2926,
2927,
2939,
2940,
3331,
3332,
3341,
3342,
3385,
3386,
3397,
3398,
3835,
3836,
4202,
4203,
4975,
4976,
6200,
6201,
6209,
6210,
6222,
6223,
6402,
6403,
6444,
6445,
7129,
7130,
7163,
7164,
7858,
7859,
7896,
7897,
8843,
8851,
8852,
8888,
8889,
8901,
8902,
8921,
8922,
8930,
8931,
8941,
8942,
8949,
8950,
8971,
8972,
8977,
8978,
8982,
8983,
8990,
8991,
9012,
9013,
9018,
9019,
9029,
9030,
9051,
9052,
9057,
9058,
9061,
9062,
9072,
9073,
9094,
9095,
9100,
9101,
9138,
9139,
9180,
9181,
9973,
9974,
10008,
10009,
10612,
10613,
10682,
10683,
11276,
11277,
11439,
11440,
11461,
11462,
11880,
11881,
11889,
11890,
11953,
11954,
12303,
12304,
12554,
12555,
12620,
12621,
12810,
12817,
12818,
13134,
13135,
13219,
13220,
13453,
13460,
13461,
13759,
13760,
13800,
13801,
14242,
14249,
14250,
14670,
14671,
14795,
14796,
15474,
15481,
15482,
15905,
15906,
16254,
16261,
16262,
16441,
16442,
16453,
16454,
17496,
17497,
18129,
18130,
18795,
18796,
19539,
19540,
19980,
19981,
20906,
20907,
20918,
20919,
21230,
21231,
21244,
21245,
21268,
21269,
21533,
21534,
21555,
21556,
22200,
22201,
22218,
22219,
22405,
22406,
22426,
22427,
22621,
22622,
22657,
22658,
22744,
22745,
22769,
22770,
22853,
22854,
22897,
22898,
23163,
23164,
23172,
23173,
23841,
23842,
23859,
23860,
23979,
23980,
24566,
24567,
24589,
24590,
24594,
24664,
24668,
24720,
24724,
24811,
24815,
24902,
24903,
24914,
24915,
25044,
25235,
25392,
25571,
25697,
25865,
26052,
26187,
26319,
26536,
26783,
27092,
27300,
27532,
27768,
28034,
28326,
28560,
28750,
29194,
29415,
29680,
29963,
30391,
30745,
31083,
31487,
31660,
31956,
32151,
32350,
32488,
32785,
33066,
33314,
33637,
33852,
34180,
34424,
34675,
34971,
34972,
34982,
34983,
35004,
35005
],
"line_end_idx": [
16,
17,
31,
32,
52,
53,
65,
66,
220,
221,
238,
256,
276,
295,
312,
335,
362,
390,
391,
433,
434,
456,
457,
484,
485,
513,
514,
523,
524,
535,
536,
1462,
1463,
1471,
1472,
1993,
1994,
2002,
2003,
2926,
2927,
2939,
2940,
3331,
3332,
3341,
3342,
3385,
3386,
3397,
3398,
3835,
3836,
4202,
4203,
4975,
4976,
6200,
6201,
6209,
6210,
6222,
6223,
6402,
6403,
6444,
6445,
7129,
7130,
7163,
7164,
7858,
7859,
7896,
7897,
8843,
8851,
8852,
8888,
8889,
8901,
8902,
8921,
8922,
8930,
8931,
8941,
8942,
8949,
8950,
8971,
8972,
8977,
8978,
8982,
8983,
8990,
8991,
9012,
9013,
9018,
9019,
9029,
9030,
9051,
9052,
9057,
9058,
9061,
9062,
9072,
9073,
9094,
9095,
9100,
9101,
9138,
9139,
9180,
9181,
9973,
9974,
10008,
10009,
10612,
10613,
10682,
10683,
11276,
11277,
11439,
11440,
11461,
11462,
11880,
11881,
11889,
11890,
11953,
11954,
12303,
12304,
12554,
12555,
12620,
12621,
12810,
12817,
12818,
13134,
13135,
13219,
13220,
13453,
13460,
13461,
13759,
13760,
13800,
13801,
14242,
14249,
14250,
14670,
14671,
14795,
14796,
15474,
15481,
15482,
15905,
15906,
16254,
16261,
16262,
16441,
16442,
16453,
16454,
17496,
17497,
18129,
18130,
18795,
18796,
19539,
19540,
19980,
19981,
20906,
20907,
20918,
20919,
21230,
21231,
21244,
21245,
21268,
21269,
21533,
21534,
21555,
21556,
22200,
22201,
22218,
22219,
22405,
22406,
22426,
22427,
22621,
22622,
22657,
22658,
22744,
22745,
22769,
22770,
22853,
22854,
22897,
22898,
23163,
23164,
23172,
23173,
23841,
23842,
23859,
23860,
23979,
23980,
24566,
24567,
24589,
24590,
24594,
24664,
24668,
24720,
24724,
24811,
24815,
24902,
24903,
24914,
24915,
25044,
25235,
25392,
25571,
25697,
25865,
26052,
26187,
26319,
26536,
26783,
27092,
27300,
27532,
27768,
28034,
28326,
28560,
28750,
29194,
29415,
29680,
29963,
30391,
30745,
31083,
31487,
31660,
31956,
32151,
32350,
32488,
32785,
33066,
33314,
33637,
33852,
34180,
34424,
34675,
34971,
34972,
34982,
34983,
35004,
35005,
35018
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 35018,
"ccnet_original_nlines": 294,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2210988998413086,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.07472527027130127,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.27824175357818604,
"rps_doc_frac_unique_words": 0.30357494950294495,
"rps_doc_mean_word_length": 5.597076892852783,
"rps_doc_num_sentences": 414,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 6.252994060516357,
"rps_doc_word_count": 5063,
"rps_doc_frac_chars_dupe_10grams": 0.07625803351402283,
"rps_doc_frac_chars_dupe_5grams": 0.17164231836795807,
"rps_doc_frac_chars_dupe_6grams": 0.14041216671466827,
"rps_doc_frac_chars_dupe_7grams": 0.12163878977298737,
"rps_doc_frac_chars_dupe_8grams": 0.10893499851226807,
"rps_doc_frac_chars_dupe_9grams": 0.09397275745868683,
"rps_doc_frac_chars_top_2gram": 0.021243559196591377,
"rps_doc_frac_chars_top_3gram": 0.008398620411753654,
"rps_doc_frac_chars_top_4gram": 0.008927940391004086,
"rps_doc_books_importance": -3289.46728515625,
"rps_doc_books_importance_length_correction": -3289.46728515625,
"rps_doc_openwebtext_importance": -1872.0540771484375,
"rps_doc_openwebtext_importance_length_correction": -1872.0540771484375,
"rps_doc_wikipedia_importance": -1222.715087890625,
"rps_doc_wikipedia_importance_length_correction": -1222.715087890625
},
"fasttext": {
"dclm": 0.024006960913538933,
"english": 0.8718887567520142,
"fineweb_edu_approx": 2.259511709213257,
"eai_general_math": 0.1522504687309265,
"eai_open_web_math": 0.31630587577819824,
"eai_web_code": 0.00484221987426281
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "612.62",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
},
"secondary": {
"code": "612.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
3,537,300,277,890,897,400 | Bell, Sir Charles
(redirected from Bell paralysis)
Also found in: Encyclopedia.
Bell, Sir Charles
(bel)
Scottish physiologist and surgeon, 1774–1842.
Bell law
, Bell-Magendie law
The fact that anterior spinal nerve roots contain only motor fibers and posterior roots only sensory fibers.
Synonym: law of Magendie
Bell nerve
Long thoracic nerve; nervus thoracicus longus.
Enlarge picture
BELL PALSY: Asymmetrical smile in patient with Bell Palsy
Bell palsy
Paralysis of the facial nerve. Bell palsy is usually caused by a reactivation of herpes simplex virus although other infections (such as syphilis or Lyme disease) are sometimes implicated. Complications may include corneal drying and ulceration and mild dysarthria. Either side of the face may be affected. Attacks recur in about 10% of cases. Synonym: Bell paralysisfacial palsy; facial nerve palsy; facial nerve paralysis; facial paralysis
Symptoms
Paralysis of the facial nerve typically results in an asymmetrical facial appearance. The affected patient is unable to raise one side of the mouth to smile or to wrinkle or raise the eyebrow on the same side. This peripheral nerve dysfunction is distinguished from strokes that alter facial movement by the involvement of both the forehead and the mouth. Paralysis of the face caused by strokes usually only limits movement of the oral muscles. See: illustration
Treatment
Tapering doses of prednisone without antiviral drugs provide the most effective results. In addition, the affected eye should be protected from drying with artificial tears or unmedicated ointments. Some practitioners advise wearing sunglasses during the palsy or patching the eye to protect it from foreign bodies or drying.
Prognosis
Partial facial paralysis is usually resolved within several months. The likelihood of complete recovery after total paralysis varies from 20% to 90%.
Bell paralysis
Bell palsy.
Bell phenomenon
Rolling of the eyeball upward and outward when an attempt is made to close the eye on the side of the face affected in peripheral facial paralysis.
Bell,
Sir Charles, Scottish surgeon, anatomist, and physiologist, 1774-1842.
Bell law - the ventral spinal roots are motor, the dorsal are sensory. Synonym(s): Bell-Magendie law; Magendie law
Bell-Magendie law - Synonym(s): Bell law
Bell palsy - paresis or paralysis, usually unilateral, of the facial muscles, caused by dysfunction of the 7th cranial nerve. Synonym(s): peripheral facial paralysis
Bell phenomenon - upward movement of the eye on attempted eyelid closure in a patient with peripheral facial paralysis.
Bell respiratory nerve - Synonym(s): long thoracic nerve
Bell spasm - involuntary twitching of the facial muscles. Synonym(s): facial tic
external respiratory nerve of Bell - Synonym(s): long thoracic nerve | {
"url": "https://medical-dictionary.thefreedictionary.com/Bell+paralysis",
"source_domain": "medical-dictionary.thefreedictionary.com",
"snapshot_id": "crawl=CC-MAIN-2018-34",
"warc_metadata": {
"Content-Length": "44204",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JRJWUDBHHTOQVCLN54JZNCSLSRAJDP7M",
"WARC-Concurrent-To": "<urn:uuid:4bde617f-4412-4f5b-bd82-0407d3ccaa6c>",
"WARC-Date": "2018-08-16T03:13:45",
"WARC-IP-Address": "45.34.10.165",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:GDHXOGWHGGFPFK7EK6SAKIACJACOEXWF",
"WARC-Record-ID": "<urn:uuid:ce6ced6a-7b8c-40be-9090-258c127776cd>",
"WARC-Target-URI": "https://medical-dictionary.thefreedictionary.com/Bell+paralysis",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:247f4ce0-6b9c-4593-ab89-20bc4986a8b3>"
},
"warc_info": "isPartOf: CC-MAIN-2018-34\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2018\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-199-169.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 0.11-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
18,
19,
52,
81,
82,
100,
101,
107,
153,
154,
163,
164,
184,
293,
318,
319,
330,
331,
378,
394,
452,
453,
464,
465,
907,
908,
917,
918,
1382,
1383,
1393,
1394,
1720,
1721,
1731,
1732,
1882,
1883,
1898,
1899,
1911,
1912,
1928,
1929,
2077,
2078,
2084,
2085,
2156,
2271,
2312,
2478,
2598,
2655,
2736
],
"line_end_idx": [
18,
19,
52,
81,
82,
100,
101,
107,
153,
154,
163,
164,
184,
293,
318,
319,
330,
331,
378,
394,
452,
453,
464,
465,
907,
908,
917,
918,
1382,
1383,
1393,
1394,
1720,
1721,
1731,
1732,
1882,
1883,
1898,
1899,
1911,
1912,
1928,
1929,
2077,
2078,
2084,
2085,
2156,
2271,
2312,
2478,
2598,
2655,
2736,
2804
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2804,
"ccnet_original_nlines": 55,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2673267424106598,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.003960399888455868,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.17425742745399475,
"rps_doc_frac_unique_words": 0.4503631889820099,
"rps_doc_mean_word_length": 5.510895729064941,
"rps_doc_num_sentences": 26,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.689398765563965,
"rps_doc_word_count": 413,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.02196837030351162,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.026362039148807526,
"rps_doc_frac_chars_top_3gram": 0.0193321593105793,
"rps_doc_frac_chars_top_4gram": 0.0382249616086483,
"rps_doc_books_importance": -202.8196258544922,
"rps_doc_books_importance_length_correction": -202.8196258544922,
"rps_doc_openwebtext_importance": -127.70075225830078,
"rps_doc_openwebtext_importance_length_correction": -127.70075225830078,
"rps_doc_wikipedia_importance": -113.04327392578125,
"rps_doc_wikipedia_importance_length_correction": -113.04327392578125
},
"fasttext": {
"dclm": 0.30011963844299316,
"english": 0.8839547038078308,
"fineweb_edu_approx": 3.069175958633423,
"eai_general_math": 0.013483519665896893,
"eai_open_web_math": 0.20001333951950073,
"eai_web_code": 0.0011898300144821405
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.82",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-290,210,546,107,846,700 | Skip to main content
Advertisement
The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity
Abstract
Background
Phosphatidylserine receptor is a key molecule that mediates the phagocytosis of apoptotic cells. Milk fat globule-EGF factor 8 (MFG-E8) is a phosphatidylserine receptor that is expressed on various macrophage lineage cells, including microglia in the central nervous system (CNS). Targeted clearance of degenerated neurons by microglia is essential to maintain healthy neural networks. We previously showed that the CX3C chemokine fractalkine is secreted from degenerated neurons and accelerates microglial clearance of neuronal debris via inducing the release of MFG-E8. However, the mechanisms by which microglia produce MFG-E8 and the precise functions of MFG-E8 are unknown.
Methods
The release of MFG-E8 from microglia treated with conditioned medium from neurons exposed to neurotoxic substances, glutamate or oligomeric amyloid β (oAβ) was measured by ELISA. The neuroprotective effects of MFG-E8 and MFG-E8 − induced microglial phagocytosis of oAβ were assessed by immunocytochemistry. The effects of MFG-E8 on the production of the anti-oxidative enzyme hemeoxygenase-1 (HO-1) were determined by ELISA and immunocytochemisty.
Results
MFG-E8 was induced in microglia treated with conditioned medium from neurons that had been exposed to neurotoxicants, glutamate or oAβ. MFG-E8 significantly attenuated oAβ-induced neuronal cell death in a primary neuron − microglia coculture system. Microglial phagocytosis of oAβ was accelerated by MFG-E8 treatment due to increased CD47 expression in the absence of neurotoxic molecule production, such as tumor necrosis factor-α, nitric oxide, and glutamate. MFG-E8 − treated microglia induced nuclear factor E(2) − related factor 2 (Nrf2) − mediated HO-1 production, which also contributed to neuroprotection.
Conclusions
These results suggest that microglia release MFG-E8 in response to signals from degenerated neurons and that MFG-E8 protects oAβ-induced neuronal cell death by promoting microglial phagocytic activity and activating the Nrf2-HO-1 pathway. Thus, MFG-E8 may have novel roles as a neuroprotectant in neurodegenerative conditions.
Background
Milk fat globule-EGF factor 8 (MFG-E8, lactadherin homolog in humans) is a phosphatidylserine (PS) receptor that acts as a cellular bridge between apoptotic cells and phagocytic cells and triggers the engulfment of cellular debris [1, 2]. Recently, we showed that MFG-E8 is expressed in microglia and secreted in response to factors released from degenerated neurons, such as the CX3C chemokine fractalkine (FKN) [3]. FKN-induced MFG-E8 enhances microglial clearance of damaged neuronal debris. MFG-E8 has been shown to improve the pathogenesis of Alzheimer’s disease (AD) by eliminating amyloid β (Aβ) plaques [4]. In addition to microglia, MFG-E8 is also expressed in astrocytes, oligodendrocytes, and neurons [5], although it is uncertain what cell type predominantly produces MFG-E8. MFG-E8 is also implicated in the pathogenesis of immune-related diseases in the periphery. MFG-E8 expression was reduced in lesions associated with murine experimental colitis, and MFG-E8 treatment markedly ameliorated disease progression [6]. This suggests that MFG-E8 acts as a suppressor of the peripheral immune system and that MFG-E8 may be a therapeutic target for immune-mediated bowel diseases [7, 8].
Microglia are resident immune cells in the central nervous system (CNS). In neurodegenerative diseases, such as AD and Parkinson’s disease, microglia accumulate in lesions where they are thought to have both neurotoxic and neuroprotective functions [9]. In addition to producing various neuroprotective factors, microglia also phagocytose and remove injured neuronal debris or foreign antigens and this process is critically involved in maintaining healthy neuronal networks. However, the phagocytic activity of microglia is not only beneficial to neurons, but also exerts adverse effects by producing pro-inflammatory factors [10]. In the case of microglial Aβ clearance, various cellular surface receptors are involved in recognizing and appropriately eliminating accumulated Aβ plaques. These include CD14, CD36, CD47, CD200R, PS receptors, Toll-like receptors (TLRs), and receptors for advanced glycation end products (RAGE) [11, 12]. Lipopolysaccharide (LPS) activates microglia and increases phagocytosis through the LPS receptor CD14, which may be involved in AD pathology [13, 14]. Recent reports indicated that fibrillar Aβ increases CD36 and CD47 expression in microglia [15], and CD36 is required for microglial phagocytosis of Aβ1-42 [16]. CD47 is a key molecule in CNS inflammation that reduces macrophage activation and induces monocyte migration [17]. Intact myelin expresses CD47, which suppresses microglial phagocytosis of myelin [18]. Thus, CD47 seems to act as a “self” marker and inhibits excessive phagocytosis under normal conditions. On the other hand, Aβ phagocytosis correlates with CD47 expression [19], which also suggests that CD47 plays a crucial role in target clearance during pathological conditions.
Aβ-induced oxidative stress is caused by reactive oxygen species (ROS) produced from microglia and astrocytes, and exacerbates the pathological conditions of AD [20, 21]. Induction of the nuclear factor E(2) − related factor 2 (Nrf2) signaling pathway could induce neuroprotection against some Aβ-related oxidative stressors.
In the present study, we show that MFG-E8 is released from microglia in response to various soluble factors (for example, FKN) released from degenerated neurons. MFG-E8 increases microglial neuroprotective activity against oAβ-induced neuronal cell death. This neuroprotection is mediated through enhanced microglial phagocytic activity via the CD47 pathway and activation of the Nrf2-HO-1 pathway.
Materials and methods
Reagents
L-glutamate and LPS were purchased from Sigma (St. Louis, MO, USA). MFG-E8 was obtained from R&D Systems (Minneapolis, MN, USA). Tin (IV)-mesoporphyrin IX dichloride (SnMP), a specific inhibitor of HO-1, was obtained from Frontier Scientific (Logan, UT, USA), and was dissolved in an arginine-containing solution as previously described [22, 23].
Preparation of oligomeric amyloid β (oAβ) solutions
Aβ1-42 solution was prepared as previously described [24]. Briefly, synthetic human Aβ1-42 (Peptide institute, Osaka, Japan) was dissolved to 1 mM in 100% 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). HFIP was dried using a vacuum desiccator and resuspended to a concentration of 5 mM in DMSO. To form oligomers, amyloid peptide was diluted to a final concentration of 100 μM with Ham’s F-12, incubated at 4°C for 24 h, and then immediately added to cultures at a final concentration of 5 μM. Formation of oAβ was confirmed using western blot analysis as previously described [24].
Cell culture
All animal protocols were approved by the Animal Experiment Committee of Nagoya University. Primary neuronal cultures were prepared from the cortices of C57BL/6 mouse embryos at embryonic Day 17 (E17) as previously described [25]. Briefly, cortical fragments were dissociated into single cells in dissociation solution (Sumitomo Bakelite, Akita, Japan), and resuspended in neuron culture medium (Sumitomo Bakelite). Neurons were seeded onto 12-mm polyethyleneimine-coated glass coverslips (Asahi Techno Glass Corp., Chiba, Japan) at a density of 5.0 × 104 cells/well in 24-well plates and incubated at 37°C in a humidified atmosphere containing 5% CO2. The purity of the cultures was more than 95% as determined by NeuN-specific immunostaining.
Microglia were isolated from primary mixed glial cell cultures prepared from newborn C57BL/6 mice at Day in vitro (DIV) 14 using the “shaking off” method, as previously described [26]. The purity of the cultures was 97 to 100% as determined by immunostaining for the Fc receptor. Cultures were maintained in Dulbecco’s modified Eagle medium supplemented with 10% fetal calf serum, 5 μg/mL bovine insulin and 0.2% glucose. Microglia were seeded at a density of 7.0 × 104 or 1.0 × 105 cells/well in 96- or 48-well plates, respectively.
Neuron–microglia co-cultures were prepared by adding 1.0 × 105 microglia in 100 μL neuronal medium to neuronal cultures (5.0 × 104 neuronal cells) on DIV 14 in 24-well plates. The cultures were maintained in neuron culture medium.
Measurement of MFG-E8 levels
MFG-E8 secreted from mouse primary microglia or cortical neurons was measured using an ELISA (R&D Systems, Minneapolis, MN, USA) according to the manufacturer’s instructions. Neurons and microglia were treated with oAβ (5 μM) or L-glutamate (20 μM) for 24 h at 37°C. In addition, neuronal conditioned medium (Neu CM) was prepared as follows: 5.0 × 104 neuronal cells in neuronal medium were treated with oAβ (5 μM) or L-glutamate (20 μM) for 24 h, and the supernatant was collected. A total of 1.0 × 105 microglia were treated with Neu CM for 24 h, and then MFG-E8 in the supernatant was measured.
RT-PCR
Total RNA was extracted from microglia and neurons using an RNeasy Mini Kit (Qiagen, Tokyo, Japan). A first-strand cDNA library was obtained using SuperScript II (Invitrogen, Carlsbad, CA, USA) and oligo (dT)12–18 (Invitrogen) as the first-strand primer. Negative control reactions were performed using the same system after heat denaturing the reverse transcriptase. Transcripts encoding mouse CD36, CD47, and glyceraldehydes-3-phosphate dehydrogenase (GAPDH) were amplified by RT-PCR using 0.1 μg of first-strand cDNA, Blend Taq polymerase (Toyobo Co., Osaka, Japan), and oligonucleotide primers (Table 1).
Table 1 Oligonucleotide primers of CD14, CD36, CD47 and GAPDH
Immunocytochemistry
Cells were fixed with 4% paraformaldehyde for 15 minutes at room temperature, blocked with 5% serum, and permeabilized with 0.05% Triton X-100. Neurons were stained with mouse polyclonal anti-MAP-2 antibodies (1:1,000; Chemicon, Temecula, CA, USA) and Alexa 488 − conjugated secondary antibodies (1:1,000; Invitrogen). Microglia were stained with Cy5-conjugated rat anti-mouse CD11b monoclonal antibodies (1:300; BD Biosciences, Franklin Lakes, NJ, USA) prior to fixation. Images were analyzed using a deconvolution fluorescence microscope system (BZ-8000; Keyence Corporation, Osaka, Japan).
Surviving neurons were identified based on their cytoskeletons as previously described [25]. Viable neurons stained strongly with an anti-MAP-2 antibody, whereas damaged neurons showed weaker staining. MAP-2 − positive neurons were counted in representative areas in each well. In five independent experiments, more than 200 neurons were evaluated in each well by a scorer who was blind to the experimental conditions. The number of viable neurons in untreated cultures was set to 100%.
Evaluation of microglial phagocytosis of oAβ
Microglia were seeded at a density of 6.0 × 104 cells/well in a poly-L-lysine − coated eight-well chamber plate. Cells were pre-treated with MFG-E8 (1 to 100 ng/mL) for 1 h, and then oAβ (5 μM) was added to the culture for 6 h. The cells were subsequently fixed in 4% paraformaldehyde. Microglia were stained with a rabbit polyclonal anti-Rab7 antibody (1:200; Cell Signaling Technology, Danvers, MA, USA) and Alexa 568 − conjugated secondary antibody (1:1,000; Invitrogen). oAβ was stained with a mouse polyclonal anti-4 G8 antibody (1:1000; Chemicon,) and Alexa 488 − conjugated secondary antibody (1:1,000; Invitrogen). Immunostained images were observed under confocal laser scanning microscope (LSM 710; ZEISS, Jena, Germany).
Fluorescence-activated cell sorting (FACS) analysis of cell surface antigen expression
Microglia were seeded at a density of 1.0 × 106 cells/dish in a 6-cm dish. Cells were treated with 100 ng/mL MFG-E8 for 72 h, and then immunostaining was performed using standard procedures. The primary antibodies included anti-CD36 (1:200; BD Biosciences) and anti-CD47 (1:200; BD Biosciences) and the secondary antibodies were conjugated to FITC (1:1,000; BD Biosciences).
Measurement of HO-1, tumor necrosis factor-α (TNF-α), nitric oxide (NO), and glutamate
Microglia were treated with LPS or MFG-E8 (1 to 100 ng/mL) and oAβ for 48 h. The supernatants were assessed using a TNF-α ELISA (BD Pharmingen, Franklin Lakes, NJ, USA). Cells were lysed in extraction buffer (1% NP-40 in PBS) and assayed for HO-1 with an ELISA (Takara Bio, Mie, Japan). The NO levels were determined using the Griess reaction as previously reported [27]. To measure glutamate levels, a colorimetric assay kit (Yamasa Corporation, Tokyo, Japan) was used as previously described [28].
Statistical analysis
Statistically significant differences between the experimental groups were determined by one-way ANOVA followed by Dunnett’s or Tukey’s tests for multiple comparisons. Statistical analyses were performed using Prism 4 for Windows (GraphPad Software, San Diego, CA, USA). P-values less than 0.05 were considered significant.
Results
Microglia secrete MFG-E8 in response to factors released from degenerated neurons
We first examined whether microglia produce MFG-E8 in response to soluble factors released from degenerated neurons. The direct glutamate or oAβ treatment did not induce MFG-E8 secretion from either microglia or neurons. The MFG-E8 levels in the culture medium for neurons or microglia were negligible (Figure 1A). However, the levels of MFG-E8 secreted from microglia significantly increased when the cells were treated with conditioned medium from neurons that had been exposed to glutamate or oAβ (Figure 1A). The Western blot analysis for oAβ used in the experiments was shown in Figure 1B. Neurons released significant amounts of soluble fractalkine (sFKN) when exposed to oAβ as well as glutamate (Figure 1C). In a previous study, we showed that sFKN is secreted from glutamate-damaged neurons and induces MFG-E8 expression in microglia [3], suggesting that sFKN may play a role as a mediator to induce MFG-E8 release from microglia.
Figure 1
figure1
Induction of MFG-E8 by soluble factors released from degenerated neurons. (A) The levels of MFG-E8 secreted from microglia (Mi) and cortical neurons (Neu) treated with 20 μM glutamate (Glu) or 5 μM oligomeric amyloid β (oAβ) were measured by ELISA. In addition, MFG-E8 released from microglia exposed to neuronal conditioned medium (Neu CM) that had been treated with Glu or oAβ was also measured. Results are presented as the means with S.E.M. (n = 3). Glu- or oAβ-treated neuronal conditioned medium significantly induced MFG-E8 expression from microglia compared with the untreated control samples. ***: P <0.001 (one-way ANOVA with Dunnett’s post-hoc test). (B) The Western blot data of oAβ used in the present study. The blot was incubated in mouse anti-Aβ monoclonal antibody (6E10) (1:1,000, Chemicon). (C) The levels of the soluble secreted form of fractalkine (sFKN) released from cortical neurons treated with 20 μM glutamate (Glu) or 5 μM oligomeric amyloid β (oAβ) were measured. The results are presented as the means with S.E.M. (n = 3). Glu and oAβ treatment significantly induced sFKN release from neurons compared to the untreated control samples. **: P <0.01 (one-way ANOVA with Dunnett’s post-hoc test).
MFG-E8 directly induces microglial neuroprotective effects
We then examined the direct effects of MFG-E8 on neuronal survival. There has been little evidence indicating that MFG-E8 exerts neuroprotective effects, aside from our previous report in which neutralizing MFG-E8 markedly attenuated sFKN-induced neuroprotection [3]. Therefore, we first determined whether MFG-E8 has direct neuroprotective effects against oAβ toxicity in neuron–microglia cocultures (Figure 2Aa − e) or in neuronal cultures (Figure 2Ba − c). Treating neurons with 5 μM oAβ for 24 h induced obvious cell death in both neuron − microglia cocultures (Figure 2Ab, C) and neuron cultures (Figure 2Bb, C). MFG-E8 significantly inhibited oAβ-induced cell death in a dose-dependent manner in neuron − microglia cocultures (Figure 2Ac − e, C), but not in neuron cultures (Figure 2Bc, C).
Figure 2
figure2
MFG-E8 exerts neuroprotective effects in the presence of microglia. The effect of MFG-E8 treatment against oAβ toxicity in both neuron − microglia co-cultures (A) and neuronal cultures (B). Neurons were stained with an anti-MAP-2 antibody (green), microglia were stained with a Cy5-conjugated anti-CD11b antibody (blue), and oAβ was stained with an anti-4 G8 antibody (red). Scale bar = 50 μm. Untreated neuronal cultures and neuron − microglia cocultures (1:2 neurons to microglia) (cont; a). Five micromolar of oAβ induced neuronal loss in both neuronal and neuron–microglia cocultures (b). In the presence of microglia, MFG-E8 treatment induced neuroprotective effects in a dose-dependent manner (doses were 1 ng/mL (c), 10 ng/mL (d), 100 ng/mL (e) in (A)). On the other hand, MFG-E8 did not show any effects on oAβ-induced neurotoxicity, even at the highest dose (100 ng/mL; c in (B)). (C) Neuronal survival was estimated as the percentage of intact neurons in the treated sample relative to the untreated sample. The results are presented as the means with S.E.M. (n = 3), in which 10 randomly selected fields were analyzed. Significant differences compared to samples only treated with oAβ are noted. *: P <0.05, ***: P <0.001, (one-way ANOVA with Dunnett’s post-hoc test).
MFG-E8 increases phagocytosis of oAβ through a CD47-mediated signaling pathway in microglia
To explore the detailed mechanisms by which MFG-E8 exerts neuroprotection in the presence of microglia, we investigated whether MFG-E8 increased microglial phagocytosis of Aβ under confocal laser scanning microscope. Non-treated microglia minimally engulfed Aβ, as determined by the co-localization of the phagosome maturation marker Rab-7 and Aβ (Figure 3Aa). However, MFG-E8 increased microglial phagocytosis of Aβ in a dose-dependent manner (Figure 3Ab − d). The ratio of phagocytic to total cells is shown graphically (Figure 3B) and treating with 10 ng/mL and 100 ng/mL MFG-E8 significantly increased this ratio. The neurotoxic molecules, such as TNF-α, NO, and glutamate, were not induced by MFG-E8- induced microglial phagocytosis of Aβ (Figure 3C-E).
Figure 3
figure3
MFG-E8 induces microglial phagocytosis of oAβ. (A) Microglia were pre-treated with 1 ng/mL (b), 10 ng/mL (c) or 100 ng/mL (d) MFG-E8 for 1 h, and then 5 μM oAβ was added to the culture for 6 h. Primary antibodies recognizing Rab7 (green), oAβ (red) and nuclei (blue) were used (a − d). A few oAβ-incorporated microglia were detected in the absence of MFG-E8 (a), while a sufficient number of microglia that had engulfed oAβ were detected in the presence of the higher MFG-E8 dose (d) under confocal laser scanning microscope. Scale bar = 50 μm. (B) Quantification of the phagocytosis index, which is defined as the percentage of total microglial-Rab7 staining (green) that overlaps with oAβ staining (red). The results are presented as the means with S.E.M. (n = 3), in which 10 randomly selected fields were analyzed. Significant differences compared with samples that were only treated with oAβ (oAβ) are noted. *: P <0.05 (one-way ANOVA with Dunnett’s post-hoc test). The measurement of TNF-α (C), nitrite (D), and glutamate (E) produced by microglia treated with MFG-E8 plus oAβ was performed. After 24 h treatment with 1 ng/mL, 10 ng/mL or 100 ng/mL MFG-E8 with 5 μM oAβ, the supernatants of microglial cultures were analyzed. 100 ng/mL LPS treatment for 24 h was used as a positive control. The results are presented as the means with S.E.M. (n = 5). Significant differences compared to untreated microglia (NT) are noted. ***: P <0.001, (one-way ANOVA with Dunnett’s post-hoc test). (F) mRNA expression levels of oAβ phagocytosis-related cellular membrane surface antigens, CD36 and CD47, in microglia treated with 100 ng/mL MFG-E8 for 24 h was assessed using RT-PCR. GAPDH expression was used as a control. (D) CD36 and CD47 protein levels were assessed by FACS analysis. Microglia were treated with 100 ng/mL MFG-E8 for 72 h. The gray-filled curve represents the isotype-matched control. The black and blue lines indicate untreated (NT) and MFG-E8-treated samples, respectively.
We next examined the effects of MFG-E8 on the expression of principal phagocytosis-related surface receptors in microglia. The expression of the classical microglial phagocytosis receptors CD14 and TLR4, which are LPS receptors, was unchanged with MFG-E8 treatment, and TLR6 and TLR9 expression was also unchanged (data not shown). In AD brains, microglia reportedly interact with amyloid plaque by forming functional receptors including α6β1 integrin, CD36 and CD47, which act concertedly to engulf Aβ [19, 29]. Thus, we next examined the effect of MFG-E8 on CD36 and CD47 expression in microglia. Treating microglia with 100 ng/mL of MFG-E8 markedly induced CD47 mRNA expression but not CD36 expression (Figure 3F). FACS analysis for CD36 and CD47 protein levels yielded similar results; treating microglia with MFG-E8 for 72 h increased microglial CD47 expression, but not CD36 expression (Figure 3G).
Then, we examined the involvement of these cellular surface antigens in Aβ phagocytosis. MFG-E8 (100 ng/mL) increased phagocytosis almost two-fold relative to the unstimulated control (Figure 4Ab, B). Although blocking CD36 with a specific antibody did not have an effect (Figure 4Ac, B), blocking CD47 with a specific antibody completely suppressed MFG-E8 − induced phagocytosis (Figure 4Ad, B). High concentrations of 4N1K, a CD47 blocking peptide [30], similarly inhibited phagocytosis (Figure 4Ae f, B). These data suggest that Aβ was recognized and phagocytosed by microglia through a CD47-mediated pathway. Moreover, we examined whether blockade of CD47 affects neuronal survival by MFG-E8-treated microglia. We confirmed that blockade of CD47 with anti-CD47 antibody or 4N1K decreased neuronal survival (Figure 4C).
Figure 4
figure4
MFG-E8 enhances microglial phagocytosis of oAβ through CD47. (A) Microglia were treated with 1 μg/mL of isotype-matched control IgG (a, b), 100 ng/mL MFG-E8 (b − f), 1 μg/mL of anti-CD36 neutralizing antibody (c), 1 μg/mL of anti-CD47 neutralizing antibody (d), the peptide antagonist 4N1K 10 μg/mL (e) or 100 μg/mL (f) for 1 h, and then 5 μM oAβ was added to the culture for 24 h. Primary antibodies against Rab7 (green), oAβ (red) and nuclei (blue) were used (a − f). Scale bar = 50 μm. (B) Quantification of the phagocytosis index. Results show the means with S.E.M. (n = 3), in which 10 randomly selected fields were analyzed. Significant differences compared with the isotype-matched control samples (#) or samples treated only with MFG-E8 (*) are noted. ***: P <0.001; ###: P <0.001 (one-way ANOVA with Tukey’s post-hoc test). (C) The effects of blockade of CD36 and CD47 in MFG-E8-treated microglia on neuronal survival. Neuron − microglia co-cultures were pre-treated with MFG-E8 for 1 h in the presence of anti-CD36 neutralizing antibody, anti-CD47 neutralizing antibody, and 10 μg/mL or 100 μg/mL 4N1K. Then, the cultures were treated with oAβ for 24 h. The neuronal survival rate was estimated. The results are presented as the means with S.E.M. (n = 5), in which 10 randomly selected fields were analyzed. Significant differences compared with the isotype-matched control samples (#) or samples treated only with MFG-E8 (*) are noted. *: P <0.05; ###: P <0.001 (one-way ANOVA with Tukey’s post-hoc test).
MFG-E8 induces neuroprotective effects in microglia through the Nrf2-HO-1 pathway
We previously showed that neuroprotection by sFKN is initiated by the nuclear translocation of the transcription factor Nrf2 and subsequent HO-1 production [3]. Thus, we examined whether MFG-E8 induces a change in the subcellular localization of Nrf2. MFG-E8 markedly enhanced the nuclear translocation of Nrf2 in a dose-dependent manner, as determined by immunostaining (Figure 5A). In addition, MFG-E8 also dose-dependently increased HO-1 production (Figure 5B). However, the expression of another Nrf2-induced phase-II enzyme, NAD(P)H quinine oxidoreductase-1 (NQO-1), was not changed by MFG-E8 (data not shown). Finally, we examined the role of HO-1 in MFG-E8 − induced neuroprotection against Aβ toxicity. The neuroprotective effects of MFG-E8 were abolished by treating with 10 μM SnMP, an HO-1 inhibitor, although a lower concentration of SnMP did not exert these effects (Figure 5C). We also examined the expression of neuroprotectants other than HO-1 and NQO-1. MFG-E8 did not affect the mRNA levels of BDNF, GDNF, NGF, TGF-β or IL-10 (data not shown ). Therefore, Nrf2-induced HO-1 production by microglia may contribute to the neuroprotective effects of MFG-E8.
Figure 5
figure5
MFG-E8 exerts neuroprotective effects by activating the Nrf-2-HO-1 pathway in microglia. (A) Immunofluorescence images of Nrf2 (green) and nuclei (Hoechst; blue) in microglia treated with the indicated concentrations of MFG-E8. Scale bar = 10 μm. (B) After microglia were treated with the indicated concentrations of MFG-E8 for 24 h, HO-1 protein expression levels were measured by ELISA. Significant differences compared with untreated samples (*) are noted. ***: P <0.001 (one-way ANOVA with Dunnett’s post-hoc test). (C) Neuron − microglia co-cultures were pre-treated with MFG-E8 for 3 h in the presence of the HO-1 inhibitor SnMP. Then, the cultures were treated with oAβ for 24 h. The neuronal survival rate in the presence of MFG-E8 and SnMP was estimated. The results are presented as the means with S.E.M. (n = 3), in which 10 randomly selected fields were analyzed. Significant differences compared with oAβ plus MFG-E8 treated samples are noted. ***: P <0.001 (one-way ANOVA with Dunnett’s post-hoc test).
Discussion
In this study, we showed for the first time that MFG-E8 has neuroprotective effects against oAβ toxicity by enhancing microglial phagocytic activity and exerting anti-oxidant effects. MFG-E8 was initially described as a mouse mammary epithelial cell surface protein but was more recently identified as a glycoprotein secreted from macrophages in germinal centers of the spleen and lymph nodes [1]. Phagocytosis is thought to be induced by “eat-me” signals, such as the nucleotide GDP and PS. MFG-E8 is a PS receptor and promotes apoptotic cell clearance [31]. In the present study, it is clear that MFG-E8 also plays a role in the engulfment of Aβ by microglia. It has been shown that MFG-E8 enhances phagocytosis of UV-treated apoptotic neurons by microglia [32], and that a MFG-E8/lactadherin deficiency markedly reduces Aβ phagocytosis by macrophages [4]. We also revealed that microglial phagocytosis of Aβ is mediated through CD47 expressed on microglia. Other microglial phagocytosis-related receptors, such as CD14, and components of the senile plaque-interacted receptor, such as CD36, were not affected by MFG-E8. Although both CD14 and CD36 have been associated with MFG-E8 [33] or microglial Aβ phagocytosis [16], they were not induced by MFG-E8 treatment in this study. Blocking CD47 with a neutralizing antibody or the 4N1K peptide significantly reduced Aβ phagocytosis. The CD47 ligand is a signal regulatory protein-α (SIRPα) that is expressed on the cellular membrane of neurons as well as glial cells [17]. SIRPα is also reportedly a negative regulator of the CD47-mediated signaling pathway [17, 18]. We previously showed that MFG-E8 expression is induced by sFKN released from degenerated neurons [3]. sFKN increased HO-1 production via the JNK MAPK-Nrf2 pathway in microglia and exerted neuroprotection against excitotoxicity. In this study, MFG-E8 increased the nuclear translocation of Nrf2 and enhanced HO-1 production in microglia. Since the expression of another Nrf2-induced anti-oxidative enzyme, NQO-1, was not increased by MFG-E8, HO-1 might mediate MFG-E8 − induced neuroprotection against Aβ toxicity. Accordingly, MFG-E8 may be downstream of sFKN in microglia. Aβ-induced oxidative stress is mediated through ROS production by glial cells and also by neurons [20, 21, 3436]. ROS may lead to neuronal degeneration in AD. These results delineate a novel function for MFG-E8 in neuroprotection by microglia.
oAβ is toxic to neuronal cells in the present study. It has been reported that Aβ also enhances microglial activation to produce pro-inflammatory molecules [3740]. oAβ induces microglia to have a pro-inflammatory character [37], and increases microglial TNF-α secretion through a tyrosine kinase dependent pathway [39]. NO-mediated microglial neurotoxicity by oAβ is reported [40]. oAβ disturbs microglial phagocytosis and clearance of fibrillar Aβ [15].
However, oAβ did not induce inflammatory molecules, such as TNF-α, NO and glutamate in microglia in the present and previous studies [24]. The synthetic oAβ used in the present study contains oligomers of different sizes and shapes, so that microglia may respond to this heterogeneous oAβ in various ways. Furthermore, synthetic oAβ is less potent than oAβ isolated from the transfected cell cultures.
Since MFG-E8 is a ligand for αvβ3 and αvβ5 integrins, MFG-E8 presumably interacts with microglia by binding to integrins [1, 41]. MFG-E8 forms a cellular bridge between the integrin on phagocytes and PS on target cells. MFG-E8 induces CD47 expression in microglia. CD47 directly interacts with Aβ to form a complex that induces microglial engulfment [29], after which MFG-E8 increases Aβ clearance via CD47. RAGE is a surface molecule that directly interacts with Aβ and activates NFκB-mediated signaling pathways in microglia [42, 43]. Recent reports showed that RAGE also directly interacts with PS and enhances macrophage phagocytosis [44]. RAGE simultaneously enhances the inflammatory status. On the other hand, MFG-E8 enhances microglial phagocytosis without inducing inflammation.
Our data are schematically summarized in Figure 6. Glutamate and oAβ damage neurons, which then release soluble factors, including FKN, as “help-me” signals. In response to these factors, microglia release MFG-E8. MFG-E8 directly increases Aβ phagocytosis by microglia via CD47 expression and also increases HO-1 expression in microglia via nuclear translocation of the transcription factor Nrf2. Each of these processes contributes to microglial neuroprotection. Therefore, MFG-E8 or agents that increase its expression may be potential therapeutic targets for neurodegenerative diseases, including AD.
Figure 6
figure6
Model of the neuroprotective role of MFG-E8 against Aβ toxicity. MFG-E8 is secreted from microglia in response to soluble factors (for example, FKN) produced by degenerated neurons. MFG-E8 enhances Aβ phagocytosis by microglia through CD47 expression. MFG-E8 also directly increases the nuclear translocation of the transcriptional factor Nrf2, which induces expression of the antioxidant enzyme HO-1. Therefore, MFG-E8 is a potent downstream molecule of sFKN and is an intrinsic neuroprotectant for damaged yet surviving neurons.
Conclusions
Here we show that MFG-E8 is released from microglia in response to soluble factors (for example, FKN) secreted from degenerated neurons. MFG-E8 induces microglial neuroprotective activity against oAβ toxicity. This neuroprotection is mediated through enhanced microglial phagocytic activity via the CD47 pathway and progression of the Nrf2-HO-1 pathway. These data indicate that MFG-E8 may have novel roles as a neuroprotectant that is produced from microglia during neurodegenerative conditions.
Abbreviations
AD:
Alzheimer’s disease
CNS:
Central nervous system
FKN:
Fractalkine
GAPDH:
Glyceraldehydes-3-phosphate dehydrogenase
HO-1:
Hemeoxygenase-1
LPS:
Lipopolysaccharide
MFG-E8:
Milk fat globule-EGF factor 8
NO:
Nitric oxide
NQO-1:
NAD(P)H quinine oxidoreductase-1
Nrf2:
Nuclear factor E(2)-related factor 2
oAβ:
Oligomeric amyloid β
PS:
Phosphatidylserine
RAGE:
Receptor for advanced glycation end products
ROS:
Reactive oxygen species
TLRs:
Toll-like receptors
TNF-α:
Tumor necrosis factor-α.
References
1. 1.
Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S: Identification of a factor that links apoptotic cells to phagocytes. Nature 2002, 417:182–187.
2. 2.
Miyasaka K, Hanayama R, Tanaka M, Nagata S: Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur J Immunol 2004, 34:1414–1422.
3. 3.
Noda M, Doi Y, Liang J, Kawanokuchi J, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A: Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem 2011, 286:2308–2319.
4. 4.
Boddaert J, Kinugawa K, Lambert JC, Boukhtouche F, Zoll J, Merval R, Blanc-Brude O, Mann D, Berr C, Vilar J, Garabedian B, Journiac N, Charue D, Silvestre JS, Duyckaerts C, Amouyel P, Mariani J, Tedgui A, Mallat Z: Evidence of a role for lactadherin in Alzheimer's disease. Am J Pathol 2007, 170:921–929.
5. 5.
Kranich J, Krautler NJ, Falsig J, Ballmer B, Li S, Hutter G, Schwarz P, Moos R, Julius C, Miele G, Aguzzi A: Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner. J Exp Med 2010, 207:2271–2281.
6. 6.
Aziz MM, Ishihara S, Mishima Y, Oshima N, Moriyama I, Yuki T, Kadowaki Y, Rumi MA, Amano Y, Kinoshita Y: MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent αvβ3 integrin signaling. J Immunol 2009, 182:7222–7232.
7. 7.
Bu HF, Zuo XL, Wang X, Ensslin MA, Koti V, Hsueh W, Raymond AS, Shur BD, Tan XD: Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J Clin Invest 2007, 117:3673–3683.
8. 8.
Chogle A, Bu HF, Wang X, Brown JB, Chou PM, Tan XD: Milk fat globule-EGF factor 8 is a critical protein for healing of dextran sodium sulfate-induced acute colitis in mice. Mol Med 2011, 17:502–507.
9. 9.
Farfara D, Lifshitz V, Frenkel D: Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease. J Cell Mol Med 2008, 12:762–780.
10. 10.
Neumann H, Kotter MR, Franklin RJ: Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 2009, 132:288–295.
11. 11.
Alarcón R, Fuenzalida C, Santibáñez M, von Bernhardi R: Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound β-amyloid. J Biol Chem 2005, 280:30406–30415.
12. 12.
Landreth GE, Reed-Geaghan EG: Toll-like receptors in Alzheimer's disease. Curr Top Microbiol Immunol 2009, 336:137–153.
13. 13.
Hirt UA, Leist M: Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells. Cell Death Differ 2003, 10:1156–1164.
14. 14.
Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE: Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu. J Neurosci 2010, 30:15369–15373.
15. 15.
Pan XD, Zhu YG, Lin N, Zhang J, Ye QY, Huang HP, Chen XC: Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease. Mol Neurodegener 2011, 6:45.
16. 16.
Persaud-Sawin DA, Banach L, Harry GJ: Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Aβ42. Glia 2009, 57:320–335.
17. 17.
Koning N, Uitdehaag BM, Huitinga I, Hoek RM: Restoring immune suppression in the multiple sclerosis brain. Prog Neurobiol 2009, 89:359–368.
18. 18.
Gitik M, Liraz-Zaltsman S, Oldenborg PA, Reichert F, Rotshenker S: Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes. J Neuroinflammation 2011, 8:24.
19. 19.
Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE: A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J Neurosci 2003, 23:2665–2674.
20. 20.
McDonald DR, Brunden KR, Landreth GE: Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci 1997, 17:2284–2294.
21. 21.
Johnstone M, Gearing AJ, Miller KM: A central role for astrocytes in the inflammatory response to β-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 1999, 93:182–193.
22. 22.
Yasui Y, Sasao E, Sakata M, Matsui N, Fukuishi N, Akagi R, Akagi M: Upregulation of heme oxygenase-1 by degranulation in rat basophilic leukemia cells. Biol Pharm Bull 2007, 30:443–446.
23. 23.
Li Q, Li J, Zhang L, Wang B, Xiong L: Preconditioning with hyperbaric oxygen induces tolerance against oxidative injury via increased expression of heme oxygenase-1 in primary cultured spinal cord neurons. Life Sci 2007, 80:1087–1093.
24. 24.
Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M, Doi M, Michikawa M, Takeuchi H, Suzumura A: Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid β neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Am J Pathol 2009, 175:2121–2132.
25. 25.
Banno M, Mizuno T, Kato H, Zhang G, Kawanokuchi J, Wang J, Kuno R, Jin S, Takeuchi H, Suzumura A: The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia. Neuropharmacology 2005, 48:283–290.
26. 26.
Suzumura A, Mezitis SG, Gonatas NK, Silberberg DH: MHC antigen expression on bulk isolated macrophage-microglia from newborn mouse brain: induction of Ia antigen expression by γ-interferon. J Neuroimmunol 1987, 15:263–278.
27. 27.
Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, Murad F: Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A 1991, 88:10480–10484.
28. 28.
Takeuchi H, Mizuno T, Zhang G, Wang J, Kawanokuchi J, Kuno R, Suzumura A: Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 2005, 280:10444–10454.
29. 29.
Koenigsknecht J, Landreth G: Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism. J Neurosci 2004, 24:9838–9846.
30. 30.
Chung J, Gao AG, Frazier WA: Thrombspondin acts via integrin-associated protein to activate the platelet integrin αIIbβ3. J Biol Chem 1997, 272:14740–14746.
31. 31.
Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S: Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 2004, 304:1147–1150.
32. 32.
Fuller AD, Van Eldik LJ: MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol 2008, 3:246–256.
33. 33.
Komura H, Miksa M, Wu R, Goyert SM, Wang P: Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway. J Immunol 2009, 182:581–587.
34. 34.
Ray B, Chauhan NB, Lahiri DK: Oxidative insults to neurons and synapse are prevented by aged garlic extract and S-allyl-L-cysteine treatment in the neuronal culture and APP-Tg mouse model. J Neurochem 2011, 117:388–402.
35. 35.
Newington JT, Pitts A, Chien A, Arseneault R, Schubert D, Cumming RC: Amyloid β resistance in nerve cell lines is mediated by the Warburg effect. PLoS One 2011, 6:e19191.
36. 36.
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL: Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 2007, 282:11590–11601.
37. 37.
Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P: Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-β. J Neuroimmunol 2009, 210:3–12.
38. 38.
Mandrekar-Colucci S, Landreth GE: Microglia and inflammation in Alzheimer's disease. CNS Neurol Disord Drug Targets 2010, 9:156–167.
39. 39.
Dhawan G, Floden AM, Combs CK: Amyloid-β oligomers stimulate microglia through a tyrosine kinase dependent mechanism. Neurobiol Aging 2011. [Epub ahead of print]
40. 40.
Maezawa I, Zimin PI, Wulff H, Jin LW: Amyloid-β protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem 2011, 286:3693–3706.
41. 41.
Nandrot EF, Anand M, Almeida D, Atabai K, Sheppard D, Finnemann SC: Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis. Proc Natl Acad Sci U S A 2007, 104:12005–12010.
42. 42.
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM: RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 1996, 382:685–691.
43. 43.
Yan SD, Stern D, Kane MD, Kuo YM, Lampert HC, Roher AE: RAGE-Aβ interactions in the pathophysiology of Alzheimer's disease. Restor Neurol Neurosci 1998, 12:167–173.
44. 44.
Friggeri A, Banerjee S, Biswas S, de Freitas A, Liu G, Bierhaus A, Abraham E: Participation of the receptor for advanced glycation end products in efferocytosis. J Immunol 2011, 186:6191–6198.
Download references
Acknowledgements
This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation (NIBIO); a Grant-in-Aid for the global COE program from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan. Research Grant from Hayashi Memorial Foundation for Female Natural Scientists.
Author information
Correspondence to Endong Li or Mariko Noda or Tetsuya Mizuno.
Additional information
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
EL performed the RT-PCR experiments and helped draft the manuscript. MN conducted the ELISAs, microglial phagocytosis assay and FACS analysis, and drafted the manuscript. YD, BP, JK and HT performed the cell culture and were involved in the conception of the study. TM carried out the immunocytochemistry. He was also involved in the conception and design of the study, and helped draft the manuscript. AS was also involved in the conception and design of the study, as well as in the preparation of the manuscript. All authors read and approved the final manuscript.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reprints and Permissions
About this article
Keywords
• Microglia
• Neuroprotection
• MFG-E8
• Nrf2 | {
"url": "https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-9-148",
"source_domain": "jneuroinflammation.biomedcentral.com",
"snapshot_id": "crawl=CC-MAIN-2019-35",
"warc_metadata": {
"Content-Length": "308108",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:K7G33KQ4TMVRYBKPHCYT7E35V7TJLL4G",
"WARC-Concurrent-To": "<urn:uuid:96f9fb76-4ce2-4468-8939-3c8686e9f036>",
"WARC-Date": "2019-08-21T07:55:31",
"WARC-IP-Address": "151.101.248.95",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:IS7H7KTCH2KFVYRXCH6U7ILUGHDJKGPV",
"WARC-Record-ID": "<urn:uuid:9ba46169-b351-46b5-82ac-fdc88a851e6b>",
"WARC-Target-URI": "https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-9-148",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:42856d3c-cd6d-440b-911c-51f3b275cdc0>"
},
"warc_info": "isPartOf: CC-MAIN-2019-35\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-85.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
21,
22,
36,
37,
136,
137,
146,
147,
158,
159,
838,
839,
847,
848,
1296,
1297,
1305,
1306,
1920,
1921,
1933,
1934,
2261,
2262,
2273,
2274,
3472,
3473,
5207,
5208,
5534,
5535,
5934,
5935,
5957,
5958,
5967,
5968,
6315,
6316,
6368,
6369,
6947,
6948,
6961,
6962,
7707,
7708,
8242,
8243,
8474,
8475,
8504,
8505,
9103,
9104,
9111,
9112,
9721,
9722,
9784,
9785,
9805,
9806,
10399,
10400,
10887,
10888,
10933,
10934,
11666,
11667,
11754,
11755,
12130,
12131,
12218,
12219,
12719,
12720,
12741,
12742,
13066,
13067,
13075,
13076,
13158,
13159,
14099,
14100,
14109,
14117,
14118,
15341,
15342,
15401,
15402,
16199,
16200,
16209,
16217,
16218,
17498,
17499,
17591,
17592,
18351,
18352,
18361,
18369,
18370,
20358,
20359,
21264,
21265,
22088,
22089,
22098,
22106,
22107,
23624,
23625,
23707,
23708,
24881,
24882,
24891,
24899,
24900,
25917,
25918,
25929,
25930,
28367,
28368,
28823,
28824,
29226,
29227,
30015,
30016,
30620,
30621,
30630,
30638,
30639,
31170,
31171,
31183,
31184,
31681,
31682,
31696,
31697,
31701,
31702,
31722,
31723,
31728,
31729,
31752,
31753,
31758,
31759,
31771,
31772,
31779,
31780,
31822,
31823,
31829,
31830,
31846,
31847,
31852,
31853,
31872,
31873,
31881,
31882,
31912,
31913,
31917,
31918,
31931,
31932,
31939,
31940,
31973,
31974,
31980,
31981,
32018,
32019,
32024,
32025,
32046,
32047,
32051,
32052,
32071,
32072,
32078,
32079,
32124,
32125,
32130,
32131,
32155,
32156,
32162,
32163,
32183,
32184,
32191,
32192,
32217,
32218,
32229,
32230,
32238,
32239,
32403,
32404,
32412,
32413,
32615,
32616,
32624,
32625,
32885,
32886,
32894,
32895,
33204,
33205,
33213,
33214,
33471,
33472,
33480,
33481,
33755,
33756,
33764,
33765,
34007,
34008,
34016,
34017,
34220,
34221,
34229,
34230,
34402,
34403,
34413,
34414,
34566,
34567,
34577,
34578,
34821,
34822,
34832,
34833,
34957,
34958,
34968,
34969,
35109,
35110,
35120,
35121,
35314,
35315,
35325,
35326,
35549,
35550,
35560,
35561,
35727,
35728,
35738,
35739,
35883,
35884,
35894,
35895,
36168,
36169,
36179,
36180,
36366,
36367,
36377,
36378,
36552,
36553,
36563,
36564,
36774,
36775,
36785,
36786,
36976,
36977,
36987,
36988,
37227,
37228,
37238,
37239,
37537,
37538,
37548,
37549,
37802,
37803,
37813,
37814,
38041,
38042,
38052,
38053,
38338,
38339,
38349,
38350,
38642,
38643,
38653,
38654,
38808,
38809,
38819,
38820,
38981,
38982,
38992,
38993,
39185,
39186,
39196,
39197,
39330,
39331,
39341,
39342,
39541,
39542,
39552,
39553,
39777,
39778,
39788,
39789,
39964,
39965,
39975,
39976,
40258,
40259,
40269,
40270,
40526,
40527,
40537,
40538,
40675,
40676,
40686,
40687,
40853,
40854,
40864,
40865,
41057,
41058,
41068,
41069,
41276,
41277,
41287,
41288,
41515,
41516,
41526,
41527,
41696,
41697,
41707,
41708,
41905,
41906,
41926,
41927,
41944,
41945,
42432,
42433,
42452,
42453,
42515,
42516,
42539,
42540,
42560,
42561,
42620,
42621,
42644,
42645,
43213,
43214,
43237,
43238,
43574,
43575,
43600,
43601,
43620,
43621,
43630,
43631,
43645,
43665,
43676
],
"line_end_idx": [
21,
22,
36,
37,
136,
137,
146,
147,
158,
159,
838,
839,
847,
848,
1296,
1297,
1305,
1306,
1920,
1921,
1933,
1934,
2261,
2262,
2273,
2274,
3472,
3473,
5207,
5208,
5534,
5535,
5934,
5935,
5957,
5958,
5967,
5968,
6315,
6316,
6368,
6369,
6947,
6948,
6961,
6962,
7707,
7708,
8242,
8243,
8474,
8475,
8504,
8505,
9103,
9104,
9111,
9112,
9721,
9722,
9784,
9785,
9805,
9806,
10399,
10400,
10887,
10888,
10933,
10934,
11666,
11667,
11754,
11755,
12130,
12131,
12218,
12219,
12719,
12720,
12741,
12742,
13066,
13067,
13075,
13076,
13158,
13159,
14099,
14100,
14109,
14117,
14118,
15341,
15342,
15401,
15402,
16199,
16200,
16209,
16217,
16218,
17498,
17499,
17591,
17592,
18351,
18352,
18361,
18369,
18370,
20358,
20359,
21264,
21265,
22088,
22089,
22098,
22106,
22107,
23624,
23625,
23707,
23708,
24881,
24882,
24891,
24899,
24900,
25917,
25918,
25929,
25930,
28367,
28368,
28823,
28824,
29226,
29227,
30015,
30016,
30620,
30621,
30630,
30638,
30639,
31170,
31171,
31183,
31184,
31681,
31682,
31696,
31697,
31701,
31702,
31722,
31723,
31728,
31729,
31752,
31753,
31758,
31759,
31771,
31772,
31779,
31780,
31822,
31823,
31829,
31830,
31846,
31847,
31852,
31853,
31872,
31873,
31881,
31882,
31912,
31913,
31917,
31918,
31931,
31932,
31939,
31940,
31973,
31974,
31980,
31981,
32018,
32019,
32024,
32025,
32046,
32047,
32051,
32052,
32071,
32072,
32078,
32079,
32124,
32125,
32130,
32131,
32155,
32156,
32162,
32163,
32183,
32184,
32191,
32192,
32217,
32218,
32229,
32230,
32238,
32239,
32403,
32404,
32412,
32413,
32615,
32616,
32624,
32625,
32885,
32886,
32894,
32895,
33204,
33205,
33213,
33214,
33471,
33472,
33480,
33481,
33755,
33756,
33764,
33765,
34007,
34008,
34016,
34017,
34220,
34221,
34229,
34230,
34402,
34403,
34413,
34414,
34566,
34567,
34577,
34578,
34821,
34822,
34832,
34833,
34957,
34958,
34968,
34969,
35109,
35110,
35120,
35121,
35314,
35315,
35325,
35326,
35549,
35550,
35560,
35561,
35727,
35728,
35738,
35739,
35883,
35884,
35894,
35895,
36168,
36169,
36179,
36180,
36366,
36367,
36377,
36378,
36552,
36553,
36563,
36564,
36774,
36775,
36785,
36786,
36976,
36977,
36987,
36988,
37227,
37228,
37238,
37239,
37537,
37538,
37548,
37549,
37802,
37803,
37813,
37814,
38041,
38042,
38052,
38053,
38338,
38339,
38349,
38350,
38642,
38643,
38653,
38654,
38808,
38809,
38819,
38820,
38981,
38982,
38992,
38993,
39185,
39186,
39196,
39197,
39330,
39331,
39341,
39342,
39541,
39542,
39552,
39553,
39777,
39778,
39788,
39789,
39964,
39965,
39975,
39976,
40258,
40259,
40269,
40270,
40526,
40527,
40537,
40538,
40675,
40676,
40686,
40687,
40853,
40854,
40864,
40865,
41057,
41058,
41068,
41069,
41276,
41277,
41287,
41288,
41515,
41516,
41526,
41527,
41696,
41697,
41707,
41708,
41905,
41906,
41926,
41927,
41944,
41945,
42432,
42433,
42452,
42453,
42515,
42516,
42539,
42540,
42560,
42561,
42620,
42621,
42644,
42645,
43213,
43214,
43237,
43238,
43574,
43575,
43600,
43601,
43620,
43621,
43630,
43631,
43645,
43665,
43676,
43684
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 43684,
"ccnet_original_nlines": 429,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 1,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.20563411712646484,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.10457085818052292,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.30406662821769714,
"rps_doc_frac_unique_words": 0.26325640082359314,
"rps_doc_mean_word_length": 5.390829563140869,
"rps_doc_num_sentences": 502,
"rps_doc_symbol_to_word_ratio": 0.0008768999832682312,
"rps_doc_unigram_entropy": 6.329498291015625,
"rps_doc_word_count": 6412,
"rps_doc_frac_chars_dupe_10grams": 0.06315454095602036,
"rps_doc_frac_chars_dupe_5grams": 0.17216339707374573,
"rps_doc_frac_chars_dupe_6grams": 0.12911531329154968,
"rps_doc_frac_chars_dupe_7grams": 0.09957762062549591,
"rps_doc_frac_chars_dupe_8grams": 0.08091765642166138,
"rps_doc_frac_chars_dupe_9grams": 0.06966383010149002,
"rps_doc_frac_chars_top_2gram": 0.005062779877334833,
"rps_doc_frac_chars_top_3gram": 0.009720530360937119,
"rps_doc_frac_chars_top_4gram": 0.003471619915217161,
"rps_doc_books_importance": -3741.4833984375,
"rps_doc_books_importance_length_correction": -3741.4833984375,
"rps_doc_openwebtext_importance": -1694.487548828125,
"rps_doc_openwebtext_importance_length_correction": -1694.487548828125,
"rps_doc_wikipedia_importance": -1206.210693359375,
"rps_doc_wikipedia_importance_length_correction": -1206.210693359375
},
"fasttext": {
"dclm": 0.029105959460139275,
"english": 0.906373143196106,
"fineweb_edu_approx": 2.241657257080078,
"eai_general_math": 0.3613894581794739,
"eai_open_web_math": 0.3413243889808655,
"eai_web_code": 0.013014550320804119
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.858",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.852",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "2",
"label": "Text Extraction Errors"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
7,293,649,193,882,625,000 | Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content
Volume 12, Number 10—October 2006
Perspective
Birds and Influenza H5N1 Virus Movement to and within North America
John H. Rappole*Comments to Author and Zdenek Hubálek†
Author affiliations: *Smithsonian Institution, Washington, DC, USA; †Academy of Sciences, Valtice, Czech Republic
Suggested citation for this article
Abstract
Highly pathogenic avian influenza (HPAI) H5N1 expanded considerably during 2005 and early 2006 in both avian host species and geographic distribution. Domestic waterfowl and migratory birds are reservoirs, but lethality of this subtype appeared to initially limit migrant effectiveness as introductory hosts. This situation may have changed, as HPAI H5N1 has recently expanded across Eurasia and into Europe and Africa. Birds could introduce HPAI H5N1 to the Western Hemisphere through migration, vagrancy, and importation by people. Vagrants and migratory birds are not likely interhemispheric introductory hosts; import of infected domestic or pet birds is more probable. If reassortment or mutation were to produce a virus adapted for rapid transmission among humans, birds would be unlikely introductory hosts because of differences in viral transmission mechanisms among major host groups (i.e., gastrointestinal for birds, respiratory for humans). Another possible result of reassortment would be a less lethal form of avian influenza, more readily spread by birds.
Avian influenza virus A refers collectively to a group of viruses within the family Orthomyxoviridae that has a worldwide distribution and causes a variety of diseases in birds. Classification of influenza viruses is based on 2 glycoproteins (antigens) characteristic of the group members: hemagglutinin, of which 16 forms are known; and neuraminidase, of which 9 forms have been described. In 1997, a virulent, highly pathogenic avian influenza (HPAI) A virus, identified as the H5N1 subtype, was identified in samples taken in Hong Kong (1,2). This virus has spread to several localities in Asia and, since late 2005, Europe (3) and Africa (4) (Table 1). HPAI H5N1 virus is found most commonly in domestic fowl, although as of late 2005, it has been found in migratory and resident birds of several orders (mainly Anseriformes) and in pigs, civets, house cats, tigers, leopards, and humans (3). This virus poses a potential danger to human populations; 224 human cases of H5N1 avian influenza have been reported as of May 29, 2006; 127 of these cases were fatal (17). Its discovery in migratory birds is especially troubling because of the potential for rapid dispersal of the virus across continents and hemispheres.
We review facts concerning outbreaks of H5N1; the species of birds, especially migrants, known to have been infected by this subtype; and available information on the ability of migrants to serve as reservoir or introductory hosts that move the virus from outbreak areas to new localities. On the basis of this information, we consider the avian pathways by which HPAI H5N1 might enter the Western Hemisphere and, once present, the likelihood that it will be able to disperse to new regions. We define migratory or migrant birds as those species that move annually between geographically separate breeding and wintering quarters. Migrating birds are those actually in the process of moving from 1 locality to another.
Ecology of Influenza A Viruses
Figure 1
Thumbnail of Saurus cranes (Grus antigone) over Naung Mung, Myanmar, in March 2006.
Figure 1. Saurus cranes (Grus antigone) over Naung Mung, Myanmar, in March 2006.
Avian influenza A viruses are common and widespread in birds. Most viruses in this family attack the intestinal tract of the host preferentially and are spread mainly by shedding in host feces (18,19). Waterfowl, e.g., ducks, geese, and swans (Anseriformes), and shorebirds (Charadriiformes) are particularly susceptible because they are exposed to water that may be contaminated with infected fecal matter, especially at specific sites and seasons, when these birds congregate densely at relatively confined and shallow water bodies (Figure 1). A secondary mode of viral spread is consumption of infected avian host parts by predators, including captive carnivores, avian raptors, and carrion-feeding vertebrates. Infection by most avian influenza A strains appears to be asymptomatic for the host (18). Proportions of birds shedding active virus can be high (e.g., >30% in some Canadian duck populations) among juvenile waterfowl gathered in large flocks on lakes and ponds during the summer postbreeding molting period but decrease rapidly during southward migration, falling to 1% to 2% during winter (18). Nevertheless, shedding of active virus can remain as high as 0.25% by individual birds among northbound spring migrants, sufficient to reinfect northern breeding populations (18).
Most birds appear to be more or less susceptible to >1 strain of avian influenza A, but rates of infection and levels of susceptibility to the different viral subtypes vary among taxa. For instance, H3 and H6 subtypes are common in ducks, geese, and swans (Anseriformes), while H4, H9, H11, and H13 subtypes are more prevalent in sandpipers, terns, and gulls (Charadriiformes) (20). The best opportunities for viral transmission among large numbers of anseriform hosts would likely be on lakes and ponds in summer, where large concentrations gather for weeks to undergo the postbreeding, premigratory molt (18). For charadriiformes, the greatest viral transmission opportunities would likely be at stopover sites during fall migration, where tens of thousands of individual birds congregate to feed and roost (20).
Avian Influenza in Humans
Humans and other mammals normally are not susceptible to infection by avian influenza A viruses. Nevertheless, several subtypes of avian influenza or bird-origin influenza viruses have infected humans; 3 of these subtypes have caused pandemics within the past century. At present, HPAI H5N1 is entirely an avian influenza subtype. Humans can become infected, but so far as is known, they must inhale or ingest massive viral doses from excreta or tissues of infected birds to do so. Although clinically ill humans have high death rates, ≈50%, passage of H5N1 virus from human to human is rare (3).
The more humans infected with HPAI H5N1, the greater the probability that reassortment with a human influenza virus strain will occur and produce a lethal form that is spread readily between humans (18,19). However, viral interhost transmission strategies differ fundamentally for those viruses that primarily infect humans versus those that infect birds. Bird viruses have an affinity for the host's intestinal tract, and interhost transmission occurs mainly by fecal contamination of shared water bodies. Human viruses more often attack the respiratory system and depend on shedding in respiratory effluvia for interhost transfer. If, or when, a reassortment or mutation of HPAI H5N1 produces a virus capable of efficient horizontal transfer among humans, the new virus would likely not be particularly effective in transfer among birds; migrants likely would play little role in spread of such a virus. Vaccines produced to prevent human infection by H5N1 might not be effective against a new virus produced by reassortment.
Birds as HPAI H5N1 Reservoirs and Introductory Hosts in the Old World
The main reservoirs and introductory hosts for avian influenza A viruses in general are migratory waterfowl and domestic fowl (18,19). HPAI H5N1, however, causes high rates of disabling illness and death in most avian species (21). High rates of illness would prevent migrants from being introductory hosts, since sick wild birds normally cannot move far and do not survive long. Thus, perhaps not surprisingly, no evidence exists that migrants were introductory hosts for H5N1 for several years after its initial appearance in Guangdong Province, People's Republic of China, in 1996. In fact, no deaths or even infections of migrants were reported until December 2002, when several migrants and exotic birds were found dead at a Hong Kong park and zoologic garden (10). Of 3,095 outbreaks of HPAI H5N1 reported from December 2003 through February 2005, all involved captive birds or domestic fowl (6). Until early August 2005, only 2 outbreaks of HPAI H5N1 had been confirmed in migratory birds presumed to be completely separate from domestic fowl: Qinghai Lake and Xinjiang Province, China, (April, May 2005) (12) and Lakes Erhel and Khunt in northern Mongolia (August 2005) (15). However, that situation has changed, and several new outbreaks have been recorded in migrants that were presumably separate from domestic fowl within the last few months (Appendix Table), perhaps signaling genetic modification of the virus (19).
Data based on observations of dead wild birds at sites where infections have broken out and negative results from subsequent extensive screening for seropositive or infected migrants around outbreak sites have indicated that HPAI H5N1 was lethal for most wild birds, at least until recently. Nevertheless, some studies have demonstrated that chickens, domestic ducks, and geese infected under laboratory conditions, as well as some wild birds exposed under quasilaboratory conditions (e.g., birds fed, watered, and protected at zoologic parks or gardens), survive infection and shed the virus in active form (10,22,23). The work by Komar et al. (24) on wild birds exposed to West Nile virus (WNV) under laboratory conditions may be instructive in this regard. These researchers found that in species like the fish crow (Corvus ossifragus), in which individual birds were known to have high death rates on exposure to the New York 99 subtype of WNV in the wild (on the basis of large numbers of birds found dead and failure to find free-flying birds captured that were seropositive), survival rates from exposure in the laboratory were 45%. When one considers that birds kept in a laboratory have ready access to food and water during their illness, as well as protection from inclement weather and predators, this finding perhaps is not surprising. However, wild birds associating with free-ranging domestic fowl at farm ponds, or captive exotic birds at city parks or zoological gardens, may receive some of the same benefits as laboratory birds, experiencing conditions conducive to survival of infection by HPAI H5N1.
Recent detections of HPAI H5N1 in free-ranging migrants may be a result of heightened awareness and thus the virus could have been circulating in migrants, although undetected. This explanation is unlikely considering the extensive screening of blood and feces of migrants in the past several years in Europe, parts of Asia, and North America. These screenings have searched for birds seropositive for H5N1 and other avian influenza type A viruses. These searches have involved sampling thousands of birds of hundreds of species (25,26). The virus may also have changed to some degree (2,19), allowing higher survival rates among some species of migrants. Both explanations may have some relevance to the current situation. In any event, some migratory birds may now be able to move HPAI H5N1 in active form over considerable distances (Table A1). Increasing numbers of recent reports document apparent movement of the virus, whereas before April 2005, no evidence existed of HPAI H5N1 in free-ranging migratory birds distant from domestic fowl, despite years of sampling of tens of thousands of migratory waterfowl of several species from wetland sites across the European continent (25).
Possible Role of Birds in Arrival of HPAI H5N1 Avian Influenza in New World
To date, HPAI H5N1 has not been recorded in the New World, although outbreaks of related avian influenza viruses lethal to domestic fowl have occurred in Ontario, Canada, in 1966 (H5N9); Pennsylvania, United States in 1983 (H5N2); Puebla, Mexico, in 1994 (H5N2); Chile in 2002 (H7N3); Canada in 2004 (H7N3); and Texas, United States, in 2004 (H5N2) (27). All of these outbreaks occurred in domestic poultry and were controlled without further diffusion. We see 3 possible modes by which HPAI H5N1 might gain entry to the New World if birds were the introductory host: 1) normal interhemispheric migration, 2) vagrancy, and 3) legal and illegal importation of birds as explained in the following section.
Normal Interhemispheric Migration
Figure 2
Thumbnail of Map of known routes for natural interhemispheric bird movement: route 1, migrants breeding in Alaska and wintering in East Asia; route 2, migrants breeding in East Asia and wintering along the Pacific Coast of North America; route 3, migrants breeding in Iceland or northwestern Europe and wintering along the Atlantic Coast of North America; route 4, vagrants from West Africa carried by tropical storm systems across the Atlantic to eastern North America.
Figure 2. Map of known routes for natural interhemispheric bird movement: route 1, migrants breeding in Alaska and wintering in East Asia; route 2, migrants breeding in East Asia and wintering along the...
Few individual birds within few species undertake regular, interhemispheric migration. However, some do, and the waterfowl (Anseriformes, Charadriiformes, Ciconiiformes) could be introductory hosts for HPAI H5N1 to the New World (Table 2). Three pathways are used annually by a small number of waterfowl species to travel between the hemispheres: 1) Alaska–East Asia, in which birds that breed in Alaska winter in East Asia; 2) East Asia–Pacific North America, in which birds that breed in northeast Asia winter along the Pacific Coast of North America; and 3) Europe–Atlantic North America, in which birds that breed in Iceland or northwestern Europe winter along the Atlantic Coast of North America (Figure 2, Table 2).
Two lines of evidence argue against normal, interhemispheric migration as a likely mode of entry for HPAI H5N1 into the Western Hemisphere. First, as discussed previously, data indicate that most infected individual birds of most species of migrants become extremely ill and either cannot migrate far in their weakened state or die at the place of infection. Second, investigation of the genetics of avian influenza viruses has shown that little natural interchange occurs between the Eastern and Western Hemispheres: each hemisphere appears to have an avian influenza virus community that is largely distinct (18). This fact is particularly noteworthy when one considers that most avian influenza A viruses appear to be asymptomatic, and migrants readily transport them in infectious form, in stark contrast to the situation for HPAI H5N1. Presumably, the distinct nature of the avian influenza A community in each hemisphere results from the fact that the main reservoir for these viruses is migrants, and few migrants move regularly between the hemispheres (32).
Vagrancy
Perhaps a third or more of Eurasian waterfowl species have traveled into the Western Hemisphere as vagrants; some occur more regularly than others, including those listed in Table 2. However, all Eurasian vagrants are, by definition, extremely rare in the New World (a few birds per decade). One mode of interhemispheric vagrancy is tropical storm systems that originate off the West African coast during the Atlantic hurricane season, which lasts from June to November each year. These systems can, and occasionally do, sweep up and transport Old World birds, especially waterfowl, across the Atlantic to the New World (route 4, Figure 2). Vagrancy is much rarer (by several orders of magnitude) than normal interhemispheric migration and seems an even less likely mode of entry for HPAI H5N1.
Legal and Illegal Importations
Human traffic in birds and bird products is the sole documented means of HPAI H5N1 movement between geographically separate regions to date (19). While migratory birds have been suspected of involvement, particularly in cases in which no obvious human interchange of infected birds or products has occurred, these conclusions are inferred (19). Thus, if HPAI H5N1 is to be kept out of the Western Hemisphere, control of legal and illegal imports should be the primary focus of prevention efforts.
The legal importation of exotic birds has declined dramatically in the United States since enactment of the 1992 Wild Bird Conservation Act. Nevertheless, 2,770 birds entered the country through the New York port of entry in 1999, including 323 pet birds and 2,447 commercial birds. In addition, 12,931 birds passed through in transit (S. Kaman, US Department of Agriculture [USDA], pers. comm.) Legal importations are controlled by USDA Animal and Plant Health Inspection Service and the US Fish and Wildlife Service. Most imported birds undergo a 30-day quarantine at USDA facilities located near each of the 3 allowed ports of entry: New York, Miami, and Los Angeles. Quarantine procedures include isolation in indoor, air-filtered cages and standard testing for common poultry diseases, including avian influenza. The number of illegally imported birds is not known. These birds are not subject to quarantine and testing and could be a mode of entry for HPAI H5N1. Hawk eagles from Thailand infected with the virus were recently detected while being smuggled into Belgium (11). Although these birds were detected and quarantined, they serve as an example of how such imports could spread the virus. Species commonly associated with the transhemispheric bird trade are listed in Table 2.
If birds turn out to be responsible for entry of HPAI H5N1 into the Western Hemisphere, illegal import of an infected bird or bird product seems the most likely mode of entry. We base this conclusion on the fact that illegally imported birds, unlike infected, free-flying migrants, are provided food and water ad libitum and protected from predators, greatly increasing their chances of survival in an infectious state. Furthermore, these birds often end up in close association with other, similarly protected birds, sharing the same food or water, a situation that provides ample opportunity for viral transmission.
Possible Role of Birds in Movement of HPAI H5N1 in Western Hemisphere
Movement of HPAI H5N1 by sale of infected domestic fowl or poultry products in the United States and Canada is unlikely, given existing regulations. Thus, a major mode of HPAI spread available in much of Eurasia would be ruled out. Also, most domestic fowl are kept separate from wild migratory waterfowl in both countries, which would rule out a second major mode of introduction and cross-infection. Mixing of wild migratory birds with captive, exotic birds is relatively common, however, at North American zoos. Birds in such exhibits should be screened regularly for H5N1 or whatever HPAI virus is in circulation during a given year.
The HPAI H5N1 subtype of avian influenza A causes high mortality rates in most wild birds, at least in its present form. The situation is similar to that found for the form of WNV introduced into the Western Hemisphere in 1999 (24,3234). Even under conditions in which food, water, and protection from predators are provided, death rates are high. These kinds of death rates could result if the current form of HPAI H5N1 were introduced into New World bird populations. In such a scenario, migrants might not be capable of moving the virus far from its point of introduction, at least initially. Also, the die-offs occurring at the site of entry likely would be obvious to wildlife disease monitors, which would allow for rapid quarantine. However, if the H5N1 virus were introduced into the Western Hemisphere, migratory birds, particularly anseriforms (ducks, swans, geese), might serve as dispersal agents, especially if the virus were to change to a less lethal form through reassortment or mutation.
A key difference between mosquitoborne WNV and birdborne HPAI H5N1 is the virtual absence of effective reservoir hosts other than birds for the latter. WNV can be maintained without birds because infected mosquitoes can pass active virus to subsequent generations through vertical transmission (35). So far as is known, no alternative to birds exists as major reservoir hosts for HPAI H5N1.
An additional consideration concerning the future of HPAI H5N1, should it gain wide circulation in migratory birds, is the possibility of infection of a bird already infected with another form of avian influenza virus. Such infection could result in reassortment and production of a new virus, possibly less lethal than HPAI H5N1 but more readily spread.
Conclusions
HPAI H5N1 spread rapidly across Eurasia during 2005 for reasons that are not entirely understood. Despite this rapid movement, effective introduction (i.e., under conditions allowing its spread) of the virus to the New World through migratory or vagrant birds seems unlikely. Few individual members of few waterfowl species migrate between hemispheres, and should a bird make the journey while shedding sufficient active virus to infect birds in the Western Hemisphere, newly infected birds would probably die before being able to transport the virus from the entry site. If spread of HPAI H5N1 to the New World occurs in its current form (e.g., through domestic or pet bird trade or smuggling), it should be readily detectable because of the large number of dead native birds likely to result. However, the virus is changing (19), and a modified H5N1 virus introduced into the Western Hemisphere could be moved more readily by migratory waterfowl. If this event were to occur, the virus should be amenable to control through isolation and quarantine. If viral reassortment or mutation occurs to produce a new virus that is readily transmissible to humans, the role of birds in general and migrants in particular may be moot because of the fundamentally different methods of infection favored by viruses infecting humans and birds. Viruses infecting birds preferentially attack the intestinal tract and are shed with the feces; by contrast, human viruses mainly attack the respiratory tract and are shed with respiratory effluvia. If HPAI H5N1 were to gain wide circulation among migrants, it might infect a bird already infected with another form of avian influenza A and undergo reassortment to produce a low-pathogenic form that is more readily spread.
Dr Rappole is a research scientist with the Smithsonian National Zoological Park's Conservation and Research Center. His principal research interests are migratory bird ecology and evolution, sub-Himalayan ornithogeography, and avian conservation.
Dr Hubálek is a scientist at the Academy of Sciences of the Czech Republic. He is interested in the ecology of arthropodborne human pathogenic viruses and bacteria.
References
1. Li KS, Guan Y, Wang J, Smith G, Xu K, Duan L, Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature. 2004;430:20913. DOIPubMed
2. Zhou NN, Shortridge K, Claas E, Krauss S, Webster R. Rapid evolution of H5N1 influenza viruses in chickens in Hong Kong. J Virol. 1999;73:336674.PubMed
3. Fauci AS. Pandemic influenza threat and preparedness. Emerg Infect Dis. 2006;12:737.PubMed
4. Enserink M. H5N1 moves into Africa, European Union, deepening global crisis. Science. 2006;311:932. DOIPubMed
5. Xu X, Subbarao K, Cox N, Guo Y. Genetic characterization of the pathogenic influenza A/Goose/Guangdong/1/96 (H5N1) virus: similarity of its hemagglutinin gene to those of H5N1 viruses from the 1997 outbreaks in Hong Kong. Virology. 1999;261:159. DOIPubMed
6. Morris R, Jackson R. Epidemiology of H5N1 avian influenza in Asia and implications for regional control. Rome: Food and Agricultural Organization of the United Nations; 2005.
7. Sims LD, Ellis T, Liu K, Dyrting K, Wong H, Peiris M, Avian influenza in Hong Kong 1997–2002. Avian Dis. 2003;47:8328. DOIPubMed
8. Nguyen DC, Uyeki T, Jadhao S, Maines T, Shaw M, Matsuoka Y, Isolation and characterization of avian influenza viruses, including highly pathogenic H5N1, from poultry in live bird markets in Hanoi, Vietnam, in 2001. J Virol. 2005;79:420112. DOIPubMed
9. Ng EK, Cheng P, Ng A, Hoang T, Lim W. Influenza A H5N1 detection. Emerg Infect Dis. 2005;11:13035.PubMed
10. Ellis TM, Bousfield R, Bisset L, Dyrting K, Luk G, Tsim S, Investigation of outbreaks of highly pathogenic H5N1 avian influenza in waterfowl and wild birds in Hong Kong in late 2002. Avian Pathol. 2004;33:492505. DOIPubMed
11. Van Borm S, Thomas I, Hanquet G, Lambrecht B, Boschmans M, DuPont G, Highly pathogenic H5N1 influenza virus in smuggled Thai eagles, Belgium. Emerg Infect Dis. 2005;11:7025.PubMed
12. Chen H, Smith G, Zhang S, Qin K, Wang J, Li K, H5N1 virus outbreak in migratory waterfowl. Nature. 2005;436:1912. DOIPubMed
13. World Health Organization. H5N1 avian influenza timeline: 28 Oct 2005 [cited 2006 Oct 23]. Available from http://www.who.int/entity/csr/disease/avian_influenza/Timeline_28_10a.pdf
14. Brown I, Gaidet N, Guberti V. Marangon, Olsen B, editors. Mission to Russia to assess the avian influenza situation in wildlife and the national measures being taken to minimize the risk of international spread. Office International des Epizooties 2005 [cited 2005 Oct 23]. Available from http://www.oie.int/downld/Missions/2005/ReportRussia2005Final2.pdf
15. Office International des Epizooties. Update on avian influenza in animals (type H5) 24 May 2006 [cited 2006 May 24]. Available from http://www.oie.int/downld/AVIAN%20INFLUENZA/A_AI-Asia.htm
16. Department for Environment, Food, and Rural Affairs (DEFRA), United Kingdom. Epidemiology report on avian influenza in a quarantine premises in Essex [cited 2006 May 29]. Available from http://www.defra.gov.uk/animalh/diseases/notifiable/disease/ai/pdf/ai-epidemrep111105.pdf
17. World Health Organization (WHO). Cumulative number of confirmed human cases of avian influenza A/ (H5N1) reported to WHO as of 29 May 2006 [article in French] [cited 2006 May 29]. Available from http://www.who.int/csr/disease/avian_influenza/country/cases table_2006_05_29/en/index.html
18. Webster RG, Bean W, Gorman O, Chambers T, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev. 1992;56:15279.PubMed
19. Webster RG, Peiris M, Chen H, Guan Y. H5N1 outbreaks and enzootic influenza. Emerg Infect Dis. 2006;12:38.PubMed
20. Kawaoka Y, Chambers T, Sladen W, Webster G. Is the gene pool of influenza viruses in shorebirds and gulls different from that in wild ducks? Virology. 1988;163:24750. DOIPubMed
21. Perkins LE, Swayne D. Comparative susceptibility of selected avian and mammalian species to a Hong Kong–origin H5N1 high-pathogenicity avian influenza virus. Avian Dis. 2003;47:95667. DOIPubMed
22. Shortridge KF, Zhou N, Guan Y, Gao P, Ito T, Kawaoka Y, Characterization of avian H5N1 influenza viruses from poultry in Hong Kong. Virology. 1998;252:33142. DOIPubMed
23. Hulse-Post DJ, Sturm-Ramirez K, Humberd J, Seiler P, Govorkova E, Krauss S, Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia. Proc Natl Acad Sci U S A. 2005;102:106827. DOIPubMed
24. Komar N, Langevin S, Hinten S, Nemeth E, Edwards D, Hettler B, Experimental infection of North American birds with the New York 1999 strain of West Nile virus. Emerg Infect Dis. 2003;9:31122.PubMed
25. Munster VJ, Wallensten A, Baas C, Rimmelzwann G, Schutten M, Olsen B, Mallards and highly pathogenic avian influenza ancestral viruses, northern Europe. Emerg Infect Dis. 2005;11:154551.PubMed
26. Spackman E, Stallknecht D, Slemons R, Winker K, Suarez D, Scott M, Phylogenetic analyses of type A influenza genes in natural reservoir species in North America reveals genetic variation. Virus Res. 2005;114:89100. DOIPubMed
27. Werner O. [Highly pathogenic avian influenza--a review.] [Article in German.]. Berl Munch Tierarztl Wochenschr. 2006;119:14050.PubMed
28. Kessel B, Gibson D. Status and distribution of Alaska birds. Studies in Avian Biology. 1978;1:1100.
29. Palmer R. Handbook of North American birds. Vol 2. New Haven (CT):Yale University Press; 1976.
30. American Ornithologists' Union (AOU). The A.O.U. check-list of North American birds. 7th ed. Washington: American Ornithologists' Union; 1998.
31. Rasmussen P, Anderton J. Birds of South Asia: the Ripley guide. Barcelona: Lynx Ed.; 2005.
32. Rappole JH, Derrickson S, Hubálek Z. Migratory birds and spread of West Nile virus in the Western Hemisphere. Emerg Infect Dis. 2000;6:31928. DOIPubMed
33. Bernard KA, Maffei J, Jones S, Kauffman E, Ebel G, Dupuis A II, West Nile virus infection in birds and mosquitoes, New York State, 2000. Emerg Infect Dis. 2001;7:67985. DOIPubMed
34. Brault AC, Langevin S, Bowen R, Panella N, Biggerstaff B, Miller B, Differential virulence of West Nile strains for American crows. Emerg Infect Dis. 2004;10:21618.PubMed
35. Nasci RS, Savage HM, White DJ, Miller JR, Cropp BC, Godsey MS, West Nile virus in overwintering Culex mosquitoes, New York City, 2000. Emerg Infect Dis. 2001;7:7427. DOIPubMed
Figures
Tables
Suggested citation for this article: Rappole JH, Hubálek Z. Birds and influenza H5N1 virus movement to and within North America. Emerg Infect Dis [serial on the Internet]. 2006 Oct [date cited]. http://dx.doi.org/10.3201/eid1210.051577
DOI: 10.3201/eid1210.051577
Table of Contents – Volume 12, Number 10—October 2006
Comments to the Authors
Please use the form below to submit correspondence to the authors or contact them at the following address:
John H. Rappole, 1500 Remount Rd, Front Royal, VA 22630, USA
character(s) remaining.
Comment submitted successfully, thank you for your feedback.
Comments to the EID Editors
Please contact the EID Editors via our Contact Form.
TOP | {
"url": "http://wwwnc.cdc.gov/eid/article/12/10/05-1577_article",
"source_domain": "wwwnc.cdc.gov",
"snapshot_id": "crawl=CC-MAIN-2014-49",
"warc_metadata": {
"Content-Length": "155312",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:Q4FHBHNQIPT2YPVLSRSUFBDCK6HMBZYH",
"WARC-Concurrent-To": "<urn:uuid:8f7cff2f-fdd6-485d-a5b6-af3cdc56cc56>",
"WARC-Date": "2014-11-27T17:04:11",
"WARC-IP-Address": "23.3.13.34",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:6T2PZH4GJBXNJCGQKKL64S7C4NVY6KJM",
"WARC-Record-ID": "<urn:uuid:630c2f04-6bf3-4cd5-a7aa-5ec2633cbd21>",
"WARC-Target-URI": "http://wwwnc.cdc.gov/eid/article/12/10/05-1577_article",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:2b9d94da-a254-4d1d-91fa-514ebbb6ec1a>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-235-23-156.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-49\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for November 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
113,
114,
148,
149,
161,
162,
230,
231,
287,
401,
402,
438,
439,
448,
449,
1521,
1522,
2742,
2743,
3461,
3462,
3493,
3494,
3503,
3504,
3588,
3589,
3670,
3671,
4962,
4963,
5778,
5779,
5805,
5806,
6403,
6404,
7432,
7433,
7503,
7504,
8934,
8935,
10556,
10557,
11747,
11748,
11824,
11825,
12529,
12530,
12564,
12565,
12574,
12575,
13046,
13047,
13253,
13254,
13976,
13977,
15043,
15044,
15053,
15054,
15849,
15850,
15881,
15882,
16379,
16380,
17671,
17672,
18290,
18291,
18361,
18362,
19000,
19001,
20006,
20007,
20398,
20399,
20754,
20755,
20767,
20768,
22524,
22525,
22773,
22774,
22939,
22940,
22951,
22952,
23131,
23288,
23384,
23499,
23760,
23940,
24074,
24329,
24439,
24668,
24854,
24984,
25170,
25532,
25728,
26010,
26303,
26444,
26563,
26746,
26946,
27120,
27375,
27579,
27778,
28009,
28149,
28255,
28356,
28505,
28602,
28760,
28945,
29122,
29304,
29305,
29313,
29314,
29321,
29322,
29558,
29559,
29587,
29588,
29642,
29643,
29667,
29668,
29776,
29777,
29838,
29839,
29863,
29864,
29925,
29926,
29954,
29955,
30008,
30009
],
"line_end_idx": [
113,
114,
148,
149,
161,
162,
230,
231,
287,
401,
402,
438,
439,
448,
449,
1521,
1522,
2742,
2743,
3461,
3462,
3493,
3494,
3503,
3504,
3588,
3589,
3670,
3671,
4962,
4963,
5778,
5779,
5805,
5806,
6403,
6404,
7432,
7433,
7503,
7504,
8934,
8935,
10556,
10557,
11747,
11748,
11824,
11825,
12529,
12530,
12564,
12565,
12574,
12575,
13046,
13047,
13253,
13254,
13976,
13977,
15043,
15044,
15053,
15054,
15849,
15850,
15881,
15882,
16379,
16380,
17671,
17672,
18290,
18291,
18361,
18362,
19000,
19001,
20006,
20007,
20398,
20399,
20754,
20755,
20767,
20768,
22524,
22525,
22773,
22774,
22939,
22940,
22951,
22952,
23131,
23288,
23384,
23499,
23760,
23940,
24074,
24329,
24439,
24668,
24854,
24984,
25170,
25532,
25728,
26010,
26303,
26444,
26563,
26746,
26946,
27120,
27375,
27579,
27778,
28009,
28149,
28255,
28356,
28505,
28602,
28760,
28945,
29122,
29304,
29305,
29313,
29314,
29321,
29322,
29558,
29559,
29587,
29588,
29642,
29643,
29667,
29668,
29776,
29777,
29838,
29839,
29863,
29864,
29925,
29926,
29954,
29955,
30008,
30009,
30012
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 30012,
"ccnet_original_nlines": 155,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 2,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.27723971009254456,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.054652370512485504,
"rps_doc_frac_lines_end_with_ellipsis": 0.00641026021912694,
"rps_doc_frac_no_alph_words": 0.2241438925266266,
"rps_doc_frac_unique_words": 0.2868959605693817,
"rps_doc_mean_word_length": 5.26621675491333,
"rps_doc_num_sentences": 335,
"rps_doc_symbol_to_word_ratio": 0.0001729500072542578,
"rps_doc_unigram_entropy": 6.150842666625977,
"rps_doc_word_count": 4594,
"rps_doc_frac_chars_dupe_10grams": 0.026536600664258003,
"rps_doc_frac_chars_dupe_5grams": 0.0741950199007988,
"rps_doc_frac_chars_dupe_6grams": 0.04526102915406227,
"rps_doc_frac_chars_dupe_7grams": 0.03711817041039467,
"rps_doc_frac_chars_dupe_8grams": 0.029430000111460686,
"rps_doc_frac_chars_dupe_9grams": 0.026536600664258003,
"rps_doc_frac_chars_top_2gram": 0.012896290048956871,
"rps_doc_frac_chars_top_3gram": 0.005373459775000811,
"rps_doc_frac_chars_top_4gram": 0.005952130071818829,
"rps_doc_books_importance": -2419.823974609375,
"rps_doc_books_importance_length_correction": -2419.823974609375,
"rps_doc_openwebtext_importance": -1376.2763671875,
"rps_doc_openwebtext_importance_length_correction": -1376.2763671875,
"rps_doc_wikipedia_importance": -1102.896484375,
"rps_doc_wikipedia_importance_length_correction": -1102.896484375
},
"fasttext": {
"dclm": 0.03254156932234764,
"english": 0.9114605784416199,
"fineweb_edu_approx": 3.158050298690796,
"eai_general_math": 0.12344437837600708,
"eai_open_web_math": 0.3238169550895691,
"eai_web_code": 0.0028253199998289347
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "611.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Anatomy"
}
},
"secondary": {
"code": "598.07",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Zoology",
"level_3": "Birds"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
5,126,463,475,106,651,000 | Structural Integration
Structural Integration is a system of manual therapy and sensorimotor education that purports to improve human biomechanical functioning as a whole rather than to treat particular symptoms.
Joint Capsule
The joint capsule resembles a sac-like envelope that forms a sleeve around the synovial joint and encloses its cavity. The joint capsule is a dense fibrous connective tissue that is attached to the bones via specialized attachment zones at the end of each involved bone. It seals the joint space, provides passive stability by limiting movements, provides active stability via its proprioceptive nerve endings, and may form articular surfaces for the joint. It varies in thickness according to the stresses to which it is subject, is locally thickened to form capsular ligaments, and may also incorporate tendons.
The release technique in the Shaolin methodology is a gentle procedure using intended energy to open and release areas within the joint capsule which may be limiting mobility and causing pain.
manitou-wellness-center-colorado-springs-structural-integration
Chinese Medicine
Growing interest in the martial arts has been accompanied by curiosity about Chinese sports medicine, and the healing power of Shaolin treatments for traumatic injuries, both acute and chronic, is no longer a secret.
In China, the official practice of Chinese medicine was reduced to internal medicine during the 20th century, mostly for political reasons too complicated to explain here. The traditional wisdom and expertise of martial arts masters practicing kung fu medicine were suppressed and had to survive in secrecy, which explains why most university-educated doctors of Chinese medicine don’t know much about treating sports injuries. But some of this knowledge survived and has found its way to the West.
The Shaolin Temple, the center of the Shaolin tradition of Buddhism in China, played an important role in the Chinese martial arts and was a storehouse of practical information on treating warriors injured during combat or training.
This knowledge was closely guarded because it bestowed a competitive edge on those in its possession. In the end, some of the last surviving guardians of these powerful medical insights felt the need to preserve and pass along this information before it got extinguished.
We are fortunate that this happened because many of those strategies are safe and very effective, and can help not only martial artists but modern athletes from across the spectrum of sports to heal acute and chronic injuries and learn how to prevent them in the future.
The types of injuries these methods can treat effectively include bruises, strains, sprains, slow-healing fractures, and the associated cramps, pain, soreness, aches and fatigue.
Acupressure
Authentic Shaolin acupressure, called tuina (twee nah) in China, uses specific hand techniques, or sometimes tools, to stimulate acupoints and meridians. With acupressure, Qi that is blocked or stagnant can be released and allowed to flow freely once again. Though different than acupuncture, acupressure can be just as effective. Actually, for some conditions, like sports injuries and simple sprains, it’s more useful and easier on the person receiving treatment. | {
"url": "https://manitouwellness.com/what-we-do/structural-integration-colorado-springs/",
"source_domain": "manitouwellness.com",
"snapshot_id": "crawl=CC-MAIN-2021-31",
"warc_metadata": {
"Content-Length": "57396",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:4YBVAFWR2FWFIEKE2TT75MJK6OUELYTN",
"WARC-Concurrent-To": "<urn:uuid:5ff70746-c537-4507-9806-6a4ca5d39e46>",
"WARC-Date": "2021-08-04T11:55:03",
"WARC-IP-Address": "192.124.249.6",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:GNWBZB54RSQB7XJI75YAZ5JYDWSNYOJY",
"WARC-Record-ID": "<urn:uuid:0930aa4c-4c80-484d-bc0c-c1b2cc9724a6>",
"WARC-Target-URI": "https://manitouwellness.com/what-we-do/structural-integration-colorado-springs/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:5994c746-5ef4-400b-b1b9-4fec434b7da5>"
},
"warc_info": "isPartOf: CC-MAIN-2021-31\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for July/August 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-148.ec2.internal\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
23,
24,
214,
215,
229,
230,
844,
845,
1038,
1039,
1103,
1104,
1121,
1122,
1339,
1340,
1839,
1840,
2073,
2074,
2346,
2347,
2618,
2619,
2798,
2799,
2811,
2812
],
"line_end_idx": [
23,
24,
214,
215,
229,
230,
844,
845,
1038,
1039,
1103,
1104,
1121,
1122,
1339,
1340,
1839,
1840,
2073,
2074,
2346,
2347,
2618,
2619,
2798,
2799,
2811,
2812,
3277
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3277,
"ccnet_original_nlines": 28,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3936731219291687,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11072055995464325,
"rps_doc_frac_unique_words": 0.5838384032249451,
"rps_doc_mean_word_length": 5.470706939697266,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.201786518096924,
"rps_doc_word_count": 495,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.014771049842238426,
"rps_doc_frac_chars_top_3gram": 0.0166174303740263,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -280.265869140625,
"rps_doc_books_importance_length_correction": -280.265869140625,
"rps_doc_openwebtext_importance": -174.0611572265625,
"rps_doc_openwebtext_importance_length_correction": -174.0611572265625,
"rps_doc_wikipedia_importance": -123.2055435180664,
"rps_doc_wikipedia_importance_length_correction": -123.2055435180664
},
"fasttext": {
"dclm": 0.10303878784179688,
"english": 0.9524444937705994,
"fineweb_edu_approx": 2.8902266025543213,
"eai_general_math": 0.09948348999023438,
"eai_open_web_math": 0.12481099367141724,
"eai_web_code": 0.011615869589149952
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-7,261,727,861,207,696,000 | environmental medicine air conditionerBeing the best environmental health practitioner, you can aim to inform your clients of all the essential things they need to know to protect themselves and recover from environmental hazards. The greater an awareness they have, the healthier they can be, and the more responsive they can be.
Is Environmental Medicine Real?
How can you explain how real this branch of medicine is so that your clients understand? Explain to them how chemicals and external substances in the environment impact health. They may not realize that environmental factors can affect their health just as biological or stress factors can. Some clients may be fully aware of how modalities like chiropractic tools and acupuncture can help ease many, but there is another useful electrodermal screening tool called BioScan.
Being aware of how external substances can impact health is a big step in preventing poor health. Let your patients know that the branch of environmental medicine involves chemistry and science and that environmental illnesses are genuine.
Identify Symptoms
Headaches might only occur at the workplace due to the HVAC system pumping out germs and debris. Reactions may occur when an individual uses certain lotions or soaps. They can also arise when someone lives in an area where things like heavy metals are present. All can impact the human body often in a negative way resulting in pathological manifestations.
You can help your patient learn to identify symptoms that are indicative of environmental illness. They might experience itching, sore throats, or other reactions only when they use certain products or are at specific locations. Letting them know this will help create an effective testing plan using all types of modalities.
What You Can Do Using BioScan
Reassure your client that you can work with them to address symptoms or syndromes that result from exposure to environmental toxins. In addition to helping them watch what they eat, what they expose themselves to, and practicing mindfulness , you can also add BioScan to the package.
BioScan finds imbalances in the body’s meridian energy system using a stylus and a computer measuring acupuncture points on your patient’s feet or hands. It picks up any imbalanced areas and displays them on your computer screen. This information helps better identify where environmental medicine is centered.
Images might indicate that the most significant imbalance is in the digestive system. It helps you target an overall protocol that will correct the imbalance in that area and improve the patient’s entire system.
BioScan makes use of bio-resonance, which picks up signals with electrodes placed strategically on your patient’s skin. Using a BioScan will help you help your patients better, and it will help them understand how to better target environmental issues.
Lets integrate BioScan into YOUR practice!
| {
"url": "https://www.ihtbio.com/environmental-medicine-testing/",
"source_domain": "www.ihtbio.com",
"snapshot_id": "crawl=CC-MAIN-2021-04",
"warc_metadata": {
"Content-Length": "74177",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:KEMLHB46JC6XGCFEWC4ASNLQJMQS57IA",
"WARC-Concurrent-To": "<urn:uuid:8e244013-6734-4ec0-80db-b9be127d3f87>",
"WARC-Date": "2021-01-16T12:13:14",
"WARC-IP-Address": "104.21.83.18",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:RKZGKPQ7C4M7U6Q33OCBJYHOEMWSSIQI",
"WARC-Record-ID": "<urn:uuid:4c6d73b7-ec03-4f5d-8feb-62c79a5acfd5>",
"WARC-Target-URI": "https://www.ihtbio.com/environmental-medicine-testing/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:3ef6bc12-9483-4475-bff0-719c1102b603>"
},
"warc_info": "isPartOf: CC-MAIN-2021-04\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for January 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-254.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
331,
332,
364,
365,
839,
840,
1080,
1081,
1099,
1100,
1457,
1458,
1784,
1785,
1815,
1816,
2100,
2101,
2412,
2413,
2625,
2626,
2879,
2880,
2881,
2924
],
"line_end_idx": [
331,
332,
364,
365,
839,
840,
1080,
1081,
1099,
1100,
1457,
1458,
1784,
1785,
1815,
1816,
2100,
2101,
2412,
2413,
2625,
2626,
2879,
2880,
2881,
2924,
2925
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2925,
"ccnet_original_nlines": 26,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4534653425216675,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.003960399888455868,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.08316832035779953,
"rps_doc_frac_unique_words": 0.49563318490982056,
"rps_doc_mean_word_length": 5.270742416381836,
"rps_doc_num_sentences": 26,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.020103454589844,
"rps_doc_word_count": 458,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.012427509762346745,
"rps_doc_frac_chars_top_3gram": 0.007456500083208084,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -234.62652587890625,
"rps_doc_books_importance_length_correction": -234.62652587890625,
"rps_doc_openwebtext_importance": -118.39160919189453,
"rps_doc_openwebtext_importance_length_correction": -118.39160919189453,
"rps_doc_wikipedia_importance": -55.71906661987305,
"rps_doc_wikipedia_importance_length_correction": -55.71906661987305
},
"fasttext": {
"dclm": 0.5220934152603149,
"english": 0.9295371174812317,
"fineweb_edu_approx": 3.3288345336914062,
"eai_general_math": 0.06541358679533005,
"eai_open_web_math": 0.2144208550453186,
"eai_web_code": 0.013891940005123615
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-4,246,755,387,029,829,600 | Who Is Not Suitable For A Low-Carb Diet?
Embarking on a low-carb diet has become a popular pathway for many aiming to lose weight or enhance their health. It’s a journey I’ve seen countless friends and readers undertake with varying degrees of success. However, it’s not a one-size-fits-all solution, and I’ve learned that some individuals might find this diet more of a hindrance than a help.
Through my exploration and conversations with nutrition experts, I’ve discovered that certain health conditions and lifestyle factors can make a low-carb diet less than ideal. It’s crucial to understand who might need to steer clear or approach this diet with caution. Let’s dive into the specifics and shed light on who might not be the best candidate for a low-carb lifestyle.
Reasons to Avoid a Low-Carb Diet
Drawing from my extensive experience in the field of nutritional science, I’ve encountered numerous instances where a low-carb diet may not be the best approach for everyone. While the benefits of cutting carbohydrates can be significant for many, certain factors make this diet less suitable, or even detrimental, for others.
Firstly, individuals with certain health conditions need to tread carefully. Those with a history of eating disorders, for example, might find strict dietary restrictions triggering. The focus on eliminating specific food groups can sometimes reinforce unhealthy behaviors and thought patterns related to food. Similarly, people with kidney disease should avoid a low-carb diet due to the increased protein intake, which can strain the kidneys further. High-protein diets in such conditions can exacerbate existing problems, leading to more severe health issues.
Another significant consideration is the impact on athletic performance. Athletes, particularly those in endurance sports, rely heavily on carbohydrates as a primary source of energy. Carbs are essential for fueling rigorous training sessions and ensuring optimal performance during competitions. Limiting carb intake can lead to decreased stamina and endurance, impairing an athlete’s ability to perform at their best.
Additionally, individuals with certain types of metabolic disorders, such as glycogen storage diseases, need carbohydrates in their diets to manage their conditions effectively. For these people, a low-carb diet can be more than just ineffective—it can be dangerous.
It’s also worth noting that a drastic reduction in carbohydrate intake can lead to a range of short-term side effects, popularly known as the keto flu. Symptoms include fatigue, headaches, and irritability, which while temporary, can be quite uncomfortable.
In my work at Zeroing In On Health, I’ve always advocated for personalized nutrition plans. What works for one person may not work for another, highlighting the importance of understanding one’s body and health conditions before making dietary changes.
1. Medical Conditions that Restrict Carbohydrate Intake
In my 15 years working as a nutritional expert, I’ve seen firsthand how a low-carb diet can profoundly benefit many individuals. However, it’s crucial to recognize that this approach isn’t one-size-fits-all. Certain medical conditions necessitate a careful balance or even a higher intake of carbohydrates, making a low-carb diet unsuitable, if not potentially harmful.
Eating Disorders: For those with a history of eating disorders, such as anorexia or bulimia, restrictive diets like low-carb can sometimes exacerbate problematic eating patterns or trigger a relapse. In these cases, a balanced diet that doesn’t eliminate food groups is often more beneficial for maintaining a healthy relationship with food.
Kidney Disease: Patients with kidney disease need to approach a low-carb diet with caution. Reducing carbohydrate intake significantly alters protein and fat consumption, which can put additional stress on the kidneys. My advice is always to consult a healthcare provider before making any dietary changes if you have kidney issues.
Metabolic Disorders: Individuals with metabolic disorders, such as glycogen storage diseases, require carbohydrates to manage their condition effectively. In these situations, carbohydrates aren’t just a source of energy; they’re a medical necessity. Tailoring a diet to include the right amount and types of carbohydrates can be critical.
Athletes, particularly those specializing in endurance sports, may also find that cutting carbs impacts their performance negatively. Their bodies rely heavily on carbohydrates for energy, and reducing carb intake can lead to decreased stamina and overall performance.
ConditionRecommended Approach
Eating DisordersBalanced diet, avoid restrictive diets
Kidney DiseaseConsult healthcare provider, caution with low-carb
Metabolic DisordersInclude necessary carbohydrates
Endurance AthletesMay require higher carb intake
It’s worth noting that recognizing the unique needs of your body and any underlying health conditions is the first step toward figuring out the best diet plan. For those with the mentioned conditions, or if you’re uncertain about how a low-carb diet may affect you, seeking guidance from a nutritional specialist or healthcare provider is always a wise decision. My experience has taught me the importance of personalized nutrition, and I encourage everyone to approach dietary changes with both curiosity and caution to ensure optimal health outcomes.
2. Nutritional Deficiencies and Imbalances
From my extensive experience working with patients on low-carb diets, I’ve observed firsthand how these meal plans can sometimes lead to nutritional deficiencies and imbalances. It’s crucial to understand that while reducing carbohydrate intake can bring numerous health benefits, it can also inadvertently reduce the intake of essential nutrients typically found in carb-rich foods. This is particularly true for vitamins and minerals such as vitamin C, folate, potassium, and dietary fiber, which are abundant in fruits, whole grains, and legumes.
To mitigate these risks, I always emphasize the importance of well-formulated low-carb diets that incorporate a variety of nutrient-dense foods. For example, consuming leafy greens and non-starchy vegetables can help offset the lack of fiber and several key vitamins. Additionally, incorporating seeds, nuts, and avocados can provide healthy fats and nutrients like magnesium and potassium, which might be less available in a diet low in fruits and grains.
I’ve also noted that some individuals on strict low-carb or ketogenic diets might experience an imbalance in their electrolyte levels. This is because the process of ketosis leads to increased water and sodium loss. If not properly managed, this can result in symptoms like fatigue, headaches, and muscle cramps. To combat this, I advise increasing salt intake moderately and supplementing with magnesium and potassium, either through diet or supplements, depending on the individual’s specific needs and medical history.
Through my practice and research, I’ve compiled data on the most common nutrient deficiencies observed in individuals following a low-carb diet. The table below summarizes these findings:
NutrientCommon Sources ExcludedRecommended Low-Carb Sources
Vitamin CFruits, Sweet PotatoesBell Peppers, Kale, Broccoli
FolateLegumes, GrainsAsparagus, Leafy Greens, Avocado
PotassiumBananas, PotatoesAvocado, Spinach, Mushrooms
Dietary FiberWhole Grains, LegumesChia Seeds, Almonds, Cauliflower
As a healthcare professional, I’m committed to providing guidance that helps individuals navigate these potential pitfalls, ensuring their nutritional needs are met without compromising the health benefits of a low-carb diet.
3. Athletes and High-Intensity Exercise
In my extensive experience working with athletes, I’ve observed firsthand the critical role carbohydrates play in high-intensity training and performance. Through my research and clinical practice, it’s become increasingly clear that athletes, especially those involved in endurance sports, face unique nutritional needs that a low-carb diet might not fully support.
For athletes, carbohydrates are more than just fuel; they’re a critical energy source during prolonged or high-intensity efforts. The body’s glycogen stores, primarily fueled by carbohydrates, are the most accessible energy source for muscles during exercise. When these stores are depleted, athletes often experience a significant drop in performance, commonly referred to as “hitting the wall.” This phenomenon is a stark indication that for some, slashing carbs can lead to detrimental effects on their athletic output.
Furthermore, recovery is a cornerstone of athletic training, enabling adaptations and performance improvements. Adequate carbohydrate intake supports recovery by replenishing glycogen stores, facilitating the repair process, and preparing the body for the next workout session. After years of observing athletes’ diets and recovery, I’ve concluded that those adhering to rigid low-carb diets often report longer recovery times and increased fatigue, which ultimately impacts their training and performance.
Through my work at Zeroing In On Health, I’ve aimed to guide athletes in tailoring their diets to meet their specific energy needs. It’s essential to strike a balance that supports one’s training regimen while optimizing overall health. For some athletes, this might mean incorporating moderate amounts of carbohydrates strategically around workouts to boost performance and enhance recovery.
In navigating the complex world of sports nutrition, it’s crucial to consider individual variability. Athletes’ metabolic responses to diets can vary widely, meaning a one-size-fits-all approach rarely works. My advice to athletes contemplating a low-carb diet is always to embark on this journey with caution and, ideally, under the guidance of a nutritional specialist.
4. Individuals with Eating Disorders or a History of Disordered Eating
Throughout my 15 years in nutritional science, I’ve seen firsthand the transformative power of low-carb diets in managing chronic diseases. However, I’ve also learned that these diets aren’t suitable for everyone, especially individuals with eating disorders or a history of disordered eating.
In my practice, I’ve encountered numerous cases where dietary restrictions, such as those imposed by low-carb diets, can inadvertently trigger unhealthy behaviors in individuals with this background. The focus on eliminating entire food groups, like carbohydrates, can exacerbate feelings of guilt and obsession over what is consumed, potentially leading to a relapse or worsening of their condition.
For those with anorexia, bulimia, binge eating disorder, or any form of disordered eating, the primary goal should always be to foster a healthy relationship with food—one that focuses on balance, variety, and moderation, not restriction. A low-carb diet, with its inherent focus on limiting specific types of foods, might not align with this goal. It could deter the progress made towards healing their relationship with food and their body.
When working with patients who have a history of disordered eating, I stress the importance of consulting with healthcare providers experienced in eating disorders. It’s crucial to design a nutrition plan that supports their recovery and overall well-being. Sometimes, this means incorporating more carbohydrates than a low-carb diet would typically allow, ensuring they receive a well-rounded intake of all essential nutrients without triggering disordered eating habits.
From my experience, healing and recovery in these individuals are often supported by a diet that lacks strict boundaries around food groups, particularly carbohydrates. Establishing a dietary pattern that encourages a positive and intuitive approach to eating, rather than one focused on restriction, is usually more beneficial.
5. Mental and Emotional Wellness Considerations
In my journey exploring the multifaceted world of nutritional science, I’ve discovered that diet isn’t just about physical health. It plays a crucial role in our mental and emotional wellness too. Through my years of clinical practice and research, I’ve observed how adopting a low-carb diet may inadvertently affect some individuals’ psychological state, particularly if they’re prone to anxiety or depression.
One critical aspect I’ve learned is that drastically reducing carbohydrate intake can sometimes lead to mood swings and irritability. Carbohydrates are known to boost serotonin levels, a neurotransmitter that contributes to feelings of well-being and happiness. So, when I first considered reducing my carb intake, I had to take into account how it might impact not just my body but my mind as well.
Moreover, for those with a history of eating disorders, the emphasis on food restriction inherent in low-carb diets can be triggering. It’s why I’ve always advocated for a balanced approach, prioritizing mental health as much as physical health. Collaboration with healthcare providers experienced in mental health becomes indispensable under these circumstances.
Nutritional interventions should never be one-size-fits-all. In my practice, when discussing dietary changes with my patients, especially those contemplating low-carb diets for weight loss or health improvement, I ensure to tread carefully around topics of food restriction. I aim to create a sustainable plan that fosters a positive relationship with food while achieving their health goals. This includes emphasizing whole, nutrient-dense foods and possibly integrating mindful eating practices.
Observing my patients’ journey and reflecting on my own experiences, I’ve recognized the importance of supporting not only the physical dimension of health but the mental and emotional aspects as well. It’s clear that nutrition plays a critical role in this holistic view of health, and tailoring dietary plans to individual needs becomes paramount.
Conclusion
Navigating the world of diets can be complex and the low-carb approach is no exception. It’s clear that while it may offer benefits for some, it’s not a one-size-fits-all solution. If you’re dealing with health conditions like kidney disease or metabolic disorders, or if you’re an athlete requiring ample energy, stepping back and reconsidering your diet is crucial. The same goes for anyone with a history of eating disorders or those prioritizing mental and emotional well-being. Remember, the goal is to foster a healthy relationship with food that supports both your physical and mental health. Before making any significant dietary changes it’s essential to consult with healthcare providers and nutritional specialists. They’ll help you create a plan that’s tailored to your unique needs ensuring you don’t miss out on vital nutrients. Ultimately listening to your body and making informed choices is key to finding a dietary approach that works for you.
Similar Posts | {
"url": "https://zeroinginonhealth.com/low-carb/avoid/",
"source_domain": "zeroinginonhealth.com",
"snapshot_id": "CC-MAIN-2024-10",
"warc_metadata": {
"Content-Length": "79614",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:IEOERSM2DRTYMGGFML3DZK3AGI3LWMVR",
"WARC-Concurrent-To": "<urn:uuid:1e8c15bb-b5e1-4872-b6db-207bfcb3f9d0>",
"WARC-Date": "2024-02-27T22:46:43",
"WARC-IP-Address": "194.1.147.22",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:ZRA2NJYV3SYNI7R6STMITWB77ZMDCQZZ",
"WARC-Record-ID": "<urn:uuid:f82b451d-239e-49d7-b6f3-5bf2963eab40>",
"WARC-Target-URI": "https://zeroinginonhealth.com/low-carb/avoid/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:b2646b2d-6838-4e49-9f45-4acfa540724a>"
},
"warc_info": "isPartOf: CC-MAIN-2024-10\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for February/March 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-239\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
41,
42,
395,
396,
775,
776,
809,
810,
1137,
1138,
1701,
1702,
2122,
2123,
2390,
2391,
2649,
2650,
2903,
2904,
2960,
2961,
3331,
3332,
3674,
3675,
4008,
4009,
4349,
4350,
4619,
4620,
4650,
4705,
4770,
4821,
4870,
4871,
5424,
5425,
5468,
5469,
6019,
6020,
6477,
6478,
7000,
7001,
7189,
7190,
7250,
7310,
7364,
7418,
7485,
7486,
7712,
7713,
7753,
7754,
8121,
8122,
8645,
8646,
9153,
9154,
9547,
9548,
9920,
9921,
9992,
9993,
10287,
10288,
10689,
10690,
11133,
11134,
11607,
11608,
11937,
11938,
11986,
11987,
12399,
12400,
12800,
12801,
13165,
13166,
13664,
13665,
14015,
14016,
14027,
14028,
14990,
14991
],
"line_end_idx": [
41,
42,
395,
396,
775,
776,
809,
810,
1137,
1138,
1701,
1702,
2122,
2123,
2390,
2391,
2649,
2650,
2903,
2904,
2960,
2961,
3331,
3332,
3674,
3675,
4008,
4009,
4349,
4350,
4619,
4620,
4650,
4705,
4770,
4821,
4870,
4871,
5424,
5425,
5468,
5469,
6019,
6020,
6477,
6478,
7000,
7001,
7189,
7190,
7250,
7310,
7364,
7418,
7485,
7486,
7712,
7713,
7753,
7754,
8121,
8122,
8645,
8646,
9153,
9154,
9547,
9548,
9920,
9921,
9992,
9993,
10287,
10288,
10689,
10690,
11133,
11134,
11607,
11608,
11937,
11938,
11986,
11987,
12399,
12400,
12800,
12801,
13165,
13166,
13664,
13665,
14015,
14016,
14027,
14028,
14990,
14991,
15004
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 15004,
"ccnet_original_nlines": 98,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3501494824886322,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.011958150193095207,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.14611360430717468,
"rps_doc_frac_unique_words": 0.3276576101779938,
"rps_doc_mean_word_length": 5.737229824066162,
"rps_doc_num_sentences": 108,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.782924652099609,
"rps_doc_word_count": 2173,
"rps_doc_frac_chars_dupe_10grams": 0.009304559789597988,
"rps_doc_frac_chars_dupe_5grams": 0.0689018964767456,
"rps_doc_frac_chars_dupe_6grams": 0.04371540993452072,
"rps_doc_frac_chars_dupe_7grams": 0.036255721002817154,
"rps_doc_frac_chars_dupe_8grams": 0.025988610461354256,
"rps_doc_frac_chars_dupe_9grams": 0.009304559789597988,
"rps_doc_frac_chars_top_2gram": 0.012192189693450928,
"rps_doc_frac_chars_top_3gram": 0.017325740307569504,
"rps_doc_frac_chars_top_4gram": 0.004491860046982765,
"rps_doc_books_importance": -1106.8441162109375,
"rps_doc_books_importance_length_correction": -1106.8441162109375,
"rps_doc_openwebtext_importance": -714.4703979492188,
"rps_doc_openwebtext_importance_length_correction": -714.4703979492188,
"rps_doc_wikipedia_importance": -565.522216796875,
"rps_doc_wikipedia_importance_length_correction": -565.522216796875
},
"fasttext": {
"dclm": 0.5999293327331543,
"english": 0.9293422102928162,
"fineweb_edu_approx": 2.764857292175293,
"eai_general_math": 0.03805917873978615,
"eai_open_web_math": 0.2202511429786682,
"eai_web_code": 0.003917570225894451
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
6,213,966,305,399,258,000 | Format
Send to:
Choose Destination
See comment in PubMed Commons below
Ambul Pediatr. 2002 Jul-Aug;2(4):261-7.
Is there a common cold constitution?
Author information
• 1Department of Pediatrics and the Steele Memorial Children's Research Center, University of Arizona College of Medicine, Tucson 85724-5073, USA. tball@u.arizona.edu
Abstract
OBJECTIVE:
Constitutional factors might play a role in the susceptibility to clinical illness during the common cold. This study seeks to determine if the likelihood of developing frequent common colds persists during childhood.
DESIGN:
The Tucson Children's Respiratory Study involves 1246 children enrolled at birth and followed prospectively since 1980 and 1984. Parents reported the occurrence of frequent (> or =4) colds during the past year by questionnaire at 2, 3, 6, 8, 11, and 13 years of age. Blood for ex vivo interferon-gamma responses was obtained at 9 months and 11 years of age.
RESULTS:
After adjustment for potential confounding variables, children with frequent colds at year 2 or 3 were twice as likely to experience frequent colds at year 6 (relative risk [RR], 2.8; 95% confidence interval [CI], 2.1-3.9), year 8 (RR, 2.6; 95% CI, 2.1-3.3), year 11 (RR, 2.4; 95% CI, 1.8-3.1), and year 13 (RR, 2.1; 95% CI, 1.4-3.3) compared with children who had infrequent colds at years 2 and 3. At 9 months of age, children who ultimately experienced persistent frequent colds had lower interferon-gamma titers than children without persistent frequent colds (3.05 +/- 1.61 vs 3.74 +/- 1.39, P =.016); this finding persisted at 11 years of age.
CONCLUSION:
These data suggest the existence of a common cold constitution, whereby some children are more susceptible to infection and/or the expression of clinical symptoms when infected than are other children.
PMID:
12135399
[PubMed - indexed for MEDLINE]
PubMed Commons home
PubMed Commons
0 comments
How to join PubMed Commons
Supplemental Content
Loading ...
Write to the Help Desk | {
"url": "http://www.ncbi.nlm.nih.gov/pubmed/12135399",
"source_domain": "www.ncbi.nlm.nih.gov",
"snapshot_id": "crawl=CC-MAIN-2015-27",
"warc_metadata": {
"Content-Length": "77442",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:5NKIOPUTN2U2424PA2N7RCCX3JARR2UC",
"WARC-Concurrent-To": "<urn:uuid:ba6c9dd4-50bb-4a72-83df-51949c21271e>",
"WARC-Date": "2015-07-01T01:19:40",
"WARC-IP-Address": "130.14.29.110",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:NPNJ5H6MJUHGXOM6A5QAJS7PC4KGDP3J",
"WARC-Record-ID": "<urn:uuid:b7f04038-6aae-4fe2-a014-ad5fa2be4243>",
"WARC-Target-URI": "http://www.ncbi.nlm.nih.gov/pubmed/12135399",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:90e2cfa5-80a0-4ad8-a7e0-1955c4605cb7>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-179-60-89.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2015-27\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for June 2015\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
7,
8,
17,
18,
37,
73,
113,
114,
151,
152,
171,
172,
341,
342,
351,
352,
363,
364,
582,
583,
591,
592,
950,
951,
960,
961,
1611,
1612,
1624,
1625,
1827,
1828,
1834,
1843,
1874,
1894,
1895,
1910,
1911,
1922,
1949,
1950,
1975,
1976,
1992
],
"line_end_idx": [
7,
8,
17,
18,
37,
73,
113,
114,
151,
152,
171,
172,
341,
342,
351,
352,
363,
364,
582,
583,
591,
592,
950,
951,
960,
961,
1611,
1612,
1624,
1625,
1827,
1828,
1834,
1843,
1874,
1894,
1895,
1910,
1911,
1922,
1949,
1950,
1975,
1976,
1992,
2018
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2018,
"ccnet_original_nlines": 45,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.20728929340839386,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0364464707672596,
"rps_doc_frac_lines_end_with_ellipsis": 0.021739130839705467,
"rps_doc_frac_no_alph_words": 0.38952162861824036,
"rps_doc_frac_unique_words": 0.603960394859314,
"rps_doc_mean_word_length": 5.151815414428711,
"rps_doc_num_sentences": 33,
"rps_doc_symbol_to_word_ratio": 0.0022778999991714954,
"rps_doc_unigram_entropy": 4.91526985168457,
"rps_doc_word_count": 303,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.033311981707811356,
"rps_doc_frac_chars_top_3gram": 0.019218450412154198,
"rps_doc_frac_chars_top_4gram": 0.029468290507793427,
"rps_doc_books_importance": -179.0963592529297,
"rps_doc_books_importance_length_correction": -179.0963592529297,
"rps_doc_openwebtext_importance": -98.43171691894531,
"rps_doc_openwebtext_importance_length_correction": -98.43171691894531,
"rps_doc_wikipedia_importance": -51.68645095825195,
"rps_doc_wikipedia_importance_length_correction": -51.68645095825195
},
"fasttext": {
"dclm": 0.022675810381770134,
"english": 0.8946234583854675,
"fineweb_edu_approx": 2.5545456409454346,
"eai_general_math": 0.003815949894487858,
"eai_open_web_math": 0.1325908899307251,
"eai_web_code": 0.00370275997556746
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "618.9286",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Women — Health and hygiene, Children — Health and hygiene, Gynecology, and Pediatrics"
}
},
"secondary": {
"code": "616.994",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-1,675,860,776,501,626,600 | anonymous
• anonymous
explain total parenteral nutrition @explain total parenteral nutrition @Health Sciences
Health Sciences
chestercat
• chestercat
I got my questions answered at brainly.com in under 10 minutes. Go to brainly.com now for free help!
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas molestias excepturi sint occaecati cupiditate non provident, similique sunt in culpa qui officia deserunt mollitia animi, id est laborum et dolorum fuga. Et harum quidem rerum facilis est et expedita distinctio. Nam libero tempore, cum soluta nobis est eligendi optio cumque nihil impedit quo minus id quod maxime placeat facere possimus, omnis voluptas assumenda est, omnis dolor repellendus. Itaque earum rerum hic tenetur a sapiente delectus, ut aut reiciendis voluptatibus maiores alias consequatur aut perferendis doloribus asperiores repellat.
Get this expert
answer on brainly
SEE EXPERT ANSWER
Get your free account and access expert answers to this
and thousands of other questions
anonymous
• anonymous
TPN - in certain cases we cannot feed the patient through his alimentary system - for example - he doesnt have any (due to trauma, or big surgery that warrants complete prolonged bowel rest). in order to prevent malnutrition, we gotta get the food somwhow in there. the blood is a good idea, only thing is the blood cannot digest (that is why we got the digestive system), sou gotta use elementals - AA, fatty acids, simple sugars. parenteral - means through the veins (not enteric) some problems with tpn - cant be hyperosmolar - will ruin the vein through which it is give. the nutrition is heaven upon earth to hungry pathogens - so it tends to get infected
anonymous
• anonymous
The indications for the implementation of parenteral nutrition are situations when feeding via the gut is impossible, insufficient or inappropriate. Parenteral nutrition is amended as: in extensive burns, especially when involving the gastrointestinal tract: -in children with congenital defects of the digestive system and in preterm infants in whom the gastrointestinal tract is not sufficiently developed, -during chemotherapy and radiotherapy (in some cases) -in a coma and the other cases remain for a long time can lose consciousness -in the gastrointestinal tract obstruction in the gastrointestinal tract fistulae. -in the perioperative period in patients malnourished or debilitated -in short bowel syndrome -in disorders of intestinal absorption in Crohn's disease -in acute pancreatitis -sometimes to treat severe cases of anorexia and bulimia When it comes to use it in this case, each patient is interpreted individually, not every patient is equally applies.
Looking for something else?
Not the answer you are looking for? Search for more explanations. | {
"url": "http://openstudy.com/updates/4ead1db5e4b0cb91761640b6",
"source_domain": "openstudy.com",
"snapshot_id": "crawl=CC-MAIN-2017-17",
"warc_metadata": {
"Content-Length": "43867",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:M5YNCKHR7LB2X2HUAFZLLWEZHE7SSTJN",
"WARC-Concurrent-To": "<urn:uuid:b3e9170d-8cd3-441c-a8ee-79b42312d579>",
"WARC-Date": "2017-04-28T04:34:51",
"WARC-IP-Address": "52.0.184.118",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:TMABZIAEU6ZYRCACIG2HKAJIZM7LBOBV",
"WARC-Record-ID": "<urn:uuid:019e89b9-baa9-4079-9efa-a7dec164a99a>",
"WARC-Target-URI": "http://openstudy.com/updates/4ead1db5e4b0cb91761640b6",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:d65117a9-ab1c-40c1-b236-dff4a990d1f6>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-145-167-34.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-17\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for April 2017\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
10,
24,
112,
128,
139,
154,
255,
947,
948,
964,
965,
983,
984,
1002,
1003,
1059,
1092,
1093,
1103,
1117,
1778,
1788,
1802,
2775,
2776,
2804,
2805
],
"line_end_idx": [
10,
24,
112,
128,
139,
154,
255,
947,
948,
964,
965,
983,
984,
1002,
1003,
1059,
1092,
1093,
1103,
1117,
1778,
1788,
1802,
2775,
2776,
2804,
2805,
2870
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2870,
"ccnet_original_nlines": 27,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 1,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3286572992801666,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.012024049647152424,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.13627254962921143,
"rps_doc_frac_unique_words": 0.6327944397926331,
"rps_doc_mean_word_length": 5.427251815795898,
"rps_doc_num_sentences": 18,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.276464462280273,
"rps_doc_word_count": 433,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.03234042972326279,
"rps_doc_frac_chars_top_3gram": 0.040851060301065445,
"rps_doc_frac_chars_top_4gram": 0.02638298086822033,
"rps_doc_books_importance": -204.2349395751953,
"rps_doc_books_importance_length_correction": -204.2349395751953,
"rps_doc_openwebtext_importance": -130.43136596679688,
"rps_doc_openwebtext_importance_length_correction": -130.43136596679688,
"rps_doc_wikipedia_importance": -97.95594024658203,
"rps_doc_wikipedia_importance_length_correction": -97.95594024658203
},
"fasttext": {
"dclm": 0.020951449871063232,
"english": 0.7551108598709106,
"fineweb_edu_approx": 2.3114984035491943,
"eai_general_math": 0.036972519010305405,
"eai_open_web_math": 0.3205209970474243,
"eai_web_code": 0.015862759202718735
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "616.07",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "5",
"label": "Social/Forum"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "2",
"label": "Click Here References"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
2,024,860,655,010,691,000 | How to give up smoking
how to give up smoking Smoking tobacco products can lead to severe health problems and even death while quitting smoking can be very difficult for some smokers, there are smoking cessation programs and medications that can help smokers quit there are many lifelong benefits of doing so, like increased lung function and decreased risk of heart disease and cancer.
How to give up smoking forget about tomorrow, next weekend,next christmas. Read these 10 quick tips to help you quit smoking, including nicotine patches, motivation and other information on giving up smoking. How to quit smoking nicotine is one of the most harmful and widely available legal drugs in the world it's addictive and harmful both to smokers and the people passively exposed to smoke, especially children if you'd like to give up. How to persuade someone to quit smoking persuading someone to quit smoking isn't always an easy task it's possible that your smoker has tried to quit, but failed it's possible that they want to quit, but don't have the tools or support. Researchers find those using e-cigarettes daily, especially ones with refillable tanks, made more effort to give up over a year than infrequent users. The national cancer institute should be credited as the source and a link to this page included, eg, where to get help when you decide to quit smoking was originally published by the national cancer institute. Weed holding your life back learn how to stop smoking it with minimal withdrawals and natural detox lots of free articles on how to quit weed, withdrawal, natural detox, depression, top reasons to stop pot smoking the latest free research-based and practical tools to free you from weed. Quitting is a huge challenge for most smokers how to help a smoker quit -- without making kicking the habit even harder.
how to give up smoking Smoking tobacco products can lead to severe health problems and even death while quitting smoking can be very difficult for some smokers, there are smoking cessation programs and medications that can help smokers quit there are many lifelong benefits of doing so, like increased lung function and decreased risk of heart disease and cancer.
Giving up smoking is not easy but you can up your chances of stopping smoking successfully with a little forward planning and support. Give up smoking guide for a smoker, giving up cigarettes is in the same league as giving up food, water, a child even it's a serious undertaking, only achieved by the strongest and the most determined. Encouraging people to stop smoking department of mental health and substance dependence world health organization smoking causes an enormous burden on public health of readiness to quit upon completion of the module the. Is it important for someone diagnosed with cancer to quit smoking where can i get help to quit smoking what harmful chemicals does tobacco smoke contain tobacco smoke contains many chemicals that are harmful to both smokers and nonsmokers. Learn how to quit smoking smoking is an addictive disease, read about the steps to quit smoking including medication and behavior modification. Building a mindset to help you quit smoking permanently is a process use these tips to help you start to change your relationship with cigarettes.
The american lung association offers resources to help smokers figure out their reasons for quitting and then take the big step of quitting for good. Quit smoking for good using allen carr's famous easyway to stop smoking method choose one to suit you including online seminars and face-to-face sessions. It's not because you lack willpower that you can't quit smoking willpower alone is not enough to succeed at quitting smoking.
As we welcome in 2014, many will resolve to stub out smoking for good how can councils help people kick the habit. Get the help you need to quit, the way you want it, for free we just need a few details to get started. Learn the five natural ways scientifically-proven to kick your cigarette habit in the butt. Hypnotist paul mckenna has entranced millions now he is back with a new crusade - to help smokers give up the cigarettes for good follow his six point plan to quitting.
First, congratulate yourself just reading this article is a big step toward becoming tobacco-free many people don't quit smoking because they think it's too hard, and it's true that for most people quitting isn't easy after all, the nicotine in cigarettes is a powerfully addictive drug but with. Keeping busy is a great way to stay smokefree on your quit day being busy will help you keep your mind off smoking and distract you from cravings. Quit smoking nicotine is one of the most heavily used addictive drugs as well as the leading preventable cause of disease, disability, and death in the united states.
How to give up smoking
A brief description of ten helpful tips for people giving up smoking tobacco learn about the most effective methods about how to stop here.
• Half of all sa smokers tried to quit last year -and failed how can we raise the success rate.
• 13 best quit-smoking tips ever 1 / 13 1 when you stop smoking, nicotine withdrawal may give you headaches, affect your mood, or sap your energy don't try to diet while you give up cigarettes too much deprivation can easily backfire.
• For smoking cessation, quitting cold turkey was 25% more effective than gradually cutting down on cigarettes.
• Want to give up smoking, but don't know how to do it a team of researchers has analysed what works and what doesn't.
• Millions are helplessly addicted to tobacco, unaware that a natural aid for smoking cessation can be found not at the local pharmacy, but at your grocer's fruit stand.
This section provides resources such as, quit tips, quit plans, and educational materials that support your effort to quit smoking skip directly to search skip directly to a to z list skip directly to navigation skip directly to page options skip directly to site content. Life's best ideas to help a friend or relative stop smoking support in a meaningful and fun way to show you care to help someone quit smoking and that they are worth having around a little longer. Once you stop smoking, how long will it take for your body to heal and for smoking related risks to decline to levels seen in non-smokers this stop smoking benefits timetable answers that question.
how to give up smoking Smoking tobacco products can lead to severe health problems and even death while quitting smoking can be very difficult for some smokers, there are smoking cessation programs and medications that can help smokers quit there are many lifelong benefits of doing so, like increased lung function and decreased risk of heart disease and cancer.
How to give up smoking
Rated 3/5 based on 20 review
Similar articles to how to give up smoking
2018. | {
"url": "http://kapaperjzww.ultimatestructuredwater.info/how-to-give-up-smoking.html",
"source_domain": "kapaperjzww.ultimatestructuredwater.info",
"snapshot_id": "crawl=CC-MAIN-2018-30",
"warc_metadata": {
"Content-Length": "14298",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:OXMQNUIGKAAHFFZTFE653GP7U5VYRROJ",
"WARC-Concurrent-To": "<urn:uuid:d09dee9c-9b90-49e5-821f-cdffce40bc28>",
"WARC-Date": "2018-07-17T23:25:36",
"WARC-IP-Address": "104.27.174.248",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:SXLXVI4QIGLOZPDPINKJSM2HAHQKSINN",
"WARC-Record-ID": "<urn:uuid:c656bd9b-e4c9-4b28-aefd-88c2f1a6959f>",
"WARC-Target-URI": "http://kapaperjzww.ultimatestructuredwater.info/how-to-give-up-smoking.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:18bb428f-a3d3-4256-af2b-f113a4561603>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-141-37-174.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2018-30\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for July 2018\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
23,
24,
388,
389,
1839,
1840,
2204,
2205,
3294,
3295,
3726,
3727,
4207,
4208,
4819,
4820,
4843,
4844,
4984,
4985,
5083,
5320,
5434,
5555,
5727,
5728,
6396,
6397,
6761,
6784,
6813,
6814,
6857,
6858
],
"line_end_idx": [
23,
24,
388,
389,
1839,
1840,
2204,
2205,
3294,
3295,
3726,
3727,
4207,
4208,
4819,
4820,
4843,
4844,
4984,
4985,
5083,
5320,
5434,
5555,
5727,
5728,
6396,
6397,
6761,
6784,
6813,
6814,
6857,
6858,
6863
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 6863,
"ccnet_original_nlines": 34,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 1,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4502297043800354,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0007657000096514821,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.10030627995729446,
"rps_doc_frac_unique_words": 0.3726333975791931,
"rps_doc_mean_word_length": 4.783993244171143,
"rps_doc_num_sentences": 37,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.307298183441162,
"rps_doc_word_count": 1162,
"rps_doc_frac_chars_dupe_10grams": 0.16945494711399078,
"rps_doc_frac_chars_dupe_5grams": 0.1982370913028717,
"rps_doc_frac_chars_dupe_6grams": 0.18132758140563965,
"rps_doc_frac_chars_dupe_7grams": 0.18132758140563965,
"rps_doc_frac_chars_dupe_8grams": 0.18132758140563965,
"rps_doc_frac_chars_dupe_9grams": 0.16945494711399078,
"rps_doc_frac_chars_top_2gram": 0.014391079545021057,
"rps_doc_frac_chars_top_3gram": 0.01583019085228443,
"rps_doc_frac_chars_top_4gram": 0.02428494021296501,
"rps_doc_books_importance": -549.6204223632812,
"rps_doc_books_importance_length_correction": -549.6204223632812,
"rps_doc_openwebtext_importance": -326.5509033203125,
"rps_doc_openwebtext_importance_length_correction": -326.5509033203125,
"rps_doc_wikipedia_importance": -253.25303649902344,
"rps_doc_wikipedia_importance_length_correction": -253.25303649902344
},
"fasttext": {
"dclm": 0.1056470274925232,
"english": 0.957362711429596,
"fineweb_edu_approx": 2.4292991161346436,
"eai_general_math": 0.006507690064609051,
"eai_open_web_math": 0.04378407821059227,
"eai_web_code": 0.0016528399428352714
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "23",
"label": "Tutorial"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
7,713,688,747,163,377,000 | | |
Gap in Teeth
It’s better to have white, well-aligned teeth. Your luck may slip through the gaps between your teeth.
Are you concerned about your gap between teeth? In this article, we are going to talk about the causes of gap in teeth, and possible treatment options for gap in teeth. In phrenology, people often talk about good physiognomy or the correlation between facial features related to wealth. Even if you don’t believe in the old saying, many people think the gaps between teeth are a major concern. Even when you smile, you may not be able to smile openly or you may even develop habits of covering your mouth with your hands. You may also have problems with your pronunciation. In terms of oral health, dental cavities and gum diseases can easily occur, so it is recommended to improve the gaps between teeth for oral health. Let’s find out what causes this problem and ways to solve it.
What Causes Gap In Teeth?
People who are subconscious of their gaps between teeth develop habits of covering their mouths when talking or laughing. In addition, the gaps between teeth cause various inconveniences in real life, including problems with pronunciation.
So what causes the gaps between teeth? Well, they can be classified into internal and external causes.
1. Innate Causes
The size difference between jawbone and teeth
The first main cause of gaps between teeth is the size difference between jawbone and teeth. Simply put, assuming that there is a 14cm frame, and if the frame must be filled with 14 blocks, the size of the block must be uniform at 1cm to fit correctly within the frame. But if the blocks are small or gone missing, there may be gaps between these blocks. The same rule applies to our teeth. If the teeth are missing or smaller than the jawbone, there will be a space in the arrangement.
Overdevelopment of Frenulum Labii Maxillaris
The second cause is the ‘overdevelopment of frenulum labii maxillaris’. If the frenulum labii maxillaris (a band-shaped wrinkle in the inner part of the upper lip) is overly developed, the gums form wrinkles between the teeth and eventually, the teeth cannot stay in place. In this case, part of the frenulum labii maxillaris must be removed to find the alignment of teeth.
2. External causes
After Receiving Orthodontic Treatment
Usually, orthodontic treatment is chosen to straighten out your teeth, but once the treatment is finished, there may be open spaces between them, which are called the black triangles. This happens when your teeth are removed and the rest of the teeth are not completely closed to fill in those empty spaces.
Dental Malocclusion
The first main external cause is dental malocclusion. Intersection refers to the intersection of the upper and lower teeth. Usually, it is considered an ideal intersection if the top teeth slightly cover the lower teeth. If you continue to apply forces in a wrong way or grind your teeth continuously, your teeth may get pushed sideways, creating gaps.
Gum disease
The second cause is gum disease. There are differences in the degree among people, but your teeth and gums also age as you get older. Our gums hold the teeth tightly in the beginning, but once they go through the aging process or dental trauma, our teeth may start moving or shaking. In this case, the fundamental cause of gum disease should be removed through gum treatment first. However, you should be careful not to miss the time window for treatment because gum treatment does not improve your gum condition easily or instantly.
Treatment Method Options for Gap In Teeth
1. Orthodontic Treatment
Orthodontic treatment may help adjust the gaps, but it comes with disadvantages such as longer treatment periods and the patients must be putting on braces continuously during the treatment periods.
On top of the orthodontic treatment, the overdevelopment of frenulum labii maxillaris and gum disease must be dealt with at the same time, which could be limiting factors in correcting the gaps between teeth. Also, the treatment can narrow down the gap between teeth with braces (as shown above), but it may not improve the shape of the teeth in patients with square teeth.
2. Resin Treatment
It is a treatment that fills open spaces using resin, a material widely used for such treatment. We repeat the process of hardening by adding resin little by little, and because open spaces can be treated quickly by using dental fillings, the treatment can be done within a day on your first visit and the price of the treatment is affordable to most people.
However, during the filling and hardening process with heat, tooth cracks may appear in the treated area, and due to the nature of the material, there is a disadvantage of receiving another treatment again within just a few years due to the risk of tooth discoloration or the elimination of resin.
3. Crowns
If your teeth require extensive full-scale treatment, we may proceed with crown treatment. Crown treatment is a stronger and more stable treatment than resin treatment, which is applied and hardened in a way that completely covers gaps between your teeth. However, it should be considered that the tooth molding process may lead to errors, unnecessary tooth deletion to secure more space for prosthodontics and that the damaged tooth surface (enamel) cannot be regenerated.
4. Porcelain Veneer Treatment
Porcelain Veneers treatment, widely known as aesthetic therapy, can also improve the gaps between teeth. The thin porcelain veneer on the front teeth is made as wide as the original teeth to fill in the gaps. You can improve the shape and color of your teeth at the same time while filling the gaps.
However, your teeth can be deleted at an appropriate level to secure more space for porcelain veneers, and the veneers are easily susceptible to damage.
5. Minish One-day Treatment
Minish Veneer is a kind of veneer Minish Dental Hospital is providing. The production & bonding process/restoration of eggshells with state-of-the-art technology. It restores damaged teeth and gums by filling in the damaged spaces with the material that is most similar to natural teeth without unnecessary tooth deletion.
In any case, the functional recovery of your teeth is possible without damaging your teeth, and at the same time, aesthetic recovery is possible to match the oral condition and overall facial harmony. They can also be managed after treatment in the same way as natural teeth.
Treatment Example
Elimination of frenulum labii maxillaris: First, the left and right gum lines that were not symmetrical at first are now in alignment. The periodontal sac, which can be the habitat of bacteria between teeth and gums, was removed to eliminate the source of gum disease. The overdeveloped frenulum labii maxillaris, which was the main cause of the gaps between teeth, is now partially removed and sealed up to make it look shorter.
Minish Veneer Treatment: We filled in all the spaces to form natural-looking teeth. We avoided damaging the natural teeth or utilizing prosthodontics. Instead, we filled in the enamel part with Minish treatment to restore and protect natural teeth at the same time. The broken teeth right next to the left front teeth have also been recovered, improving the overall shape of every tooth.
Treatment Process
1. Organize only the contaminated and rough surfaces of the teeth (No anesthesia required)
2. After making an impression of the teeth, design the tooth pattern that fits each individual. (You can consult the doctors and dental technicians to choose the design and color you desire.)
3. Combine the design of Minish orthodontics with a suitable bonding material.
Benefits
• It is possible to recover the dental health of natural teeth weakened by damage and aging.
• It does not harm your teeth.
• It is a treatment that restores the strength of your teeth.
• Permanent use is possible depending on how the patient manages one’s teeth.
• It is aesthetically excellent and the results of treatment are natural.
• Treatment time is very short. Treatment is available on the first day of the visit.
Do I still need to receive treatment even if there is no problem with functionality?
If there are gaps between teeth, food may easily get stuck in between, affecting gum health. Also, the food stuck in those gaps may cause dental problems such as bad breath by creating an environment where bacteria can reproduce freely as well as aesthetic problems such as pronunciation problems.
Most of the patients who have visited us simply for aesthetic purposes have not had much damage to the enamel, the outer layer of their teeth. Minish Dental Hospital approaches such problems to the enamel layer differently, which is now recognized by academia.
Treatment to restore the properties of natural teeth not only allows the original natural teeth to be used for a long time, but also provides preventive effects to prevent dental problems in advance, reducing visits to the dentist in the future. Many people visit simply because of aesthetic problems, but Minish Dental Hospital takes various things into account, including dental health, aesthetic satisfaction, and the appearance and color of natural teeth.
Real Case Images – Gap In teeth
Minish treatment due to congenital development problems
Minish treatment after orthodontic treatment
Minish treatment due to gum aging accompanied by dental aging
Some people complain of various inconveniences in their daily lives with the gaps between their teeth. They sometimes have to cover their mouths due to insecurities or even take selfies out in public. On top of the orthodontic treatment, the overdevelopment of frenulum labii maxillaris and gum disease must be dealt with at the same time, which could be limiting factors in correcting the gaps between teeth. Also, the treatment can narrow down the gap between teeth with braces (as shown above), but it may not improve the shape of the teeth in patients with square teeth.
Conclusion
Have you experienced any discomfort today, such as problems with pronouncing words due to the gaps between teeth? By choosing the right treatment, you can easily recover your lost confidence and find your smile within a short period at Minish Dental Hospital.
Similar Posts | {
"url": "https://www.minishteeth.com/blog/gap-in-teeth/",
"source_domain": "www.minishteeth.com",
"snapshot_id": "CC-MAIN-2023-40",
"warc_metadata": {
"Content-Length": "166938",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:KFY636KCGIREYK7T67XI43BFOWZHQF5D",
"WARC-Concurrent-To": "<urn:uuid:c86d388e-e358-445e-8171-84d007073c39>",
"WARC-Date": "2023-09-30T07:20:18",
"WARC-IP-Address": "34.210.207.33",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:Q6GKAL42RY4FZYMXP4CX27RHDVUHO3TJ",
"WARC-Record-ID": "<urn:uuid:a8a729a7-de1e-4935-b1c9-ff2ea1d67ffd>",
"WARC-Target-URI": "https://www.minishteeth.com/blog/gap-in-teeth/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:dedef044-0a05-4de3-bbd7-7a4c42192553>"
},
"warc_info": "isPartOf: CC-MAIN-2023-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September/October 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-154\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
4,
5,
18,
19,
122,
123,
907,
908,
934,
935,
1176,
1177,
1280,
1281,
1298,
1299,
1345,
1346,
1833,
1834,
1879,
1880,
2254,
2255,
2274,
2275,
2313,
2314,
2622,
2623,
2643,
2644,
2997,
2998,
3010,
3011,
3545,
3546,
3588,
3589,
3614,
3615,
3815,
3816,
4190,
4191,
4210,
4211,
4570,
4571,
4869,
4870,
4880,
4881,
5355,
5356,
5386,
5387,
5687,
5688,
5841,
5842,
5870,
5871,
6222,
6223,
6499,
6500,
6518,
6519,
6949,
6950,
7338,
7339,
7357,
7358,
7451,
7645,
7726,
7727,
7737,
7738,
7833,
7866,
7930,
8010,
8086,
8174,
8175,
8260,
8261,
8559,
8560,
8821,
8822,
9282,
9283,
9315,
9316,
9372,
9373,
9418,
9419,
9481,
9482,
10057,
10058,
10069,
10070,
10331,
10332
],
"line_end_idx": [
4,
5,
18,
19,
122,
123,
907,
908,
934,
935,
1176,
1177,
1280,
1281,
1298,
1299,
1345,
1346,
1833,
1834,
1879,
1880,
2254,
2255,
2274,
2275,
2313,
2314,
2622,
2623,
2643,
2644,
2997,
2998,
3010,
3011,
3545,
3546,
3588,
3589,
3614,
3615,
3815,
3816,
4190,
4191,
4210,
4211,
4570,
4571,
4869,
4870,
4880,
4881,
5355,
5356,
5386,
5387,
5687,
5688,
5841,
5842,
5870,
5871,
6222,
6223,
6499,
6500,
6518,
6519,
6949,
6950,
7338,
7339,
7357,
7358,
7451,
7645,
7726,
7727,
7737,
7738,
7833,
7866,
7930,
8010,
8086,
8174,
8175,
8260,
8261,
8559,
8560,
8821,
8822,
9282,
9283,
9315,
9316,
9372,
9373,
9418,
9419,
9481,
9482,
10057,
10058,
10069,
10070,
10331,
10332,
10345
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 10345,
"ccnet_original_nlines": 111,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4239414632320404,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.00052274001063779,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11343439668416977,
"rps_doc_frac_unique_words": 0.30511462688446045,
"rps_doc_mean_word_length": 4.921222686767578,
"rps_doc_num_sentences": 93,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.317075729370117,
"rps_doc_word_count": 1701,
"rps_doc_frac_chars_dupe_10grams": 0.07215385884046555,
"rps_doc_frac_chars_dupe_5grams": 0.11061999946832657,
"rps_doc_frac_chars_dupe_6grams": 0.081471748650074,
"rps_doc_frac_chars_dupe_7grams": 0.081471748650074,
"rps_doc_frac_chars_dupe_8grams": 0.07215385884046555,
"rps_doc_frac_chars_dupe_9grams": 0.07215385884046555,
"rps_doc_frac_chars_top_2gram": 0.021024970337748528,
"rps_doc_frac_chars_top_3gram": 0.022936329245567322,
"rps_doc_frac_chars_top_4gram": 0.02042767032980919,
"rps_doc_books_importance": -836.0079956054688,
"rps_doc_books_importance_length_correction": -836.0079956054688,
"rps_doc_openwebtext_importance": -500.4734802246094,
"rps_doc_openwebtext_importance_length_correction": -500.4734802246094,
"rps_doc_wikipedia_importance": -406.6512756347656,
"rps_doc_wikipedia_importance_length_correction": -406.6512756347656
},
"fasttext": {
"dclm": 0.0902199074625969,
"english": 0.9494149088859558,
"fineweb_edu_approx": 2.853193759918213,
"eai_general_math": 0.15115857124328613,
"eai_open_web_math": 0.2639259696006775,
"eai_web_code": 0.01616436056792736
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.62",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.622",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-1,978,086,161,392,156,400 | What is a cold sore?
Definition
Cold sores are very common and are easily recognised because they often appear as blisters around the lips and mouth.
Cold sores are caused by the herpes simplex virus. There are two types: HSV-1 usually results in cold sores and HSV-2 is commonly associated with genital herpes. Both viruses lie dormant in your system until you get run down, or something triggers an attack.
Some people only get a cold sore once. Others find they have several during the year.
There's no cure! Once you've got the virus, unfortunately, you've got it for life.
Triggers
If you can work out what triggers your cold sore attacks, you can at least be prepared. For some people it's environmental, for others it's physical or emotional stress.
Learn more about triggers
What are your triggers? | {
"url": "http://www.zovirax.com.au/what-is-a-cold-sore/",
"source_domain": "www.zovirax.com.au",
"snapshot_id": "crawl=CC-MAIN-2017-09",
"warc_metadata": {
"Content-Length": "17796",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:5ZHEV76OMCF662MG3YF42I7XRPXBIAZG",
"WARC-Concurrent-To": "<urn:uuid:1f197caa-93c7-4f90-9c4e-ce12193339e6>",
"WARC-Date": "2017-02-21T07:23:00",
"WARC-IP-Address": "66.54.49.163",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:BLCNV7YZKVGPWYF4VXCWSHAWKBRGF5J3",
"WARC-Record-ID": "<urn:uuid:e675e046-42d8-4210-9bc4-da156e4d1126>",
"WARC-Target-URI": "http://www.zovirax.com.au/what-is-a-cold-sore/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:9e56b61b-e939-4a6d-89b6-5cb6c4fd8ef6>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-171-10-108.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-09\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for February 2017\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
21,
22,
33,
34,
152,
153,
412,
413,
499,
500,
583,
584,
593,
594,
764,
765,
791
],
"line_end_idx": [
21,
22,
33,
34,
152,
153,
412,
413,
499,
500,
583,
584,
593,
594,
764,
765,
791,
814
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 814,
"ccnet_original_nlines": 17,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.44117647409439087,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0117647098377347,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.15882353484630585,
"rps_doc_frac_unique_words": 0.6666666865348816,
"rps_doc_mean_word_length": 4.666666507720947,
"rps_doc_num_sentences": 12,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.364632606506348,
"rps_doc_word_count": 138,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.03726708143949509,
"rps_doc_frac_chars_top_3gram": 0.027950309216976166,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -64.1178207397461,
"rps_doc_books_importance_length_correction": -64.1178207397461,
"rps_doc_openwebtext_importance": -30.653820037841797,
"rps_doc_openwebtext_importance_length_correction": -30.630096435546875,
"rps_doc_wikipedia_importance": -22.529691696166992,
"rps_doc_wikipedia_importance_length_correction": -22.529691696166992
},
"fasttext": {
"dclm": 0.9655933976173401,
"english": 0.9743494391441345,
"fineweb_edu_approx": 2.9748764038085938,
"eai_general_math": 0.1880144476890564,
"eai_open_web_math": 0.6770190596580505,
"eai_web_code": 0.0030123000033199787
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.07",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
7,744,113,309,898,988,000 | Can an Injury to Cheekbone/orbit Result in a Deviated Septum over Time? Help!
I injured my left cheekbone three years ago and currently waiting on further investigation. My septum seems to be deviating increasingly to the right of late. Would the injury to the cheekbone have caused this (it was likely a fracture)..it seems a lot more crooked than it was before the accident. I am 28 and am having a lot of sinus issues and worried.
Doctor Answers (3)
Deviated septum from injury
+1
The mechanism of injury associated with cheekbone/orbit injuries can cause a septal fracture and deviation. A deviated septum can contribute to poor aeration and drainage from your sinuses that can be related to your sinus issues. You should see a facial plastic surgeon or otolaryngologist to assess your septum and sinuses to see if you would benefit from a septoplasty and possible sinus surgery, or if other issues are contributing to the problems you are having.
Houston Facial Plastic Surgeon
5.0 out of 5 stars 3 reviews
Cheekbone fracture and deviated septum
+1
The septum could have been fractured and be deviated from the original injury when the cheekbone was fractured. The septum would not become deviated anytime after the initial trauma. There are multiple other causes of nasal obstruction on the inside of the nose such as a valve collapse, vestibular stenosis, turbinate hypertrophy, allergies that should all be in a dressed time of examination and consultation.
William Portuese, MD
Seattle Facial Plastic Surgeon
5.0 out of 5 stars 55 reviews
Deviated septum from injury
+1
Dear e4862,
• You could have dislodged the septum during the initial injury, but the mechanism does not really matter at this far out
• If you feel like your breathing through your nose is getting worse, please schedule an appointment so you can be evaluated
• Your sinus issues can also be addressed, and they may be more related to the cheekbone fracture, not the deviated septum
Best regards,
Nima Shemirani
Nima Shemirani, MD
Beverly Hills Facial Plastic Surgeon
5.0 out of 5 stars 21 reviews
You might also like...
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship. | {
"url": "http://www.realself.com/question/injury-cheekbone-orbit-result-in-deviated-septum-time-help",
"source_domain": "www.realself.com",
"snapshot_id": "crawl=CC-MAIN-2014-23",
"warc_metadata": {
"Content-Length": "87513",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:DOTN3UIW2IMXGRJZNM3QTBCFQTZSASCC",
"WARC-Concurrent-To": "<urn:uuid:5bb76aa6-cc41-49b1-b5e0-bc1f97f220cf>",
"WARC-Date": "2014-07-29T23:27:51",
"WARC-IP-Address": "72.21.92.20",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:RWYQ4Q67LNEUG2XA4C64WNTEASNQ6Y7R",
"WARC-Record-ID": "<urn:uuid:44e16586-4202-4841-81d8-e7731e1e24aa>",
"WARC-Target-URI": "http://www.realself.com/question/injury-cheekbone-orbit-result-in-deviated-septum-time-help",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:ac88fb89-69ac-40d3-b4b1-f743215065ed>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-146-231-18.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2014-23\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web with URLs provided by Blekko for July 2014\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
78,
79,
435,
436,
455,
456,
484,
485,
488,
489,
959,
960,
961,
992,
1021,
1022,
1061,
1062,
1065,
1066,
1480,
1481,
1502,
1533,
1563,
1564,
1592,
1593,
1596,
1597,
1609,
1610,
1734,
1861,
1986,
1987,
2001,
2002,
2017,
2018,
2037,
2074,
2104,
2105,
2128,
2129
],
"line_end_idx": [
78,
79,
435,
436,
455,
456,
484,
485,
488,
489,
959,
960,
961,
992,
1021,
1022,
1061,
1062,
1065,
1066,
1480,
1481,
1502,
1533,
1563,
1564,
1592,
1593,
1596,
1597,
1609,
1610,
1734,
1861,
1986,
1987,
2001,
2002,
2017,
2018,
2037,
2074,
2104,
2105,
2128,
2129,
2398
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2398,
"ccnet_original_nlines": 46,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4337078630924225,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.011235959827899933,
"rps_doc_frac_lines_end_with_ellipsis": 0.021276600658893585,
"rps_doc_frac_no_alph_words": 0.14157302677631378,
"rps_doc_frac_unique_words": 0.47979798913002014,
"rps_doc_mean_word_length": 4.866161823272705,
"rps_doc_num_sentences": 20,
"rps_doc_symbol_to_word_ratio": 0.0022471901029348373,
"rps_doc_unigram_entropy": 4.86622428894043,
"rps_doc_word_count": 396,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.07732225954532623,
"rps_doc_frac_chars_dupe_6grams": 0.051375191658735275,
"rps_doc_frac_chars_dupe_7grams": 0.051375191658735275,
"rps_doc_frac_chars_dupe_8grams": 0.051375191658735275,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.04359107092022896,
"rps_doc_frac_chars_top_3gram": 0.04151530936360359,
"rps_doc_frac_chars_top_4gram": 0.034250129014253616,
"rps_doc_books_importance": -212.9678192138672,
"rps_doc_books_importance_length_correction": -212.9678192138672,
"rps_doc_openwebtext_importance": -109.37016296386719,
"rps_doc_openwebtext_importance_length_correction": -109.37016296386719,
"rps_doc_wikipedia_importance": -64.06004333496094,
"rps_doc_wikipedia_importance_length_correction": -64.06004333496094
},
"fasttext": {
"dclm": 0.047646280378103256,
"english": 0.9501183032989502,
"fineweb_edu_approx": 1.237740159034729,
"eai_general_math": 0.011539939790964127,
"eai_open_web_math": 0.14539992809295654,
"eai_web_code": 0.00017399000353179872
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.622",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.62",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-1,455,189,569,132,095,200 | Journal Information
Vol. 45. Issue 9.
Pages e62-e64 (December 2021)
Vol. 45. Issue 9.
Pages e62-e64 (December 2021)
Scientific Letter
Full text access
Laser meter, an alternative to determine the height in critical patients. Concordance study
Medidor láser, una alternativa para la determinación de la altura en el paciente crítico. Estudio de concordancia
Visits
2616
J. Valls-Matarín
Corresponding author
finavalls@gmail.com
Corresponding author.
, M. del Cotillo-Fuente, M. Miranda-Ramírez, A.M. Parera-Pous
Unidad de Críticos, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain
This item has received
Article information
Full Text
Bibliography
Download PDF
Statistics
Figures (1)
Full Text
To the Editor,
Estimating the height of a person while standing up is considered the gold standard. However, due to the special characteristics of critically ill patients, this method cannot be used. The common practice followed by the Spanish intensive care units (ICU) is visual estimation even though it has proven inaccurate,1,2 and far from the clinical recommendations made.
Other methods used through indirect measurements like long bone measurement—ulna length or arm span—are closer to the standard of reference that is the visual method or the measuring tape.3–6 However, these are difficult to implement due to immobilizations, the presence of medical devices or swelling.
One of the main utilities of height in critically ill patients is to estimate the patient’s ideal weight so it can be applied to the tidal volume (TV) calculation. Protective ventilation reduces the number of infections, mortality, days on mechanical ventilation, and is associated with less pulmonary damage, and a slower progression of the acute respiratory distress syndrome (ARDS).7–9 Inaccurate height measurements can, therefore, be a source of error regarding the implementation of this ventilatory strategy.
This paper exposes the concordance of 2 methods (visual and laser-based) with the gold standard (height measuring device) to obtain the height of critically ill patients. Also, it illustrates its potential implication by estimating the patient’s ideal weight and TV.
Using the convenience sampling method, a series of patients admitted to the critical care unit with a diagnosis of myocardial infarction (Killip I) were included from October 2018 through July 2019 since this type of patient facilitates height measurement in bipedalism in the same ICU within the first 24/48 hours after admission.
After signing the written informed consent, the patient’s treating nurse was asked to conduct a visual estimation of the patient’s height in the supine position. Afterwards, a member from the research team used the Bosch® Zamo laser distance measuring tool with a reach of up to de 0.15 m to 20 m, and a ± 3 mm accuracy. Measurement was performed with the patient in the supine position while his head rested in the Frankfurt horizontal plane (eye socket and auditory meatus in the same horizontal plane), upper extremities attached to both sides of the trunk, no pillow while the measuring tool pointed to the patient’s head. The end of the bed was used as the limit so that the patient’s soles could touch the end of the bed. Then, a different member from the team who was blinded to the results previously reported established the patient’s height using Seca® height measuring system (bodymeter 206)—built in Germany—with a measuring range from 0 cm to 220 cm and an accuracy of ± 5 mm. The patient was placed in bipedalism, barefoot with both heels together, body position on a steady-state, arms and shoulders relaxed, and head in the Frankfurt horizontal plane.
The patient’s ideal weight (IW) was estimated using the following formula:10
• Ideal weight (males) = 50 kg + [0.91 × height in cm − 152.4 cm]
• Ideal weight (women) = 45.5 kg + [0.91 × height in cm − 152.4 cm]
Once the IW was known, the TV was estimated at a rate of 6 mL per kg of ideal weight.
Differences > 10% of the TV between methods were considered significant differences.
Regarding the concordance analysis and its graphic representation, the Passing-Bablok method and the Bland-Altman method were used.
Since errors were found while trying to determine the patient’s height–whether by excess or default–, that is, differences in both ways with respect to the mean, the results were expressed in absolute values to explain dispersion with more clarity.
A total of 55 patients were recruited—85.5% males—with a mean age of 62.7 years (SD = 11.9), and an average stay of 3.7 days (SD = 2).
Regarding height measurement, a mean difference was found between the height measuring device and the laser of 1 cm (SD = 0.8). Also, between the height measuring device and the visual method of 4.3 cm (SD = 3.4), P < .001. Fig. 1 shows the concordance charts. Laser-based measurements revealed a nearly perfect concordance with the height measuring device (chart 1). Discrepancies were seen between the values obtained with the height measuring device and those estimated by the nurse that were greater in the extreme values of both ends (chart 2). Due to the bias reported, patients were divided into 2 subgroups based on a median of height of 168 cm. Thanks to this subdivision, it was reported that patients with heights > 168 cm were measured 2 cm (P25 = 1.7-P75 = 5) shorter compared to their actual height while patients with heights ≤ 168 cm were measured 2.5 cm (P25 = 0.6-P75 = 5) taller compared to their actual height. Bias was reported between the height measuring device and the laser of 0.8 cm (95%CI, −1.3 to 2.9). Also, between the height measuring device and the visual method of 0.4 cm (95%CI, −10.4 to 11.3). However, this last bias with a much higher concordance range that involved less accuracy in the visual method (charts 3 and 4).
Figure 1.
Concordance testing between 2 methods and the gold standard.
(0.24MB).
Regarding the measurement of the IW, the greater discrepancy found between the laser and the height measuring device was 6% (equivalent to 3 kg). In the visual estimation, 11 patients (20%) showed weight differences > 10% equivalent to 5 kg to 13 kg.
Finally, after checking the TV estimated using the height obtained with the laser-based measuring device compared to the height obtained with the height measuring device, the greatest difference was 5%, which would have been equalent to 19 mL. However, using the IW based on the height estimated by the nurse in 11 patients (20%), the TV would have been > 10% (equivalent to values between 44 mL to 80 mL).
The findings of this study suggest that establishing a patient’s height with a laser-based measuring device is an accurate method that is very close to the gold standard. As a matter of fact, it could be a reliable, safe, and easy solution during the management of critically ill patients. However, it can be limited in patients in whom it is contraindicated or when the supine position is not possible.
Acknowledgments
We wish to thank Dr. Josep Trenado for his ideas and Luis Prieto for his artistic skills.
References
[1]
M.A. García-Martínez, T. Cherednichenko, Y. Hidalgo Encinas, A.I. Catalá Espinosa, A. Arrascaeta Llanes, J.A. Acosta Escribano.
Calidad de la medición antropométricas en las Unidades de Medicina Intensiva españolas (estudio CAMIES).
Med Intensiva, 42 (2018), pp. 329-336
[2]
R. García del Moral Martín, M.E. Morales Laborías, I. Fernández López, E. Rodríguez Delgado, M.A. Díaz Castellanos.
Estimación subjetiva del peso y talla de los pacientes de UCI. Medidas poco aconsejables.
Med Intensiva, 37 (2013), pp. 50-52
[3]
A. Bojmehrani, M. Bergeron-Duchesne, C. Bouchard, S. Simard, P.A. Bouchard, A. Vanderschuren, et al.
Comparison of usual and alternative methods to measure height in mechanically ventilated patients: potential impact on protective ventilation.
Respir Care, 59 (2014), pp. 1025-1033
[4]
M.S. Tarnowski, E.I. Rabito, D. Fernandes, M. Rosa, M.L. Oliveira, V.N. Hirakata, et al.
Height prediction from ulna length of critically ill patients.
Nutr Clin Pract, 33 (2018), pp. 887-892
[5]
I.D. O’Brien, E. Shacklock, A. Middleditch, C. Bigham.
Inaccuracies in calculating predicted body weight and its impact on safe ventilator settings.
J Intensive Care Soc, 17 (2016), pp. 191-195
[6]
E. L’her, J. Martin-Babau, F. Lellouche.
Accuracy of height estimation and tidal volume setting using anthropometric formulas in an ICU Caucasian population.
Ann Intensive Care, 6 (2016), pp. 55
[7]
A. Esteban, F. Frutos-Vivar, A. Muriel, N.D. Ferguson, O. Peñuelas, V. Abraira, et al.
Evolution of mortality over time in patients receiving mechanical ventilation.
Am J Respir Crit Care Med, 188 (2013), pp. 220-230
[8]
M.C. Chan, W.C. Chao, S.J. Liang, C.H. Tseng, H.C. Wang, Y.C. Chien, et al.
First tidal volume greater than 8 mL/kg is associated with increased mortality in complicated influenza infection with acute respiratory distress syndrome.
J Formos Med Assoc, 118 (2019), pp. 378-385
[9]
R.M. Determann, A. Royakkers, E.K. Wolthuis, A.P. Vlaar, G. Choi, F. Paulus, et al.
Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial.
Crit Care, 14 (2010), pp. R1
[10]
R.G. Brower, M.A. Matthay, A. Morris, D. Schoenfeld, B.T. Thompson, A. Wheeler, Acute Respiratory Distress Syndrome Network.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med, 342 (2000), pp. 1301-1308
Please cite this article as: Valls-Matarín J, del Cotillo-Fuente M, Miranda-Ramírez M, Parera-Pous AM. Medidor láser, una alternativa para la determinación de la altura en el paciente crítico. Estudio de concordancia. Med Intensiva. 2021;45:e62–e64.
Copyright © 2020. Elsevier España, S.L.U. and SEMICYUC
Idiomas
Medicina Intensiva (English Edition)
Article options
Tools
es en
¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?
Are you a health professional able to prescribe or dispense drugs? | {
"url": "https://medintensiva.org/en-laser-meter-an-alternative-determine-articulo-S2173572721001363",
"source_domain": "medintensiva.org",
"snapshot_id": "CC-MAIN-2024-33",
"warc_metadata": {
"Content-Length": "83275",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:YNXY5X522AEOSAJWOFWJJDGM2HSJA6FO",
"WARC-Concurrent-To": "<urn:uuid:29d2fb82-0ef6-4adc-a037-f8fa956d2e26>",
"WARC-Date": "2024-08-04T21:40:45",
"WARC-IP-Address": "34.243.211.249",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:HZMWU62ZPT3WHSA5Z6M25ZP7NB62HVWP",
"WARC-Record-ID": "<urn:uuid:793c7505-8f11-472b-84ff-4afcde044d89>",
"WARC-Target-URI": "https://medintensiva.org/en-laser-meter-an-alternative-determine-articulo-S2173572721001363",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:ce335eb5-315d-4b17-8dc2-e927900975f8>"
},
"warc_info": "isPartOf: CC-MAIN-2024-33\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-199\r\nsoftware: Apache Nutch 1.20 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
20,
38,
68,
86,
116,
134,
151,
243,
357,
364,
369,
386,
407,
427,
428,
450,
512,
597,
620,
640,
650,
663,
676,
687,
699,
709,
724,
725,
1091,
1092,
1395,
1396,
1912,
1913,
2180,
2181,
2513,
2514,
3682,
3683,
3760,
3761,
3830,
3831,
3902,
3903,
3989,
3990,
4075,
4076,
4208,
4209,
4458,
4459,
4594,
4595,
5852,
5853,
5863,
5864,
5925,
5926,
5936,
5937,
6188,
6189,
6596,
6597,
7001,
7002,
7018,
7019,
7109,
7110,
7121,
7125,
7253,
7358,
7396,
7400,
7516,
7606,
7642,
7646,
7747,
7890,
7928,
7932,
8021,
8084,
8124,
8128,
8183,
8277,
8322,
8326,
8367,
8484,
8521,
8525,
8612,
8691,
8742,
8746,
8822,
8978,
9022,
9026,
9110,
9273,
9302,
9307,
9432,
9579,
9619,
9620,
9870,
9871,
9926,
9934,
9971,
9987,
9993,
9999,
10000,
10079,
10080
],
"line_end_idx": [
20,
38,
68,
86,
116,
134,
151,
243,
357,
364,
369,
386,
407,
427,
428,
450,
512,
597,
620,
640,
650,
663,
676,
687,
699,
709,
724,
725,
1091,
1092,
1395,
1396,
1912,
1913,
2180,
2181,
2513,
2514,
3682,
3683,
3760,
3761,
3830,
3831,
3902,
3903,
3989,
3990,
4075,
4076,
4208,
4209,
4458,
4459,
4594,
4595,
5852,
5853,
5863,
5864,
5925,
5926,
5936,
5937,
6188,
6189,
6596,
6597,
7001,
7002,
7018,
7019,
7109,
7110,
7121,
7125,
7253,
7358,
7396,
7400,
7516,
7606,
7642,
7646,
7747,
7890,
7928,
7932,
8021,
8084,
8124,
8128,
8183,
8277,
8322,
8326,
8367,
8484,
8521,
8525,
8612,
8691,
8742,
8746,
8822,
8978,
9022,
9026,
9110,
9273,
9302,
9307,
9432,
9579,
9619,
9620,
9870,
9871,
9926,
9934,
9971,
9987,
9993,
9999,
10000,
10079,
10080,
10146
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 10146,
"ccnet_original_nlines": 127,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.22764228284358978,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.05871725082397461,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.3071363866329193,
"rps_doc_frac_unique_words": 0.439193457365036,
"rps_doc_mean_word_length": 5.054190158843994,
"rps_doc_num_sentences": 204,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.852975368499756,
"rps_doc_word_count": 1587,
"rps_doc_frac_chars_dupe_10grams": 0.03814985975623131,
"rps_doc_frac_chars_dupe_5grams": 0.11794041097164154,
"rps_doc_frac_chars_dupe_6grams": 0.08378008008003235,
"rps_doc_frac_chars_dupe_7grams": 0.07480364292860031,
"rps_doc_frac_chars_dupe_8grams": 0.07480364292860031,
"rps_doc_frac_chars_dupe_9grams": 0.05485599860548973,
"rps_doc_frac_chars_top_2gram": 0.015708759427070618,
"rps_doc_frac_chars_top_3gram": 0.023563150316476822,
"rps_doc_frac_chars_top_4gram": 0.023937160149216652,
"rps_doc_books_importance": -906.2095947265625,
"rps_doc_books_importance_length_correction": -906.2095947265625,
"rps_doc_openwebtext_importance": -532.6950073242188,
"rps_doc_openwebtext_importance_length_correction": -532.6950073242188,
"rps_doc_wikipedia_importance": -537.7260131835938,
"rps_doc_wikipedia_importance_length_correction": -537.7260131835938
},
"fasttext": {
"dclm": 0.03381294012069702,
"english": 0.8620284795761108,
"fineweb_edu_approx": 2.5790088176727295,
"eai_general_math": 0.6380109786987305,
"eai_open_web_math": 0.3556426167488098,
"eai_web_code": 0.005375680048018694
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.075",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
1,051,237,937,027,161,500 | Spray "akvamaris": analog.
autumn and spring we especially virus attack.This results in deterioration in the general physical condition, occurrence of rhinorrhea, sneezing, headaches and temperature.It should only be exposed to rain or poorly dressed, already there is a risk to go a week with a handkerchief and constantly blow your nose in it.They say that the appearance of a cold - a reaction to viruses, but not the disease.But if left untreated, can already appear independent disease - sinusitis.To prevent this, it is important to use medicines on time, to reduce the amount of mucus.
What are the types of funds from the common cold?
Why do we assign different tools at a cold?Why some are used for colds, while others - rhinitis, some can be used many times a day, and some no more than three times?We were not even aware that there are several kinds of medical supplies from cold.Let's try to understand them.
• Antibiotics - are bacteria that are found on the mucous membranes of the nose, often used not only to treat the common cold, but also pain in the throat.
• Vasoconstrictive - runny nose is not treated, but help to breathe without edema and congestion.Often used in pediatric practice, so that children can sleep at night.
• Antivirals - act on the virus at the beginning of the disease.
• funds available as part of colloidal silver - is antiseptic, astringent and anti-inflammatory drugs.
• fitosredstv, homeopathy - the use of different herbs in the treatment of the common cold.
• humidification mucous - means having in its composition of sea salt.Designed to wash and moisturize the nasal cavity.When used together with the vasoconstrictor effect is achieved quicker.But if they do not help, there is another well-known type of drugs for the treatment of rhinitis.
• Hormones - means on the basis of certain hormones that effectively treat a runny nose, but can have side effects.
The drug "akvamaris"
This drug belongs to moisturizing.It is actively used in the pediatric and therapeutic practice."Akvamaris" analogue which may also help in the treatment of rhinitis, comprise sterile seawater.This water is valuable because it is rich in many micronutrients that help restore normal nasal mucosa.All these micronutrients promote healing and tissue repair.In addition, there is stimulation of local immunity, so after using "akvamaris" runny nose goes without consequences.
Indications for use of this tool
himself "akvamaris" analogue of this means - they are popular due to the fact that they can be used not only during the illness of the nose.They are used for the prevention of infectious diseases, as well as the finding of human or in adverse environmental conditions.This can be a harsh climate, dry and other areas.In addition, the drug "akvamaris" is used in the following cases:
• enlarged adenoids in children: in this illness find it difficult to breathe, and a means of helping to restore the normal mucosa;
• inflammation of the nose, nasopharynx and sinuses;
• rhinitis of various origins;
• a result of operations in the nasal cavity can progress various infections, the drug used for the prevention and recovery of all the functions of the nasopharynx;
• at dryness and severity of nasal breathing;
• during epidemics of SARS to prevent disease.
Dosing "akvamaris"
Spray "akvamaris" analogue which will be discussed below, contains 200 doses of the same substance.One injection is equal to one dose.This is a very convenient form of release of the drug, because when you occur throughout the irrigation of the nasal cavity.This product is used as an adjunct to other, e.g., vasoconstrictor.
"akvamaris" is injected into each nostril 2-3 times.The drug is used for children older than one year.If the child has not reached that age, it is possible to use a different form of the drug or analogue "akvamaris" for children.
in age from 1 year to 7 years of drug use by injection of 2 to 4 times a day.From 7 to 16 years of medical device to be used in these doses: 2 injection into the nasal passages from 4 to 6 times per day.Adults can use the spray more 2-3 injections 4-8 times a day.The course of treatment is not limited to one week.He is from 2 to 4 weeks of using the drug "akvamaris."An analogue of spray with the same composition is used as much.Drops are used for children 2 drops in each nostril up to 4 times a day.
What contains the spray?
basis of preparation is filtered water of the Adriatic Sea.It forms the bulk of the funds - 30 ml.In addition, in this product include purified water.Also spray consists of ions of sodium, calcium, magnesium, chlorine, sulfate ions.All minerals good influence on the nasal mucosa, restoring its functionality and removing inflammation and edema.
Contraindications
"akvamaris" can be applied to almost all people, even for pregnant women and lactating mothers.But individual sensitivity to the constituent elements of the drug it is replaced by an analog "akvamaris."For children, there are also contraindications - it is up to 1 year.
Price preparation
As with any medical device to treat the disease, "akvamaris" has a different dosage.On this depends the price of the drug.In different regions of the country it can also be different.On average, the drug can be given from 220 to 350 rubles.For those who do not fit the price, you can find analogues "akvamaris" cheap.
Does Spray counterparts?
Well, when expensive drugs can be replaced with cheaper analogues.Spending about 300 rubles for rinsing the nose is not all "afford", so some patients ask: "Is there any analogues" akvamaris "cheap?"
must say that this drug is not only cheap substitutes.For example, "Humer" is much more expensive "akvamaris."In composition, it is an analogue of the latter drug, but not everyone can afford to spend large sums for the purchase of "Humer".While reviews of patients with evidence of its maximum effectiveness in the fight against the common cold.
The most popular drug analogues include:
• "Morenazal."
• "Physiomer."
• "Marimer."
• "Salin".
• "Dr. Theiss alergol."
• "AKVAMASTER."
• "Sodium chloride bufus."
• "Aqua Rinosol."
• "No-Salt".
• "Atomer."
also possible to use more saline to replace spray "akvamaris".Analogs formulation presented above have various formulations and dosage.They are used in the form of spray and drops.The amount of substance have ranged from 10 to 100 ml.
What is the analogue of "akvamaris" children?
our children are often attacked various colds, especially in autumn and spring.It's not the most joyful day for the parents, because the clogged nozzle prevents the child sleep, cough and runny nose, or lingering promise complications.It is therefore important time to begin treatment of rhinitis by a variety of drugs in their mind.
Many young mothers interested in the question: "Spray" akvamaris "being replaced by small children?"For children younger than 1 year, there are cheaper drops of sterile saltwater.For example, "Morenazal" - a domestic product, which also contains a set of natural minerals and trace elements.They contribute to the rapid recovery of the mucosa of the nasal cavity.
In turn, "Marimer" composition is also quite suitable for the replacement of spray "akvamaris."The cost of the drug "Marimer" is somewhat different, and on average it ranges from 100 to 150 rubles per 30 ml.
Another commonly used drug is an analogue of spray "Dr. Theiss alergol."In composition, it is different from "akvamaris."The main active ingredient - are not sea water, and dry the rest of the salt sea water, diluted in purified water.Additional ingredients: benzalkonium chloride, hydrochloric acid, benzyl alcohol.Prices of the drug is lower than "akvamaris", they represent an average of 120 to 150 rubles in 20 ml.
the way, some young mothers, focusing on the principle of manufacturing spray "Dr. Theiss alergol" make home drops to wash the nose.They can be made by the following algorithm.
We need to take 1 liter of boiled water.Add to:
• one vial of magnesium sulfate;
• calcium chloride mix two vials;
• carefully stir another 1 teaspoon of iodized salt with a slide.
All components mix in water at room temperature until until completely dissolved salt.Then pipette instilled into the nasal cavity, washing it.This solution has a shelf life.It is not more than two days after preparation.What
analogues "akvamaris" cheap can use adults?
effective remedy for the common cold are all listed above.But they are not getting cheaper this drug, such as an analog of the famous "akvamaris" - spray "Physiomer."It consists of a sterile solution of sea water.In different regions of the country the price of 350 rubles.
cheaper counterparts "akvamaris" are such sprays such as "Salin" "Nariya chloride," "Mornezal."In general, low-cost substitutes this drug suitable for both adults and children.Only need to look at the form of release - for little children sprays are unacceptable, because they can cause cramps.They use the same preparations, but in the drops.
There are many analogues of the drug with a different price range.All of them are aimed at improving the state of the nasal mucosa and its full recovery.To quickly overcome the disease is necessary to use drugs from 3 to 6 times.Here, perhaps, and all information on the topic: "Preparation" akvamaris ": price, analogues, indication, the method of application."
Cheers! | {
"url": "https://healthtipsing.com/en/pages/20404",
"source_domain": "healthtipsing.com",
"snapshot_id": "crawl=CC-MAIN-2020-10",
"warc_metadata": {
"Content-Length": "24463",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:BXUXQ3CIEN54NCGWMLVNZJAMI3I26J5I",
"WARC-Concurrent-To": "<urn:uuid:831a73d5-76d2-44f5-8343-36045787c5b2>",
"WARC-Date": "2020-02-26T16:12:20",
"WARC-IP-Address": "104.27.165.208",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:6NLCDGYN5EDSJD6JFVF2VCOH4FQ62YYK",
"WARC-Record-ID": "<urn:uuid:8d6017f5-69bf-466f-b537-4e63950ee973>",
"WARC-Target-URI": "https://healthtipsing.com/en/pages/20404",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:66b5d489-213e-4e95-ad52-585553f0f636>"
},
"warc_info": "isPartOf: CC-MAIN-2020-10\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for February 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-28.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
27,
28,
594,
595,
645,
646,
924,
925,
1083,
1253,
1320,
1425,
1519,
1809,
1927,
1928,
1949,
1950,
2423,
2424,
2457,
2458,
2841,
2842,
2976,
3031,
3064,
3231,
3279,
3328,
3329,
3348,
3349,
3675,
3676,
3677,
3907,
3908,
4413,
4414,
4439,
4440,
4786,
4787,
4805,
4806,
5077,
5078,
5096,
5097,
5415,
5416,
5441,
5442,
5642,
5643,
5990,
5991,
6032,
6033,
6050,
6067,
6082,
6095,
6121,
6139,
6168,
6188,
6203,
6217,
6218,
6453,
6454,
6500,
6501,
6835,
6836,
7200,
7201,
7409,
7410,
7829,
7830,
8007,
8008,
8056,
8057,
8092,
8128,
8196,
8197,
8423,
8424,
8468,
8469,
8743,
8744,
9088,
9089,
9452,
9453
],
"line_end_idx": [
27,
28,
594,
595,
645,
646,
924,
925,
1083,
1253,
1320,
1425,
1519,
1809,
1927,
1928,
1949,
1950,
2423,
2424,
2457,
2458,
2841,
2842,
2976,
3031,
3064,
3231,
3279,
3328,
3329,
3348,
3349,
3675,
3676,
3677,
3907,
3908,
4413,
4414,
4439,
4440,
4786,
4787,
4805,
4806,
5077,
5078,
5096,
5097,
5415,
5416,
5441,
5442,
5642,
5643,
5990,
5991,
6032,
6033,
6050,
6067,
6082,
6095,
6121,
6139,
6168,
6188,
6203,
6217,
6218,
6453,
6454,
6500,
6501,
6835,
6836,
7200,
7201,
7409,
7410,
7829,
7830,
8007,
8008,
8056,
8057,
8092,
8128,
8196,
8197,
8423,
8424,
8468,
8469,
8743,
8744,
9088,
9089,
9452,
9453,
9460
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 9460,
"ccnet_original_nlines": 101,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3932114839553833,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0010443900246173143,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.20052218437194824,
"rps_doc_frac_unique_words": 0.3866490423679352,
"rps_doc_mean_word_length": 4.949768543243408,
"rps_doc_num_sentences": 124,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.529632091522217,
"rps_doc_word_count": 1513,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.00747762992978096,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01669115014374256,
"rps_doc_frac_chars_top_3gram": 0.007210580166429281,
"rps_doc_frac_chars_top_4gram": 0.004272929858416319,
"rps_doc_books_importance": -944.0868530273438,
"rps_doc_books_importance_length_correction": -944.0868530273438,
"rps_doc_openwebtext_importance": -537.6655883789062,
"rps_doc_openwebtext_importance_length_correction": -537.6655883789062,
"rps_doc_wikipedia_importance": -357.2767639160156,
"rps_doc_wikipedia_importance_length_correction": -357.2767639160156
},
"fasttext": {
"dclm": 0.03146820887923241,
"english": 0.9250087141990662,
"fineweb_edu_approx": 2.792994737625122,
"eai_general_math": 0.22352474927902222,
"eai_open_web_math": 0.3288755416870117,
"eai_web_code": 0.020029719918966293
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.622",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.62",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
7,637,397,537,946,759,000 | Skip to Content
Anaflat Compuesto
Anaflat Compuesto may be available in the countries listed below.
Ingredient matches for Anaflat Compuesto
Metoclopramide
Metoclopramide hydrochloride (a derivative of Metoclopramide) is reported as an ingredient of Anaflat Compuesto in the following countries:
• El Salvador
Pancreatin
Pancreatin is reported as an ingredient of Anaflat Compuesto in the following countries:
• El Salvador
Simeticone
Simeticone is reported as an ingredient of Anaflat Compuesto in the following countries:
• El Salvador
International Drug Name Search
Important Notice: The Drugs.com international database is in BETA release. This means it is still under development and may contain inaccuracies. It is not intended as a substitute for the expertise and judgement of your physician, pharmacist or other healthcare professional. It should not be construed to indicate that the use of any medication in any country is safe, appropriate or effective for you. Consult with your healthcare professional before taking any medication.
Hide | {
"url": "https://www.drugs.com/international/anaflat-compuesto.html",
"source_domain": "www.drugs.com",
"snapshot_id": "crawl=CC-MAIN-2017-09",
"warc_metadata": {
"Content-Length": "34872",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:43XR4L72PM4YTGHNQWV2NFJ7WDPSVQUQ",
"WARC-Concurrent-To": "<urn:uuid:358bbd19-efba-4bdd-bde8-d7b9ac067086>",
"WARC-Date": "2017-02-28T11:29:20",
"WARC-IP-Address": "23.13.164.155",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:7TFNPSFS7PFYZQ36CARMJA4BU6GMNMRN",
"WARC-Record-ID": "<urn:uuid:79accf20-7c01-497b-9ee2-6774e1567611>",
"WARC-Target-URI": "https://www.drugs.com/international/anaflat-compuesto.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:c7fd20af-3c3a-4888-91c1-bf09da1f973b>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-171-10-108.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-09\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for February 2017\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
16,
17,
35,
36,
102,
103,
144,
145,
160,
161,
301,
302,
318,
319,
330,
331,
420,
421,
437,
438,
449,
450,
539,
540,
556,
557,
588,
589,
1066,
1067
],
"line_end_idx": [
16,
17,
35,
36,
102,
103,
144,
145,
160,
161,
301,
302,
318,
319,
330,
331,
420,
421,
437,
438,
449,
450,
539,
540,
556,
557,
588,
589,
1066,
1067,
1071
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1071,
"ccnet_original_nlines": 30,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.42941176891326904,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.005882349796593189,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.10588234663009644,
"rps_doc_frac_unique_words": 0.5129870176315308,
"rps_doc_mean_word_length": 5.7272725105285645,
"rps_doc_num_sentences": 8,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.13275146484375,
"rps_doc_word_count": 154,
"rps_doc_frac_chars_dupe_10grams": 0.25850340723991394,
"rps_doc_frac_chars_dupe_5grams": 0.25850340723991394,
"rps_doc_frac_chars_dupe_6grams": 0.25850340723991394,
"rps_doc_frac_chars_dupe_7grams": 0.25850340723991394,
"rps_doc_frac_chars_dupe_8grams": 0.25850340723991394,
"rps_doc_frac_chars_dupe_9grams": 0.25850340723991394,
"rps_doc_frac_chars_top_2gram": 0.10884354263544083,
"rps_doc_frac_chars_top_3gram": 0.040816329419612885,
"rps_doc_frac_chars_top_4gram": 0.0476190485060215,
"rps_doc_books_importance": -86.5714340209961,
"rps_doc_books_importance_length_correction": -86.5714340209961,
"rps_doc_openwebtext_importance": -31.865909576416016,
"rps_doc_openwebtext_importance_length_correction": -20.55280303955078,
"rps_doc_wikipedia_importance": -14.535021781921387,
"rps_doc_wikipedia_importance_length_correction": -14.535021781921387
},
"fasttext": {
"dclm": 0.02128083072602749,
"english": 0.8183683156967163,
"fineweb_edu_approx": 1.5864217281341553,
"eai_general_math": 0.005254330113530159,
"eai_open_web_math": 0.26140379905700684,
"eai_web_code": 0.00006174999725772068
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.192",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.19",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "8",
"label": "Documentation"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "1",
"label": "No Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
6,133,123,657,565,207,000 | Human Adaptation During Hypobaric Hypoxia Exposure
Human Adaptation During Hypobaric Hypoxia Exposure
Loading
Loading Social Plug-ins...
Language: English
Save to myLibrary Download PDF
Go to Page # Page of 29
Description: Bioimpedance Cardiac Output Monitoring As A Predictor For Hypoxia Resistance - Our altitude chamber has been fitted with a poliphysiological recording device. We have used it to collect and interpret data regarding human adaptation during hypobaric hypoxia exposure. METHOD - Chamber flights were performed between 8.30 am and 12.30 am with standard rest and nutrition requirements, Simulated flight took 15 minutes, Climbs up to 5500 meters at 40 m/s speed, In minute 7 there was a physical stress t.
Author: D Vlad, A Macovei, I Capanu, D Popescu, and A Raicu (Fellow) | Visits: 1382 | Page Views: 3223
Domain: Medicine Category: Biotech/Pharma Subcategory: R&D
Upload Date:
Short URL: http://www.wesrch.com/medical/pdfME1XXFT06NCTL
Loading
Loading...
px * px *
* Default width and height in pixels. Change it to your required dimensions.
Contents:
BIOIMPEDANCE CARDIAC OUTPUT MONITORING AS A PREDICTOR FOR HYPOXIA RESISTANCE
Authors: D VLAD, A MACOVEI, I CAPANU, D POPESCU, A RAICU
NATIONAL INSTITUTE OF AEROSPACE MEDICINE Bucharest, ROMANIA
Our altitude chamber has been fitted with a poliphysiological recording device. We have used it to collect and interpret data regarding human adaptation during hypobaric hypoxia exposure.
PURPOSE AND METHOD
Resistance and training evaluation by hypobaric exposure remains one of main tools in selection and training of the flying crew
Simultaneous recordings of the modules ECG, BIOIMPEDANCE and PLETHYSMOGRAPHY from a poliphysiograf allowed us to gather relevant data for hypobaric resistance evaluation; We monitored:
- Correlations regarding hypobaric hypoxia resistance in chamber flight as appreciated by heart rate (HR), oxygen saturation (OS), stroke volume (SV) and cardiac output (CO) - Differences between smokers and non smokers
METHOD
Chamber flights were performed between 8.30 am and 12.30 am with standard rest and nutrition requirements Simulated flight took 15 minutes Climbs up to 5500 meters at 40 m/s speed In minute 7 there was a physical stress test on a treadmill for 20s at 20m/s speed Descent was made at 30 m/s speed Real time on-line monitoring of bioimpedance, ECG, pulse wave, oxygen saturation, altitude, temperature and relative humidity. Two types of subjects: candidates for pilot status and professional pilots
Recorded phases
Ground 5500 m Before effort Effort Compensation after effort Descent
STANDARD BIOIMPEDANCE ELECTRODE PLACEMENT
RESULTS AND DISCUSSIONS
Histogram of multiple variables Statistica Bioimpedanta 28v*100c 50 45 40 35 30
No of obs
25 20 15 10 5 0 0 2 4 6 8 10 12 14 16 18 20 CO CO CO CO CO CO ground at 5500 m before effort durring effort after effort descent
Histogram of multiple variables Statistica Bioimpedanta 28v*100c 45 40 35 30
No of obs
25 20 15 10 5 0 50 60 70 80 90 100 110 120 130 140 150 160 HR ground HR at 5500 m HR before effort HR during effort HR after effort HR descent
Histogram of multiple variables Statistica Bioimpedanta 28v*100c 120
100
80
No of obs
60
40
20
0 65 70 75 80 85 90 95 100 105
OS OS OS OS OS OS
ground at 5500 m before effort during effort after effort descent
Histogram of multiple variables Statistica Bioimpedanta 28v*100c 45 40 35 30
No of obs
25 20 15 10 5 0 20 40 60 80 100 120 140 160 180 SV SV SV SV SV SV ground at 5500 m before effort during effort after effort descent
Mean Plot of multiple variables Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 11,0 10,5 10,0 9,5 9,0 8,5 8,0 7,5 7,0 6,5
CO at 5500 m
CO durring effort
CO before effort
CO after effort
CO descent
CO ground
Mean Mean�0,95 Conf. Interval
Mean Plot of multiple variables Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 125 120 115 110 105 100 95 90 85 80 75
HR at 5500 m
HR before effort
HR during effort
HR after effort
HR descent
HR ground
Mean Mean�0,95 Conf. Interval
Mean Plot of multiple variables Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 100 98 96 94 92 90 88 86 84 82 80 78 76 74
OS at 5500 m
OS before effort
OS during effort
OS after effort
OS descent
OS ground
Mean Mean�0,95 Conf. Interval
Mean Plot of multiple variables Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 94 92 90 88 86 84 82 80 78 76 74 72
SV at 5500 m
SV before effort
SV during effort
SV after effort
SV descent
SV ground
Mean Mean�0,95 Conf. Interval
Mean Plot of multiple variables grouped by Smoker Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 11,5 11,0 10,5 10,0 9,5 9,0 8,5 8,0 7,5 CO ground: F(1;98) = 0,5589; p = 0,4565 7,0 CO at 5500 m: F(1;98) = 0,6513; p = 0,4216 CO before effort: F(1;98) = 0,0433; p = 0,8355 6,5 CO durring effort: F(1;98) = 1,6738; p = 0,1988 N CO after effort: F(1;98) = 0,3271; p = 0,5687 Smoker CO descent: F(1;98) = 0,1138; p = 0,7366 CO CO CO CO CO CO ground at 5500 m before effort durring effort after effort descent
Y
Mean Plot of multiple variables grouped by Smoker Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 130
120
110
100
90
80 HR ground: F(1;98) = 5,5229; p = 0,0208 HR at 5500 m: F(1;98) = 2,2659; p = 0,1355 HR before effort: F(1;98) = 1,1215; p = 0,2922 70 HR during effort: F(1;98) = 0,9108; p = 0,3423 N HR after effort: F(1;98) = 2,2383; p = 0,1378 Smoker HR descent: F(1;98) = 0,116; p = 0,7341
Y
HR ground HR at 5500 m HR before effort HR during effort HR after effort HR descent
Mean Plot of multiple variables grouped by Smoker Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 100
95
90
85
80
75
70 SV ground: F(1;98) = 0,1973; p = 0,6579 SV at 5500 m: F(1;98) = 0,0099; p = 0,9208 SV before effort: F(1;98) = 0,2219; p = 0,6386 65 SV during effort: F(1;98) = 3,1549; p = 0,0788 N SV after effort: F(1;98) = 0,2225; p = 0,6382 Smoker SV descent: F(1;98) = 0,0605; p = 0,8062
Y
SV SV SV SV SV SV
ground at 5500 m before effort during effort after effort descent
Mean Plot of multiple variables grouped by Smoker Statistica Bioimpedanta 28v*100c Mean; Whisker: Mean�0,95 Conf. Interval 100 98 96 94 92 90 88 86 84 82 80 78 OS ground: F(1;98) = 4,2226; p = 0,0426 OS at 5500 m: F(1;98) = 0,6905; p = 0,4080 76 OS before effort: F(1;98) = 2,9683; p = 0,0881 74 OS during effort: F(1;98) = 0,0087; p = 0,9257 N OS after effort: F(1;98) = 0,8975; p = 0,3458 Smoker OS descent: F(1;98) = 2,8456; p = 0,0948 OS OS OS OS OS OS ground at 5500 m before effort during effort after effort descent
Y
Scatterplot of multiple variables against CO ground Statistica Bioimpedanta 28v*100c HR ground = 41,6671+48,2125*log10(x) SV ground = -29,4548+139,7603*log10(x) 140 130 120 110 100 90 80 70 60 50 40 CO ground:HR ground: y = 57,2763 + 3,4568*x; 30 r = 0,4904; 3 = 0,00000 5 p 2 4 6 7 8 CO ground:SV ground: y = 24,0801 + 8,8814*x; CO ground r = 0,7973; p = 0.0000 9 10 11 12
HR ground SV ground
Scatterplot of multiple variables against CO at 5500 m Statistica Bioimpedanta 28v*100c HR at 5500 m = 68,3506+29,9579*log10(x) SV at 5500 m = -47,9288+149,4826*log10(x) 140
120
100
80
60
40 CO at 5500 m:HR at 5500 m: y = 78,6127 + 2,0393*x; 20 r = 0,3294; 4 = 0,0008 6 p 3 5 7 8 9 10 CO at 5500 m:SV at 5500 m: y = 14,9619 + 8,7372*x; CO at 5500 m r = 0,8361; p = 0.0000
11
12
13
HR at 5500 m SV at 5500 m
Scatterplot of multiple variables against CO before effort Statistica Bioimpedanta 28v*100c HR before effort = 77,1825+28,8652*log10(x) SV before effort = -63,2942+160,0058*log10(x) 160 140 120 100 80 60 40 20 CO before effort:HR before effort: y = 90,3705 + 1,5408*x; 0 r = 0,3173; p = 0,0013 6 2 4 8 10 12 CO before effort:SV before effort: y = 11,9411 + 8,3008*x; CO before effort r = 0,8978; p = 0.0000
14
16
HR before effort SV before effort
Scatterplot of multiple variables against CO durring effort Statistica Bioimpedanta 28v*100c HR during effort = 100,014+21,2355*log10(x) SV during effort = -81,9494+167,8509*log10(x) 160 140 120 100 80 60 40 20 0 CO durring 2 r = 0,1917; CO durring
effort:HR during effort: y = 112,7359 + 0,8164*x; 4 6 8 10 12 14 16 18 HR during effort p = 0,0560 CO y = 2,4259 + SV effort:SV during effort: durring effort 8,0715*x; r = 0,9192; p = 0.0000 during effort
Scatterplot of multiple variables against CO after effort Statistica Bioimpedanta 28v*100c HR after effort = 101,3263+16,5385*log10(x) SV after effort = -72,8017+161,8909*log10(x) 180 160 140 120 100 80 60 40 20 0 CO after effort:HR after effort: y = 8 109,527110 0,8075*x; + 2 4 6 12 14 16 r = 0,1264; p = 0,2100 CO after + 8,3788*x; r = 0,8317; p = 0.0000 CO after effort:SV after effort: y = 2,8283 effort
HR after effort SV after effort
Scatterplot of multiple variables against CO descent Statistica Bioimpedanta 28v*100c HR descent = 105,7611-1,3472*log10(x) SV descent = -74,8273+172,1083*log10(x) 160 140 120 100 80 60 40 20 CO descent:HR descent: y = 106,8285 - 0,2813*x; 0 r = -0,0432; p = 0,6695 6 2 4 8 10 CO descent:SV descent: y = -5,1726 + 10,3912*x; CO descent r = 0,8791; p = 0.0000
12
14
16
HR descent SV descent
CONCLUSIONS
It is possible to make a pattern between SV and HR dynamic for a better understanding of hypobaric hypoxia tolerance. This could be a motivation for further researches, and would enable as to have some hypoxia resistance normograms. The HR is the main contributor to CO compensation during effort, but altitude adaptation involves changes to SV. HR and SV has no significant difference between smokers and non smokers, but OS is better correlated.
Subscribe
x | {
"url": "http://www.wesrch.com/medical/paper-details/pdf-ME1XXFT06NCTL-human-adaptation-during-hypobaric-hypoxia-exposure",
"source_domain": "www.wesrch.com",
"snapshot_id": "crawl=CC-MAIN-2016-36",
"warc_metadata": {
"Content-Length": "88068",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:DOF2EL7FZVQ4NL4RUTFELMAUSSAASB47",
"WARC-Concurrent-To": "<urn:uuid:2e9358a2-f8a7-4613-a2d5-1634d62bf200>",
"WARC-Date": "2016-08-24T02:35:01",
"WARC-IP-Address": "207.140.26.57",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:VJJWL6G7VQLOZ5OI5XIKZXBS43KR3A5M",
"WARC-Record-ID": "<urn:uuid:8ffd8c60-67ed-4544-9fbb-0d913f373fa7>",
"WARC-Target-URI": "http://www.wesrch.com/medical/paper-details/pdf-ME1XXFT06NCTL-human-adaptation-during-hypobaric-hypoxia-exposure",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:eba8ab39-7474-4ad5-8a2d-1484438aef25>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-153-172-175.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2016-36\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for August 2016\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
51,
52,
103,
104,
112,
139,
157,
188,
212,
213,
728,
729,
731,
834,
895,
908,
966,
974,
985,
986,
987,
988,
1005,
1006,
1083,
1084,
1086,
1096,
1173,
1174,
1231,
1232,
1292,
1293,
1294,
1295,
1483,
1484,
1503,
1504,
1632,
1817,
1818,
1819,
2039,
2040,
2047,
2048,
2049,
2050,
2051,
2052,
2053,
2054,
2055,
2553,
2554,
2570,
2639,
2640,
2641,
2683,
2684,
2708,
2709,
2789,
2790,
2800,
2801,
2930,
2931,
3008,
3009,
3019,
3020,
3163,
3164,
3233,
3234,
3238,
3239,
3242,
3243,
3253,
3254,
3257,
3258,
3261,
3262,
3265,
3266,
3297,
3298,
3316,
3317,
3383,
3384,
3461,
3462,
3472,
3473,
3605,
3606,
3754,
3755,
3768,
3769,
3787,
3788,
3805,
3806,
3822,
3823,
3834,
3835,
3845,
3846,
3876,
3877,
4021,
4022,
4035,
4036,
4053,
4054,
4071,
4072,
4088,
4089,
4100,
4101,
4111,
4112,
4142,
4143,
4291,
4292,
4305,
4306,
4323,
4324,
4341,
4342,
4358,
4359,
4370,
4371,
4381,
4382,
4412,
4413,
4554,
4555,
4568,
4569,
4586,
4587,
4604,
4605,
4621,
4622,
4633,
4634,
4644,
4645,
4675,
4676,
5206,
5207,
5209,
5210,
5337,
5338,
5342,
5343,
5347,
5348,
5352,
5353,
5356,
5357,
5635,
5636,
5638,
5639,
5723,
5724,
5851,
5852,
5855,
5856,
5859,
5860,
5863,
5864,
5867,
5868,
5871,
5872,
6151,
6152,
6154,
6155,
6173,
6174,
6240,
6241,
6764,
6765,
6767,
6768,
7142,
7143,
7163,
7164,
7338,
7339,
7343,
7344,
7348,
7349,
7352,
7353,
7356,
7357,
7541,
7542,
7545,
7546,
7549,
7550,
7553,
7554,
7580,
7581,
7988,
7989,
7992,
7993,
7996,
7997,
8031,
8032,
8281,
8282,
8487,
8488,
8897,
8898,
8930,
8931,
9290,
9291,
9294,
9295,
9298,
9299,
9302,
9303,
9325,
9326,
9338,
9339,
9340,
9341,
9342,
9343,
9791,
9792,
9802
],
"line_end_idx": [
51,
52,
103,
104,
112,
139,
157,
188,
212,
213,
728,
729,
731,
834,
895,
908,
966,
974,
985,
986,
987,
988,
1005,
1006,
1083,
1084,
1086,
1096,
1173,
1174,
1231,
1232,
1292,
1293,
1294,
1295,
1483,
1484,
1503,
1504,
1632,
1817,
1818,
1819,
2039,
2040,
2047,
2048,
2049,
2050,
2051,
2052,
2053,
2054,
2055,
2553,
2554,
2570,
2639,
2640,
2641,
2683,
2684,
2708,
2709,
2789,
2790,
2800,
2801,
2930,
2931,
3008,
3009,
3019,
3020,
3163,
3164,
3233,
3234,
3238,
3239,
3242,
3243,
3253,
3254,
3257,
3258,
3261,
3262,
3265,
3266,
3297,
3298,
3316,
3317,
3383,
3384,
3461,
3462,
3472,
3473,
3605,
3606,
3754,
3755,
3768,
3769,
3787,
3788,
3805,
3806,
3822,
3823,
3834,
3835,
3845,
3846,
3876,
3877,
4021,
4022,
4035,
4036,
4053,
4054,
4071,
4072,
4088,
4089,
4100,
4101,
4111,
4112,
4142,
4143,
4291,
4292,
4305,
4306,
4323,
4324,
4341,
4342,
4358,
4359,
4370,
4371,
4381,
4382,
4412,
4413,
4554,
4555,
4568,
4569,
4586,
4587,
4604,
4605,
4621,
4622,
4633,
4634,
4644,
4645,
4675,
4676,
5206,
5207,
5209,
5210,
5337,
5338,
5342,
5343,
5347,
5348,
5352,
5353,
5356,
5357,
5635,
5636,
5638,
5639,
5723,
5724,
5851,
5852,
5855,
5856,
5859,
5860,
5863,
5864,
5867,
5868,
5871,
5872,
6151,
6152,
6154,
6155,
6173,
6174,
6240,
6241,
6764,
6765,
6767,
6768,
7142,
7143,
7163,
7164,
7338,
7339,
7343,
7344,
7348,
7349,
7352,
7353,
7356,
7357,
7541,
7542,
7545,
7546,
7549,
7550,
7553,
7554,
7580,
7581,
7988,
7989,
7992,
7993,
7996,
7997,
8031,
8032,
8281,
8282,
8487,
8488,
8897,
8898,
8930,
8931,
9290,
9291,
9294,
9295,
9298,
9299,
9302,
9303,
9325,
9326,
9338,
9339,
9340,
9341,
9342,
9343,
9791,
9792,
9802,
9803
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 9803,
"ccnet_original_nlines": 270,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.1502753645181656,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.09952793270349503,
"rps_doc_frac_lines_end_with_ellipsis": 0.00738007016479969,
"rps_doc_frac_no_alph_words": 0.5106215476989746,
"rps_doc_frac_unique_words": 0.2581658363342285,
"rps_doc_mean_word_length": 4.589824199676514,
"rps_doc_num_sentences": 39,
"rps_doc_symbol_to_word_ratio": 0.0011801699874922633,
"rps_doc_unigram_entropy": 5.185415744781494,
"rps_doc_word_count": 1592,
"rps_doc_frac_chars_dupe_10grams": 0.3570548892021179,
"rps_doc_frac_chars_dupe_5grams": 0.47817161679267883,
"rps_doc_frac_chars_dupe_6grams": 0.4536745548248291,
"rps_doc_frac_chars_dupe_7grams": 0.4189133644104004,
"rps_doc_frac_chars_dupe_8grams": 0.39072123169898987,
"rps_doc_frac_chars_dupe_9grams": 0.36909812688827515,
"rps_doc_frac_chars_top_2gram": 0.021349389106035233,
"rps_doc_frac_chars_top_3gram": 0.02299164980649948,
"rps_doc_frac_chars_top_4gram": 0.031750380992889404,
"rps_doc_books_importance": -1235.08935546875,
"rps_doc_books_importance_length_correction": -1235.08935546875,
"rps_doc_openwebtext_importance": -619.54638671875,
"rps_doc_openwebtext_importance_length_correction": -619.54638671875,
"rps_doc_wikipedia_importance": -210.05453491210938,
"rps_doc_wikipedia_importance_length_correction": -210.05453491210938
},
"fasttext": {
"dclm": 0.32384562492370605,
"english": 0.7661906480789185,
"fineweb_edu_approx": 1.8969541788101196,
"eai_general_math": 0.7264439463615417,
"eai_open_web_math": 0.6229501962661743,
"eai_web_code": 0.2925570607185364
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.075",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
871,136,262,363,635,300 | Skip to Content
Drug Interactions between budesonide and Vitamin D3
This report displays the potential drug interactions for the following 2 drugs:
• budesonide
• Vitamin D3 (cholecalciferol)
Edit list (add/remove drugs)
Interactions between your drugs
No interactions were found between budesonide and Vitamin D3. This does not necessarily mean no interactions exist. Always consult your healthcare provider.
budesonide
A total of 340 drugs are known to interact with budesonide.
Vitamin D3
A total of 60 drugs are known to interact with Vitamin D3.
Drug and food interactions
Moderate
budesonide food
Applies to: budesonide
You should avoid the regular consumption of large amounts of grapefruits and grapefruit juice while taking budesonide. Grapefruit can raise the levels of budesonide in your body and lead to increased side effects. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.
Switch to professional interaction data
Therapeutic duplication warnings
No warnings were found for your selected drugs.
Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.
Drug Interaction Classification
These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.
Further information
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances. | {
"url": "https://www.drugs.com/drug-interactions/budesonide-with-vitamin-d3-431-0-646-5790.html",
"source_domain": "www.drugs.com",
"snapshot_id": "crawl=CC-MAIN-2020-40",
"warc_metadata": {
"Content-Length": "63969",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:T46J23RKUA6DCDTW4VOYWMESGB5SDOBB",
"WARC-Concurrent-To": "<urn:uuid:da6f97d7-6446-4bf8-a8a6-b206f9f442a0>",
"WARC-Date": "2020-09-19T10:20:24",
"WARC-IP-Address": "104.100.20.10",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:3FSHPJER5L4V2NMROQGXPATJABH2CYCT",
"WARC-Record-ID": "<urn:uuid:d0fd9c2f-4af9-437d-adc3-99bf3de85a29>",
"WARC-Target-URI": "https://www.drugs.com/drug-interactions/budesonide-with-vitamin-d3-431-0-646-5790.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:f7f47e4d-f136-473b-b162-a90c653cde0c>"
},
"warc_info": "isPartOf: CC-MAIN-2020-40\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for September 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-127.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
16,
17,
69,
70,
150,
151,
166,
199,
200,
229,
230,
262,
263,
420,
421,
432,
433,
493,
494,
505,
506,
565,
566,
593,
594,
603,
604,
620,
621,
644,
645,
972,
973,
1013,
1014,
1047,
1048,
1096,
1097,
1237,
1238,
1270,
1271,
1498,
1606,
1719,
1902,
1948,
1949,
1969,
1970
],
"line_end_idx": [
16,
17,
69,
70,
150,
151,
166,
199,
200,
229,
230,
262,
263,
420,
421,
432,
433,
493,
494,
505,
506,
565,
566,
593,
594,
603,
604,
620,
621,
644,
645,
972,
973,
1013,
1014,
1047,
1048,
1096,
1097,
1237,
1238,
1270,
1271,
1498,
1606,
1719,
1902,
1948,
1949,
1969,
1970,
2098
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2098,
"ccnet_original_nlines": 51,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.31192660331726074,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.021406730636954308,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11620794981718063,
"rps_doc_frac_unique_words": 0.5205479264259338,
"rps_doc_mean_word_length": 5.982876777648926,
"rps_doc_num_sentences": 21,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.679934978485107,
"rps_doc_word_count": 292,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.12879222631454468,
"rps_doc_frac_chars_dupe_6grams": 0.06868918240070343,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.025758439674973488,
"rps_doc_frac_chars_top_3gram": 0.02919290028512478,
"rps_doc_frac_chars_top_4gram": 0.046365201473236084,
"rps_doc_books_importance": -132.25595092773438,
"rps_doc_books_importance_length_correction": -132.25595092773438,
"rps_doc_openwebtext_importance": -65.99832153320312,
"rps_doc_openwebtext_importance_length_correction": -65.99832153320312,
"rps_doc_wikipedia_importance": -48.367767333984375,
"rps_doc_wikipedia_importance_length_correction": -48.367767333984375
},
"fasttext": {
"dclm": 0.03306156024336815,
"english": 0.8548758625984192,
"fineweb_edu_approx": 2.287529945373535,
"eai_general_math": 0.00771141005679965,
"eai_open_web_math": 0.348905086517334,
"eai_web_code": 0.00391477020457387
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.19",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.54",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "8",
"label": "Documentation"
},
"secondary": {
"code": "21",
"label": "Customer Support"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-8,036,096,140,730,952,000 | Surgery
Image
Surgery
Expect to be at Canberra Eye Laser for approximately 2 hours. This enables us to complete the necessary paperwork and gives you an opportunity to ask any last minute questions whilst we program the lasers.
You will be in the treatment room for about 20-30 minutes, but the crucial laser time is only seconds for each eye. During the procedure, you will be asked to lie on a bed and look up into the laser's centering light. Anaesthetic eye drops will be given and a small lid speculum will prevent your eyelids from blinking. The laser and the surgeon will ensure that your eye is centered during the procedure.
Dress comfortably and bring a companion on the day of treatment to drive you home. They are welcome to stay and watch the procedure from our viewing area if you wish, and we can supply a video copy of your procedure upon request.
Post-operative drops and detailed instructions will be provided before you leave the facility. | {
"url": "https://www.canberraeyelaser.com.au/understanding-process/surgery",
"source_domain": "www.canberraeyelaser.com.au",
"snapshot_id": "CC-MAIN-2024-33",
"warc_metadata": {
"Content-Length": "18042",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:FGX4HODSNMSO5N2USB7GG6MK7N4Q6QQ6",
"WARC-Concurrent-To": "<urn:uuid:99fe61d8-846e-4c30-9398-7f1c30dabb14>",
"WARC-Date": "2024-08-15T13:13:18",
"WARC-IP-Address": "103.11.147.186",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:Z3OEMT5F23PPSMUELW4JE3OUQY7IFJ46",
"WARC-Record-ID": "<urn:uuid:7ea3fa6e-36aa-4d3c-af31-ccd7b75f97ed>",
"WARC-Target-URI": "https://www.canberraeyelaser.com.au/understanding-process/surgery",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0ddbfadb-a873-43ab-b5f9-32895eaec2e7>"
},
"warc_info": "isPartOf: CC-MAIN-2024-33\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-59\r\nsoftware: Apache Nutch 1.20 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
8,
9,
15,
23,
24,
230,
231,
639,
640,
871,
872
],
"line_end_idx": [
8,
9,
15,
23,
24,
230,
231,
639,
640,
871,
872,
966
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 966,
"ccnet_original_nlines": 11,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4784946143627167,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.09677419066429138,
"rps_doc_frac_unique_words": 0.6309523582458496,
"rps_doc_mean_word_length": 4.61904764175415,
"rps_doc_num_sentences": 9,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.367182731628418,
"rps_doc_word_count": 168,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.030927840620279312,
"rps_doc_frac_chars_top_3gram": 0.02319587953388691,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -88.91574096679688,
"rps_doc_books_importance_length_correction": -88.91574096679688,
"rps_doc_openwebtext_importance": -57.7256965637207,
"rps_doc_openwebtext_importance_length_correction": -44.13944625854492,
"rps_doc_wikipedia_importance": -52.63260269165039,
"rps_doc_wikipedia_importance_length_correction": -52.63260269165039
},
"fasttext": {
"dclm": 0.26005810499191284,
"english": 0.8963632583618164,
"fineweb_edu_approx": 0.977572500705719,
"eai_general_math": 0.012634930200874805,
"eai_open_web_math": 0.23181992769241333,
"eai_web_code": 0.0019376300042495131
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.72",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "1",
"label": "Factual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "21",
"label": "Customer Support"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "1",
"label": "No Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
6,387,559,239,614,253,000 | Impacts OF TESTOSTERONE AND ITS BENEFITS
Benefits of Testosterone Boosters. Testosterone is a crucial component in ordinary prosperity for the two sexual directions. As we age, nevertheless, the ordinarily happening levels of the substance begin to decline, especially in folks.
Around the age of 25, testosterone levels decline ceaselessly as the year progresses. decline, and when you show up at 30 years of age, testosterone levels in men will most likely decrease by around 2% every year.
But ordinary upgrades of this compound could uphold helping the strength of your muscles there are various advantages to advertisers for prosperity.
Muscle building Boosters
The ongoing local enhancements don’t contain. You can buy testosterone Tadalista or shots using the medication of an expert Natural testosterone advertisers are exceptionally successful in typically raising the levels of synthetics.
The extended proportion of local improvements can achieve extended strength and mass of muscles.
The improvements will help your energy levels and mean more blazing activities and in this manner give wellbeing attempts.
Additional Health Benefits
Low levels of can be a wellspring of wiped out influences on your prosperity, for instance,
Low Sex Drive
Less bone thickness
Sluggishness
Exhaustion
Irritability
The demeanor changes
Demoralization
The advantages of testosterone patrons could really look at a part of these issues, overhauling mental clearness and sex drive, energy levels, heart prosperity bone thickness as well as skin prosperity. The testosterone advertisers can moreover be used to treat pity.
Ordinarily conveyed supplements have shown convincing being developed and progression and, shockingly, retouching.
Numerous people, particularly females have involved substance allies to stay aware of change in their bodies following the treatment for the sickness, or menopausal signs.
See also Coryxkenshin; You ought to be aware of these
Drops In Testosterone with Age
By far most know in any event menopausal signs in women, most people don’t understand that experts are dynamically seeing that there is a male variety of this stage, consistently known as andropause.
The effects of menopausal developing won’t impact each man comparatively like menopausal changes are different for every woman.
Assuming it starts, regardless, it ordinarily is an issue for men some place in the scope of 40 and 55 years old.
Prosperity Information
Like another upgrade, you ought to visit with your essential consideration doctor prior to taking typical testosterone supports, particularly for the more energetic people.
The Best Testosterone Boosters and Their Effects
The best testosterone supports are those that balance the need the body. It’s in like manner present in females, in any case, folks are on various occasions the aggregate.
Testosterone has discretionary sexual characteristics and the best allies ought to duplicate the effects. There are different advertisers accessible, in any case.
There is a collection of procedures for making it available to the body. It is plausible to mix it clearly into the body.
The manufactured mixtures injectable are cypionate, or enanthate tracked down in the oil. All that advertisers can be mixtures, in any case, other than.
That it’s similarly possible to get utilizing oral ingestion or skin fixes, creams, and gels that limit of the transdermal procedure.
Testosterone isn’t sold accessible and ought to be suggested by a specialist specifically. The best patrons are convincing and can achieve the ideal changes at any rate the estimation ought to be inside the most dependable limits.
See also ZODIAC SIGNS: ARE YOU THE MARRIAGE TYPE?
Testosterone is routinely used as a show overhaul drug for contenders. It helps the making of protein in the body.
To grow these oddly low degrees, it should be controlled falsely. Several the best testosterone allies in like manner decline the chance of making osteoporosis, coronary ailment, diabetes, beefiness, and different other mental wellbeing issues and add to life range.
Moreover, they fill the fundamental need of improving and staying aware of the sexual characteristics that are assistant to the body, thusly ensuring strong and normal prosperity.
Be insightful that advertisers don’t have a really long prosperity record. Various dangers to well-are being that are connected. To be sure, even the most amazing allies go with these prosperity bets.
There is an extended chance of treating prostate illness. Research has shown a higher bet of prostate illness among individuals who have taken supplements.
Best Testosterone Boosters Why Are They Needed?
This has achieved testosterone being utilized to update the show Aurogra 100 expertly endorsed drug. The best allies of the aim are those that grant contenders to become skilled performers through more conspicuous strength.
Thusly, contenders can find the best testosterone backers to make arrangements for upon the appearance of their wedding.
The most consistently elaborate legitimate and reasonable usage for treating hypogonadism, or reduced creation that results from the lessened activity of the balls.
The compound testosterone is principal to ensure the suitable development, improvement, and limit of the body.
Therefore, a decrease in levels of synthetic compounds is sad. Thusly, testosterone is misleadingly injectable into the body. The best advertisers will do as such without negative reactions.
See also The most effective method to FIND THE BEST KITCHEN CONTRACTORS
For people who haven’t gotten assistant sexual characteristics, testosterone can assist with accomplishing these changes.
Helper sexual traits are qualities like shoulder extension and facial hair development advancement as well as the improvement of muscles, an augmentation in bone thickness, the stretching out of the voice, and creating body hair.
Men who have a low level of testosterone won’t have the choice to suitably cultivate these properties.
So they look for the best testosterone allies open to deal with the issues. In any case, talk with a specialist as isn’t speedily open as a medication.
There are many advantages to taking the best supporters. It upholds the advancement of protein inside the body.
Anyway, being familiar with the adverse consequences of promoters is fundamental. There aren’t any long security surveys open, and a couple of assessments have shown a higher bet of making prostate sickness among individuals taking testosterone.
Click here
Latest articles
BIOGRAPHY OF KARI LAKE
Sniffies
Who is tom brady net worth
What is about is Wario64
spot_imgspot_img
Related articles
Leave a reply
Please enter your comment!
Please enter your name here | {
"url": "https://techstorys.com/impacts-of-testosterone-and-its-benefits/",
"source_domain": "techstorys.com",
"snapshot_id": "CC-MAIN-2023-14",
"warc_metadata": {
"Content-Length": "404517",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:HCUMGZW2FZ242W77SHF42IDIKU37QFVR",
"WARC-Concurrent-To": "<urn:uuid:b031eec6-2fcf-4154-84e0-b72cdff1f2ac>",
"WARC-Date": "2023-03-23T23:59:24",
"WARC-IP-Address": "162.213.251.140",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:3S6RK3TGGGKCDORTD2MSXWUCAJ72W7IX",
"WARC-Record-ID": "<urn:uuid:9c904003-a655-402e-a71c-828ee45c54c2>",
"WARC-Target-URI": "https://techstorys.com/impacts-of-testosterone-and-its-benefits/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:9ffb7a25-2e81-4ade-b9b0-eff4c081dd29>"
},
"warc_info": "isPartOf: CC-MAIN-2023-14\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for March/April 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-81\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
41,
42,
280,
281,
495,
496,
645,
646,
671,
904,
905,
1002,
1003,
1126,
1127,
1154,
1246,
1247,
1261,
1281,
1294,
1305,
1318,
1339,
1354,
1622,
1623,
1738,
1739,
1911,
1912,
1967,
1968,
1999,
2199,
2200,
2328,
2329,
2443,
2444,
2467,
2640,
2641,
2690,
2862,
2863,
3026,
3027,
3149,
3150,
3303,
3304,
3438,
3439,
3670,
3671,
3722,
3723,
3838,
4105,
4106,
4286,
4287,
4488,
4489,
4645,
4646,
4694,
4918,
4919,
5040,
5205,
5206,
5317,
5318,
5509,
5510,
5583,
5584,
5706,
5707,
5937,
5938,
6041,
6193,
6194,
6306,
6307,
6553,
6554,
6565,
6566,
6582,
6583,
6606,
6607,
6616,
6617,
6644,
6645,
6670,
6671,
6688,
6689,
6706,
6707,
6721,
6722,
6749
],
"line_end_idx": [
41,
42,
280,
281,
495,
496,
645,
646,
671,
904,
905,
1002,
1003,
1126,
1127,
1154,
1246,
1247,
1261,
1281,
1294,
1305,
1318,
1339,
1354,
1622,
1623,
1738,
1739,
1911,
1912,
1967,
1968,
1999,
2199,
2200,
2328,
2329,
2443,
2444,
2467,
2640,
2641,
2690,
2862,
2863,
3026,
3027,
3149,
3150,
3303,
3304,
3438,
3439,
3670,
3671,
3722,
3723,
3838,
4105,
4106,
4286,
4287,
4488,
4489,
4645,
4646,
4694,
4918,
4919,
5040,
5205,
5206,
5317,
5318,
5509,
5510,
5583,
5584,
5706,
5707,
5937,
5938,
6041,
6193,
6194,
6306,
6307,
6553,
6554,
6565,
6566,
6582,
6583,
6606,
6607,
6616,
6617,
6644,
6645,
6670,
6671,
6688,
6689,
6706,
6707,
6721,
6722,
6749,
6776
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 6776,
"ccnet_original_nlines": 109,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 7,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3879828155040741,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.018025750294327736,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11158797889947891,
"rps_doc_frac_unique_words": 0.438289612531662,
"rps_doc_mean_word_length": 5.4266276359558105,
"rps_doc_num_sentences": 60,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.444879055023193,
"rps_doc_word_count": 1029,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.006088830064982176,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.013789400458335876,
"rps_doc_frac_chars_top_3gram": 0.017012890428304672,
"rps_doc_frac_chars_top_4gram": 0.005014330148696899,
"rps_doc_books_importance": -617.519287109375,
"rps_doc_books_importance_length_correction": -617.519287109375,
"rps_doc_openwebtext_importance": -367.1873779296875,
"rps_doc_openwebtext_importance_length_correction": -367.1873779296875,
"rps_doc_wikipedia_importance": -242.5900421142578,
"rps_doc_wikipedia_importance_length_correction": -242.5900421142578
},
"fasttext": {
"dclm": 0.01984434947371483,
"english": 0.9205239415168762,
"fineweb_edu_approx": 1.5271044969558716,
"eai_general_math": 0.021778879687190056,
"eai_open_web_math": 0.2883067727088928,
"eai_web_code": 0.000925239990465343
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.857",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "2",
"label": "Click Here References"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "2",
"label": "Partially Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-6,804,032,761,773,426,000 | Why Do You Have Pelvic Pain When Coughing?
Your pelvic area is beneath your belly button in the lower abdomen. If you are experiencing discomfort in this part of your body, the cause may be hard to diagnose because there are so many possibilities. If you are having pelvic pain with coughing, you should see your doctor right away for an exam. Depending on your symptoms, your exam may include blood and imaging tests.
Woman holding lower abdomen
Causes of Pelvic Pain When Coughing
1. Ovarian Cysts
Most women will experience ovarian cysts during their lifetime. The cysts are sacs filled with fluid found in either your ovaries or attached outside it. They typically resolve on their own and are not dangerous. However, if you have severe pain in your pelvic area that comes on suddenly, you should get medical attention right away. If you are also experiencing fever, rapid breathing, weakness, vomiting or dizziness, go to the emergency room.
2. Pelvic Inflammatory Disease
Considered a potentially dangerous illness, pelvic inflammatory disease is a condition which involves the infection of the cervix, ovaries, uterus and fallopian tubes. Also referred to as PID, it is a bacterial disease that is transmitted sexually. Symptoms include pelvic pain when coughing and possibly nausea, fever or vomiting. PID can result in tubal ectopic pregnancies or infertility, especially if not diagnosed and treated early.
3. Ectopic Pregnancy
Sometimes a fertilized egg will attach itself outside the uterus. When this occurs it is called an ectopic pregnancy. Often this type of pregnancy happens inside the fallopian tubes, but can also occur in the ovaries. A woman does not usually know the condition exists until a rupture, but sometimes before the burst she may have pelvic pain and a bloated abdomen. While some ectopic pregnancies detach on their own and are expelled, oftentimes surgery is needed.
4. Round Ligament Pain
If you are pregnant and start to feel pain on the sides of your stomach, you may be experiencing round ligament pain. Do not panic. It is common for a woman to feel this discomfort in her second trimester. Round ligaments are located in the pelvis and go around the uterus. As your unborn baby grows, your uterus will expand and stretch the ligaments. To help compensate, they thicken so they can continue to support your uterus. Sudden pelvic pain when coughing or changing positions may actually be round ligament pain.
5. Appendicitis
If your appendix gets a bacterial infection and becomes inflamed, you have an illness called appendicitis. Left untreated, it can become a life-threatening condition as your appendix fills with pus and risks of rupture rises. Pelvic pain is the most common symptom. Usually, it intensifies very quickly and is worse when you move suddenly, cough or stretch.
6. Bowel Obstruction
Your bowel can become obstructed when a scar forms in your colon or small intestine after surgery, trauma or infection. Signs of an obstruction include tenderness in the pelvic area, pain around your belly button, abdominal pain with coughing, nausea, severe constipation, stomach cramps or vomiting.
7. Endometriosis
When cells usually found in your uterus grow outside of it on organs like the bladder, ovaries, and rectum, you have a condition called endometriosis. Signs of this disorder include:
• Ovulation pain
• Pain with sex
• Pelvic pain with menstrual pain
• Period cramps
• Pain with urination or bowel movements
• Bloated abdomen
• Rectal bleeding during menstrual period
• Lower and mid back pain
8. Diverticulitis
If you develop infected small blisters or protruding sacs in your colon or large intestine, it is referred to diverticulitis. The inflamed areas are located in the lining of the organs and can affect you for as little as a couple hours to as long as 3-4 days. Signs of this condition may include:
• Abdominal swelling
• Pelvic pain when coughing
• Abdominal pain with movement
• Bloated sensation
• Loss of appetite
• Nausea or vomiting
When to See a Doctor
Anytime you have sudden and extreme pelvic pain, you should get medical attention right away. It is important to see your doctor for proper diagnosis of your condition, especially if it interrupts your daily routine or keeps getting worse.
Current time: 06/28/2017 04:48:08 am (America/New_York) Memory usage: 2140.71KB | {
"url": "http://www.newhealthadvisor.com/pelvic-pain-when-coughing.html",
"source_domain": "www.newhealthadvisor.com",
"snapshot_id": "crawl=CC-MAIN-2017-26",
"warc_metadata": {
"Content-Length": "18715",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:5BJRVG2RKLF27CBSIREAIVLSGIE3EL7P",
"WARC-Concurrent-To": "<urn:uuid:494b51e3-2868-4863-9e79-885ef8df862f>",
"WARC-Date": "2017-06-28T08:48:04",
"WARC-IP-Address": "104.31.68.225",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:DQ3TXKI6RCHEPOOUAYMLQXYBJKLAYO52",
"WARC-Record-ID": "<urn:uuid:1456de53-d663-4133-8d64-ca7580d8d3ed>",
"WARC-Target-URI": "http://www.newhealthadvisor.com/pelvic-pain-when-coughing.html",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:cc7bd701-e5e6-43f8-9e4a-288ede9e5740>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-166-26-198.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2017-26\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for June 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
43,
44,
420,
421,
449,
450,
486,
487,
504,
505,
952,
953,
984,
985,
1424,
1425,
1446,
1447,
1911,
1912,
1935,
1936,
2458,
2459,
2475,
2476,
2834,
2835,
2856,
2857,
3158,
3159,
3176,
3177,
3360,
3361,
3380,
3398,
3434,
3452,
3495,
3515,
3559,
3587,
3588,
3606,
3607,
3904,
3905,
3928,
3958,
3991,
4013,
4034,
4057,
4058,
4079,
4080,
4320,
4321,
4323,
4325
],
"line_end_idx": [
43,
44,
420,
421,
449,
450,
486,
487,
504,
505,
952,
953,
984,
985,
1424,
1425,
1446,
1447,
1911,
1912,
1935,
1936,
2458,
2459,
2475,
2476,
2834,
2835,
2856,
2857,
3158,
3159,
3176,
3177,
3360,
3361,
3380,
3398,
3434,
3452,
3495,
3515,
3559,
3587,
3588,
3606,
3607,
3904,
3905,
3928,
3958,
3991,
4013,
4034,
4057,
4058,
4079,
4080,
4320,
4321,
4323,
4325,
4404
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4404,
"ccnet_original_nlines": 62,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 3,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.37362638115882874,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.004883999936282635,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.15506716072559357,
"rps_doc_frac_unique_words": 0.41258740425109863,
"rps_doc_mean_word_length": 4.946853160858154,
"rps_doc_num_sentences": 47,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.177499294281006,
"rps_doc_word_count": 715,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.029968900606036186,
"rps_doc_frac_chars_dupe_6grams": 0.02092169038951397,
"rps_doc_frac_chars_dupe_7grams": 0.02092169038951397,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.02827255055308342,
"rps_doc_frac_chars_top_3gram": 0.019790779799222946,
"rps_doc_frac_chars_top_4gram": 0.031099800020456314,
"rps_doc_books_importance": -365.8063659667969,
"rps_doc_books_importance_length_correction": -365.8063659667969,
"rps_doc_openwebtext_importance": -207.92752075195312,
"rps_doc_openwebtext_importance_length_correction": -207.92752075195312,
"rps_doc_wikipedia_importance": -157.39047241210938,
"rps_doc_wikipedia_importance_length_correction": -157.39047241210938
},
"fasttext": {
"dclm": 0.13991957902908325,
"english": 0.9334467053413391,
"fineweb_edu_approx": 2.869539260864258,
"eai_general_math": 0.005487559828907251,
"eai_open_web_math": 0.2611986994743347,
"eai_web_code": 0.0006829500198364258
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.07",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
1,741,750,275,605,689,900 | Knee protection
Navigation:Home > Joint Surgery > Arthritis > Knee protection
As the saying goes "old before old legs", the first leg in the knee trouble. A lot of old friends because of knee pain tortured before, flex
Content
As the saying goes "old before old legs", the first leg in the knee trouble. A lot of old friends because of knee pain tortured before, flexible and vigorous figure does not exist, walk away no, climbing up the downhill no, the previous simple squat stand up now it is very difficult. This is because our knees have degenerated.
The so-called degenerative osteoarthritis, a simple definition, refers to the articular surface of the cartilage loss of elasticity, so that the bone under the cartilage stress increased, resulting in accelerated joint wear, thinning, joint space narrowing. As a result, the movement of power directly to the subchondral bone, bone sclerosis, deformation, cystic change, and so on, resulting in joint function of the disease. Department of joint surgery, Nanfang Hospital, Southern Medical University, Shi Zhanjun
In general, after 30 years of age began to gradually wear cartilage, then, with the increasing age, joint damage, cartilage damage is also more and more serious, leading to the emergence of senile arthritis. Therefore, young people should learn to care as well as the maintenance of the machine parts of the knee, as far as possible to delay the onset of knee arthritis.
Why the knee joint is easy to aging
Our knees under the body almost all the weight, whether it's exercise, walking, stair, articular cartilage everyday under the weight and the impact force caused by various activities, all joint "pressure" the biggest. Under the natural condition, the knee is affected by the age, the chemical substance, the muscle use, needs to maintain the vigor through the diet, the standing posture, the appropriate activity.
As early as adolescence, articular cartilage began to degenerate. With the increase of age, blood circulation and muscle weakness, joint parts for lubricating liquid secretion decline and dry, soft tissue elasticity, more vulnerable to the threat of injury, the cartilage becomes easy peeling; meniscus began to deteriorate and lack of the ability of reconstruction, the problem for weight gain and deterioration. The physiological structure such as curved legs, flat feet, tenesmus ankle, inner character, these natural factors and often injured, will cause the knee deviate from growth track. To know from the foot to the hip linkage is highly independent, if a part from the track, the whole system will fail.
The use of a certain amount of exercise or exercise can result in an imbalance in the proportion of muscle tissue. For example, cyclists at the front of the thigh muscle is unusually rich. Some sports have high levels of vibration on the knees, such as running and most ball games, which can increase the likelihood of a knee injury if not combined with a low vibration exercise such as swimming and cycling.
Knee maintenance
Recipes for joints
Joints, like other parts of the body, need plenty of vegetables and fruits. Eat at least 5 kinds of vegetables and fruits every day. This is the only way to get micronutrients, vitamins and minerals. The body needs calcium, zinc, and vitamin C to heal, multivitamins may be effective, but there is no better source of fresh food. Refined oil will also help to a joint weekly in the diet plus several deep-sea fish (or -3 substitute), olive oil, avocado and almonds will significantly help.
Pay attention to moisture cold
As the knee is "skinny", lack of muscle and fat protection, not enough heat supply, so the temperature is lower than other parts of the body, do weatherization is very important, especially in patients with chronic synovitis. The knee is afraid of wet, do not sleep in the dark and wet places, summer sweat do not immediately rinse with cold water knee.
weight control
The main cause of knee degeneration is the long-term wear, weight and aging of the joint, coupled with the loss of calcium, a lot of fat in the form of middle-aged and older women are the main victims of knee arthritis. Therefore, weight control is the most direct way to reduce the weight of the knee joint, it is very important to reduce the aging of the joints.
Choose a scientific way of movement
At present, there is a common confusion, patients with osteoarthritis: Osteoarthritis like? Answer the total principle is: both prevention and treatment of osteoarthritis, to exercise, exercise can make bone sturdy, muscular, enhancement of articular cartilage, improve nutrition, delaying the cartilage aging, which is to prevent bone from the fundamental way of arthritis.
But the point is that there should be a right way and activity.
Pay attention to the preparation of physical exercise to do a good job in the preparation of the activities, gently stretch the knee at least 1 minutes.
Often change posture and posture attention to change the position and posture, avoid sedentary or long standing. When you are engaged in sitting or squatting work, should stand up and walk around for a period of time, you can also massage the knee joint, so that the knee will not be fixed in the same position for a long time. This not only helps to promote the blood circulation of the knee joint, but also can reduce the internal and external tissue adhesion.
To strengthen the activities of lower limb exercise here introduces two exercise methods.
Methods a supine position, a height of about 10 cm in the pillow behind the knee, let the leg alternating up to full knee extension, and then put down, every time 20~30 times, can be arranged before sleep wake up in the morning and evening, it can make the knee fully stretch, rotation, prevent its stiffness tonic.
Methods two straight leg raising exercise. Supine position, the lower limb completely straight raise, lift off the bed about 30 degrees. Adhere to 5~10 seconds, put down, relax 2~3 seconds. Exercise 15 minutes a day, two times a day. The main point of the action is the whole process of the knee to be completely straight, not bent, the purpose is to exercise our muscles around the knee, muscle strength is the best support for the knee.
In general, people with poor knee function should avoid 3 kinds of exercise:
Joint weight-bearing exercise, such as running and mountain climbing; frequent twisting knee exercise, such as yangko dance; repeated squat exercise.
It is ideal for swimming, cycling and stretching to lower the weight of joints.
Treatment of osteoarthritis
Osteoarthritis of the knee is a very common chronic rheumatism, at present there is no cure for the world. But the general incidence of this disease is slow, intermittent attacks, in case of climate change, increased joint pain and fatigue after trauma, early onset through lifestyle changes, proper exercise and drug therapy can alleviate the symptoms, slow development and improve the quality of life. If not treated in time, to a high rate of late disability, such as the rehabilitation of the disabled not only increase the pain, but the cost of treatment is very high, one side of the knee replacement surgery costs tens of thousands of dollars.
Now there is a new medical term called "time window", "time window" refers to the best treatment time of the disease, when the "window" opened, it means that the disease can be cured or at the time, but when the "window" closed, equal to miss the best diagnosis a period of treatment, and treatment is not easy to cure, so early prevention and early treatment is the key to prevent disability.
The treatment of osteoarthritis is to alleviate symptoms, delay the change of joint structure, maintain joint function and improve the quality of life.
American College of Rheumatology 1995 Pyramid proposed scheme in the treatment of osteoarthritis, in 2000 the European League Against Rheumatism of osteoarthritis treatment recommendations are three aspects, namely the non drug treatment, drug treatment and surgical treatment. Treatment plan is not in accordance with the above order, should be based on the severity of the disease to give appropriate treatment.
Non drug treatment should pay attention to life guidance, to participate in a reasonable physical exercise, the use of physical therapy such as hyperthermia, hydrotherapy, infrared, electrical stimulation, etc.. Drugs have anti-inflammatory painkillers (aspirin, Bloven, Ni Mei Shug Leigh etc.); to alleviate the symptoms of drugs is glucosamine, chondroitin sulfate, glycosaminoglycans, intra-articular injection of hyaluronic acid or hormone.
Some drugs to relieve symptoms need to use a few months to take effect, there are indications that the use of drugs to alleviate symptoms can significantly delay the development of the disease, is a key treatment for prevention of disability.
Hyaluronic acid (HA) is the main component of the joint fluid, and the use of hyaluronic acid intra-articular injection has protective effect on joint, lubrication, shock absorption, relief of pain and improvement of joint function. For patients with severe disease and obvious joint dysfunction, surgical treatment may be considered. Surgery of knee joint cavity and artificial joint replacement.
www.Cure001.comwww.Cure999.com
Cerebral Vascular Disease,Acne,Heart Disease,Deaf,Headache,Std,Condyloma Acuminatum,Fibroid,Pneumonia,Brain Trauma,。 Rehabilitation Blog
Rehabilitation Blog @ 2017 | {
"url": "http://www.scleritis.net/joint-surgery/arthritis/EVZBVFNSX.html",
"source_domain": "www.scleritis.net",
"snapshot_id": "crawl=CC-MAIN-2017-39",
"warc_metadata": {
"Content-Length": "23026",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:V2AVKWAPFPM72WGTNU3PV3TZFPKVKTPB",
"WARC-Concurrent-To": "<urn:uuid:f84dd1e3-b74e-4f9c-b4ed-e8560ec6d6b2>",
"WARC-Date": "2017-09-21T03:08:39",
"WARC-IP-Address": "204.44.85.141",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:7S2HL4MIFSRXQEK57PRRIVYYWW6OKEUS",
"WARC-Record-ID": "<urn:uuid:d8a05c4e-d543-4dcd-aa33-673edb2f349f>",
"WARC-Target-URI": "http://www.scleritis.net/joint-surgery/arthritis/EVZBVFNSX.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:2e0669a1-163f-4bab-963a-c2126fb0e5d9>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-147-62-137.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2017-39\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for September 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
16,
17,
79,
80,
221,
222,
230,
231,
560,
561,
1075,
1076,
1447,
1448,
1484,
1485,
1899,
1900,
2613,
2614,
3023,
3024,
3041,
3042,
3061,
3062,
3552,
3553,
3584,
3585,
3939,
3940,
3955,
3956,
4321,
4322,
4358,
4359,
4734,
4735,
4799,
4800,
4953,
4954,
5417,
5418,
5508,
5509,
5825,
5826,
6265,
6266,
6343,
6344,
6494,
6495,
6575,
6576,
6604,
6605,
7256,
7257,
7651,
7652,
7804,
7805,
8219,
8220,
8665,
8666,
8909,
8910,
9308,
9309,
9311,
9312,
9343,
9344,
9482,
9483
],
"line_end_idx": [
16,
17,
79,
80,
221,
222,
230,
231,
560,
561,
1075,
1076,
1447,
1448,
1484,
1485,
1899,
1900,
2613,
2614,
3023,
3024,
3041,
3042,
3061,
3062,
3552,
3553,
3584,
3585,
3939,
3940,
3955,
3956,
4321,
4322,
4358,
4359,
4734,
4735,
4799,
4800,
4953,
4954,
5417,
5418,
5508,
5509,
5825,
5826,
6265,
6266,
6343,
6344,
6494,
6495,
6575,
6576,
6604,
6605,
7256,
7257,
7651,
7652,
7804,
7805,
8219,
8220,
8665,
8666,
8909,
8910,
9308,
9309,
9311,
9312,
9343,
9344,
9482,
9483,
9509
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 9509,
"ccnet_original_nlines": 80,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.37348735332489014,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.002200220013037324,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1556655764579773,
"rps_doc_frac_unique_words": 0.3826998770236969,
"rps_doc_mean_word_length": 5.02162504196167,
"rps_doc_num_sentences": 61,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.451553821563721,
"rps_doc_word_count": 1526,
"rps_doc_frac_chars_dupe_10grams": 0.027404410764575005,
"rps_doc_frac_chars_dupe_5grams": 0.03914916142821312,
"rps_doc_frac_chars_dupe_6grams": 0.034190259873867035,
"rps_doc_frac_chars_dupe_7grams": 0.027404410764575005,
"rps_doc_frac_chars_dupe_8grams": 0.027404410764575005,
"rps_doc_frac_chars_dupe_9grams": 0.027404410764575005,
"rps_doc_frac_chars_top_2gram": 0.014354689978063107,
"rps_doc_frac_chars_top_3gram": 0.007046849932521582,
"rps_doc_frac_chars_top_4gram": 0.003914920147508383,
"rps_doc_books_importance": -859.6280517578125,
"rps_doc_books_importance_length_correction": -859.6280517578125,
"rps_doc_openwebtext_importance": -454.36883544921875,
"rps_doc_openwebtext_importance_length_correction": -454.36883544921875,
"rps_doc_wikipedia_importance": -280.80218505859375,
"rps_doc_wikipedia_importance_length_correction": -280.80218505859375
},
"fasttext": {
"dclm": 0.1251649260520935,
"english": 0.9285678267478943,
"fineweb_edu_approx": 2.836811065673828,
"eai_general_math": 0.11902523040771484,
"eai_open_web_math": 0.2638516426086426,
"eai_web_code": 0.006653429940342903
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.1",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "613.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "3",
"label": "Apply"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "3",
"label": "Procedural"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "2",
"label": "Click Here References"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "6",
"label": "Content Listing"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-7,548,983,887,998,497,000 | RESEARCH ARTICLE
Pre-Transplant Screening for Latent Adenovirus in Donors and Recipients
Gabriella Piatti*, 1, 2
1 Department of Surgical and Diagnostic Sciences, Section of Microbiology, University of Genoa, Italy
2 Division of Microbiology, San Martino Hospital, Genoa, Italy
Article Metrics
CrossRef Citations:
0
Total Statistics:
Full-Text HTML Views: 4370
Abstract HTML Views: 2630
PDF Downloads: 848
ePub Downloads: 705
Total Views/Downloads: 8553
Unique Statistics:
Full-Text HTML Views: 1944
Abstract HTML Views: 1414
PDF Downloads: 590
ePub Downloads: 463
Total Views/Downloads: 4411
Creative Commons License
© Gabriella Piatti; Licensee Bentham Open.
open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
* Address correspondence to this author at the Department of Surgical and Diagnostic Sciences, Section of Microbiology, University of Genoa, Italy; Tel: 39-320 4207437; 39-010 3537658; E-mail: piatti@unige.it
Abstract
Human adenoviruses are frequent cause of slight self-limiting infections in immune competent subjects, while causing life-threatening and disseminated diseases in immunocompromised patients, particularly in the subjects affected by acquired immunodeficiency syndrome and in bone marrow and organ transplant recipients. Here, infections interest lungs, liver, encephalon, heart, kidney and gastro enteric tract. To date, human adenoviruses comprise 51 serotypes grouped into seven species, among which species C especially possesses the capability to persist in infected tissues. From numerous works, it emerges that in the recipient, because of loss of immune-competence, both primary infection, via the graft or from the environment, and reactivated endogenous viruses can be responsible for transplantation related adenovirus disease. The transplants management should include the evaluation of anti-adenovirus pre-transplant screening similar to that concerning cytomegalovirus. The serological screening on cytomegalovirus immunity is currently performed to prevent viral reactivation from grafts and recipient, the viral spread and dissemination to different organs and apparatus, and potentially lethal outcome.
Keywords: Adenovirus, antibodies, latency, reactivation, real-time polymerase chain reaction, screening, serostatus, transplantation.
Introduction
Human adenovirus (HAdV) infections, frequent in children since they are naïve hosts, are common in all age groups of the population, and are generally asymptomatic or slight self-limiting in the immune competent subjects, where they present variable symptomatology and different localizations, i.e., ocular, cardiac, respiratory and gastro-intestinal. Despite their usual weak pathogenicity, HAdVs can cause severe affections, requiring hospitalization, such as acute respiratory diseases (ARDs) and intestinal lymphoid hyperplasia up to intussusception. In immunocompromised patients, particularly in the subjects suffering from acquired immunodeficiency syndrome (AIDS) and in allogenic hematopoietic stem cells (HSC) and solid organ transplant recipients, HAdV often cause life-threatening and disseminated infections, named transplantation related adenovirus disease [1]. In these subjects, adenoviruses are responsible for a broad range of evident infections, affecting bloodstream, lungs, liver, encephalon, heart, kidney, bladder and gastro enteric tract, singly or together.
To date, 51 distinct HAdV serotypes and numerous “types” are identified and grouped within seven species (A-G) defined through genomic criteria. Specific anti-adenovirus neutralizing antibodies recognize single species, while those recognizing the exon protein capsid are common to all species [2]. Different adenoviral serotypes possess different biological and pathogenetic properties, such as the oncogenic potential, detectable on in vitro and in vivo rodent’s models, the spectrum of virus-host interactions and associated diseases. Since 1958, human adenoviruses are known to establish persistent and latent infections, both in lymphatic tissue and in solid organs, like kidney and liver [3]. Adenoviruses belonging to species C (adenovirus type 1, 2, 5, 6) are the most ascertained to remain in infected organisms and the most commonly encountered in affected patients, especially in children under five. It is likely that the various features and presentations of HAdV, which depend on the infecting serotype, would occur both in immune-competent and in immunocompromised hosts [4, 5].
In the last thirty years, the number of transplanted subjects and people suffering from AIDS enormously increased and so the importance of HAdV and other latent viruses. Among these, the most relevant are those belonging to herpes family, i.e., Cytomegalovirus (CMV), Epstein-Barr (EBV), Herpes Simplex (HSV), Human Herpesvirus 6 (HHV6) and Varicella-Zoster (VZV) viruses [1]. Nevertheless, the pre-transplant protocols, which include the serological screening in donors and recipients for all Herpes viruses, do not include that for Human Adenoviruses.
Many investigations on transplantation related adenovirus disease have looked at several clinical variables, such as age of recipient and donor, kind of transplant, i.e., bone marrow or solid organs, preparatory regimen and primary disease, to summarize the common characteristics of the infection. Nowadays, it is known that the rate of adenovirus infection, the severity of disease and the incidence of mortality broadly vary, mostly depending on age of patients and kind of graft. The highest prevalence is in fact among the pediatric population transplanted with hematopoietic stem cells, while the lowest one is among adults transplanted with solid organs. In this second cluster of patients, the adenoviral infection usually occurs in the graft, often leading to transplant failure and organ loss [5-7].
However, as effectively asserted by Chakrabarti, not enough is understood regarding the specific contribution of primary infection, which can take place via the graft or environment, and the precise contribution of the reactivation of endogenous viruses [8-10]. For this reason, specific strategies to provide a correct prevention are quite missing.
Knowledge on CMV disease transplant related, and management
As previously mentioned, serological assays towards the Herpes virus family is included in pre-transplant protocols, and the relative data became more and more numerous and useful over time. Particularly, those results concerning the cytomegalovirus serostatus, collected in homogenous groups of patients, allowed to achieve a deep knowledge of the different pathways of CMV disease. The consequent preventive strategies have had a significant impact in reducing mortality over the past two decades. Another example of usefulness of serology preventive emerges from the results about EBV. The relative data, in fact, led to the discovery of the Epstein-Barr virus-associated post-transplantation lymphoproliferative disease and to the awareness of the risk associated with the transplantation procedure [9, 11].
In 2010, thanks to the analysis of CMV serostatus, George and colleagues stated that the highest risk of cytomegalovirus infection in adults was due to hematopoietic stem cell transplantation (SCT) whose recipient was positive. The lowest risk was related to CMV naïve condition of both donor and recipient, and the intermediate one was related to the negative recipient, even in the case of positive donor [12]. These finding highlighted the negligible importance of primary infections and the dramatic role of endogenous reactivations in adults for the onset of CMV infections related to stem cells transplant.
Kulberg-Lindh and colleagues, to study in children the viral opportunistic infections SCT related, retrospectively analyzed serum samples by quantitative Real-time polymerase chain reaction (RT-PCR) detection of CMV, EBV, HHV6 and HAdV DNA during the first 6-12 months after the transplant, investigated the specific serostatus prior to transplant and clinical variables. Data on DNAemia, which occurs in 47% for CMV, in 45% for EBV, in 28% for HHV6 and in 28% for HAdV, and increased to high levels in the three lethal infectious outcomes, allowed distinguishing significant infections. The serum positivity for CMV immunoglobulin G in either recipient or donor, other than the total body irradiation procedure and the anti-thymocyte globulin conditioning, indicated those patients who needed to be closely followed and treated with preventive therapy [13]. Hiwarkar and colleagues, analyzing the impact of viral reactivation in pediatric SCT recipients, reported that CMV and HAdV reactivation was the major risk factor for mortality following transplant [14]. However, the authors considered the pre-transplant CMV and EBV seropositivity in donors and recipients as the first choice of investigation. On the contrary, they assessed the presence of adenoviruses through the use of RT-PCR assay on recipient’s naso-pharyngeal aspirate and stool. The evaluation of HAdV presence was thus restricted to pre-existing viruses from very recent or acute phases of infection, in a few tracts of organism and only in recipients, wasting any detection of adenovirus during latency, in any tract of body and in donors.
Knowledge on transplantation related adenovirus disease, management and limits
Currently, the pre-hematopoietic cell transplant protocol does not include the evaluation of anti-adenovirus serostatus, since it is considered not useful because of the existence of many different serotypes and because of the little knowledge about the diagnostic efficiency of cross-reactive immunity. On the other hand, the authors of protocol affirm that cellular immune responses, cross-reactive across various serotypes, likely provide a long-term protection against the adenoviral reactivation and make serious adenovirus infections in adults uncommon [15]. These considerations led to a stratification of the risk of adenoviral disease that only concerns a generic evaluation of kind of graft and preparatory regimen, and that misses the possibility to discover subjects at specific risk of HAdV reactivation.
The management of HAdV infections related to SCT currently implies great efforts and very high coasts to monitor HAdV viremia early after transplant, like suggested in the scheme by Sive and colleagues. The scheme proposes weekly PCR on blood, and stools or nasopharyngeal samples in the case of symptoms, until day 100 [16]. This protocol is not a definitive strategy against HAdV infection, but is actually useful to early detect the disease, allowing both preventive treatment and immediate therapy, possibly preventing disease severity. The protocol fits as well with the routine weekly PCR screening for CMV and EBV [17].
Nevertheless, it is evident that the use of RT-PCR, nowadays the most suitable molecular technique for early monitoring of viral presence, can just allow the tailoring of immune-suppression [6, 18]. Unlike the treatment for CMV, no established therapy against adenovirus infections does exist and the therapeutic options are currently not satisfying. In fact, the clearance of HAdV and a definitive cure require adequate immune reconstitution after HSCT, despite the preemptive and therapeutic treatment with Cidofovir, characterized by relevant toxicity [6, 8, 19].
In 2011, Veltrop-Duits and colleagues evaluated the pre-existing HAdV serostatus in children recipients, to predict viral reactivations after hematopoietic SCT, and the presence of viral DNA in graft material, measured by PCR, to investigate as well the possible HAdV transmission from donor to recipient [20]. High pre-transplant titers of serotype specific neutralizing antibodies against HAdV appeared to predispose to infections with the same serotype after transplant, instead of protecting from it. These results, explainable by the decreased or disappeared immunity due to the preparatory regimen, contradict the statements in the pre-hematopoietic cell transplant protocol [15] about the long-term protection against HAdV reactivation. These data also suggest that reactivated endogenous viruses rather than primary infections would be the major pathway of adenoviral infection, like mentioned for CMV disease in the work by George [12]. A significant risk for adenoviral reactivation and dissemination also emerged from data about HAdV DNA presence, detected prior to SCT in feces or nasopharyngeal aspirates of pediatric recipients [18, 21]. In a previous investigation, instead, positive donor’s serostatus appeared as very important risk for HAdV infection in recipients, thus suggesting the contagious with the graft [22].
Discrepancies between different studies show how complex the problem of transplant related adenovirus infection and the need to get more information. Moreover, in the opinion of Sive and other authors, also the true incidence and the clinical significance of HAdV DNA presence in the blood, as well as the viremic titer, remain unclear because of the wide variation in the study populations and in the methodology [16, 23].
Clinicians usually perform serological tests to obtain indirect diagnosis of viral infections, but the presence of specific antibodies is especially the evidence of specific protection against acute self-limiting viral infections, such as flu and hepatitis A. Among cohorts of people where immune-competence does persist, such as children affected by cystic fibrosis and military recruits, they turned out to be protected against HAdV infection by the presence of specific neutralizing antibodies [20]. Data on serostatus are of scarce utility if the antibodies production gets weak, such as after transplant when the frequent use of blood transfusions and intravenous immunoglobulin also limit the significance [13]. Differently, when performed prior to transplant, the seropositivity towards persistent and latent viruses should represent evidence for their possible presence and for possible reactivation, which could occur after immunosuppression.
Interpretation of anti-CMV serological assay and clinical use
As already mentioned, several authors consider HAdV serostatus of recipients and donors of limited value because most individuals was in contact with one or more serotypes, while diagnostic tests usually detect generic HAdV antibodies, not type-specific [15, 20, 22, 24]. At the same, however, the immunological plurality of viral strains could also diminish the utility of serological screening for the transplant related CMV disease. In fact, the cytomegalovirus serostatus is commonly valuated with commercial enzyme-linked immunosorbent assay (ELISA) kits, which use entire CMV-infected cells as antigens and do not allow distinguishing between antibodies against different strains. A not routine, strain-specific seroepidemiology towards the conserved CMV antigen domain 2 (AD2) epitope of glycoprotein B (gB) and towards the not conserved glycoprotein H (gH) allowed observing the protection from CMV reinfection in renal transplant in patients CMV-gH antibody matched, but not in those CMV-gH antibodies mismatched [25]. The mismatching of gH serotypes was associated with CMV disease after renal transplantation and with low level of neutralizing antibodies against gB AD2. This finding described the strain-dependent immune responses, the consequent absence of protection towards different CMV strains and explained the why of viral transmission during pregnancy in mothers routinely CMV seropositive [26, 27]. The strain-specific analysis, performable at the aim of epidemiologic investigations, makes possible to recognize the relevant burden of reactivation and reinfection in the pathogenesis of transplant related CMV disease. Nevertheless, the simple routine serological screening, despite its limit, is currently performed in patients prior to transplant, resulting in the basic discovery of risk for CMV reactivation.
Interpretation of anti-HAdV serological assay and limits of clinical use
Nowadays, the genomic investigations replace the neutralization assays in the definition of HAdV types and are performed in the contest of epidemic infectious events or specific investigations [28]. The serological typing characterization of adenovirus is still useful for detecting type-specific neutralizing anti-HAdV antibodies. These assays, although represent a diagnostic effort, could be at least addressed to discovery species C, which most frequently shows the biological behavior of latency, to evaluate the dynamics of viral diffusion and to clarify basic pathogenic aspects. However, more important and feasible, any data obtained from the performance of routine cross-reacting antibodies assay should be hopeful to recognize the recipients at risk for endogenous reactivation.
As already highlighted, the persistent lack of effective therapies against HAdV makes the reconstitution of antiviral immunity of paramount importance, leading to the need of adoptive therapy. Specific cytotoxic lymphocytes can be utilized as a passive immunization for prophylaxis in high-risk allogenic hematopoietic SCT and solid organ recipients, and for the treatment in the case of infection, when any necessity would be in advance recognized. In fact, even if the new generation of virus-specific lymphocytes has increased the feasibility of their use, this therapy remains demanding in terms of cost and time [29, 30]. Moreover, it was also demonstrated that human CD4+ T cells stimulated by conserved adenovirus hexon peptides from a single species recognize cells infected with HAdV serotypes belonging to different one [31]. The cross-reactivity, while for the gene therapy may limit the utility of switching to HAdV-based vectors derived from not common adenoviral serotypes, instead may benefits the utilization of HAdV-specific T cells in transplant recipients and makes the early individuation of recipients at risk, and a careful evaluation of any reciprocal donor-recipient serostatus, necessary. Since the generation of antigen-specific T cells from naïve T cell donors is still difficult, laborious and time-consuming, allogeneic third party T-cell donors offers an alternative option for recipients with virus seronegative donors or receiving cord blood in HSCT and cadaveric graft in SO transplantation [32]. The efficient treatment of high-risk patients requires the rapid recruitment of suitable T-cell donors, selected from the allogeneic cell registry alloCELL (www.alloCELL.org) established at Hannover Medical School (MHH). Here, donor seropositivity provides an opportunity to transfer virus-specific lymphocytes to mediate immune protection in the immunosuppressed recipient. In this context, a recent work evaluated CMV-, EBV- and ADV-specific serostatus as preliminary assay to screen and monitor the relevant T-cell immunity and showed antigen-specific T cells to be present in 73% of ADV-seropositive donors [33].
JC polyomavirus: significance of sero-status in the management of a persistent virus
In the field of viral persistence, it is nowadays ascertained that the persistent infection caused by JC polyomavirus (JCV) and its reactivation are prerequisites for the onset of the progressive multifocal leukoencephalopathy (PML), observed in immunocompromised subjects [34]. Gorelik and colleagues described a JCV-specific higher-affinity ELISA performed for retrospectively assessing the JCV serostatus before the immunosuppressive therapy in multiple sclerosis patients, and to achieve a PML risk stratification. The authors detected anti-JCV antibodies in 100% of serum samples collected prior to PML diagnosis [35]. They also detected JCV DNA in urine to identify infected individuals and to establish the positive reference sera. Moreover, JCV as well shows important genomic and phenotypic plurality of strains. Particularly, a set of mutations, deletions and duplication verifying in noncoding control region (NCCR) sequence of JCV genome was found as modifying the archetype polyomavirus JC and allowing neurovirulence, i.e., the virus entrance into human central nervous system, a preliminary condition for PML onset [36]. This feature does not make vain a possible application of serology for the prevention of PML. On the contrary, it led to a project aimed to restrict the identification of high-risk subjects to those bearing JCV DNA rearrangement [37]. The diseases caused by the reactivation of JCV and HAdV due to immunosuppressive therapies, or due to any immunodeficiency status, share the lack of effective therapies and the great necessity to identify subjects at risk. The management of immunosuppressive protocols and pre-transplant screening cannot include the evaluation of anti-polyomavirus serostatus, since commercial routine assays to perform standardized measures are not nowadays available. Serological assays detecting HAdV-antibodies, instead, are suitable in microbiology laboratories for achieving diagnosis for acute and symptomatic infections in immune competent subjects [2, 38].
Conclusion
In the case of immunodeficiency planned for conditioning regimens or for therapeutic protocols, any effort have to be supported to avoid as much as possible primary infections with latent and persistent viruses and microorganisms, and their reactivation, or to be at least strictly aware of the underlying risk resulting from the treatment. The same authors who propose the PCR-based surveillance of HAdV infection are not sure whether this method is of benefit for the patients. However, they consider direct molecular assay as an opportunity they recommend not to waste [16, 23]. The management of immunosuppressive therapies performed without using every available tool to avoid or reduce the risk of consequent infections, diseases and death, could be an extreme responsibility.
To conclude, the pre-transplant screening should include the evaluation of latent HAdV infections, performing serological tests in donor and recipient, similar to the screening aimed at preventing cytomegalovirus infections. It is important to remind that the serological CMV screening is performed in spite of the existence of established and effective therapies. This screening currently represents a necessary condition, even if not sufficient, to prevent and to manage the onset of CMV infection in immunocompromised patients [11, 12]. It allows the protective matching of donors and recipients, avoiding organ transplantation from a seropositive donor to a seronegative recipient, the discovery of subjects at risk to carefully survey, the consequent preemptive therapy and active or passive immunization to prevent post-transplant CMV infections.
Improving the pre-transplant screening with serostatus towards HAdV obviously would not exclude the use of molecular assay for early surveillance, which most clinicians believe as the best method to manage the consequences of graft related immunodeficiency. Indeed, in some setting, molecular assays are not only performed on blood, to discover disseminate infections, but also on accessible tracts [18, 21]. This procedure can be useful especially in the contest of solid organ transplantation, where HAdV infections firstly involve the graft and are not early revealed by blood PCR surveillance. Moreover, prior to transplant, the detection of HAdV DNA on accessible tracts of recipients, along with that on graft’s tissue, could be performed to preliminarily know the risk of reactivation and to avoid or minimize the risk of primary infection. The HAdV serological screening would not imply any procedural waste or danger or significant increase of the coasts, representing just a complementary test.
The epidemiological data emerging from a pre-transplant HAdV serological screening could be useful for enhancing the knowledge of adenoviral pathogenesis, nowadays incomplete on several aspects. As already mentioned, the most unclear and important query concerns the true responsibility by the primary infection via the graft and by the reactivation of pre-existing viruses in the onset of the infection in the immune-compromised host [9]. The interesting association joining the graft versus host disease (GvHD) and CMV reactivation is recently found for HAdV as well [39, 40]. On the contrary, in children with severe steroid-refractory acute GvHD treated with mesenchymal stromal cells, HAdV but not CMV infection was associated with decreased survival [41]. Therefore, the knowledge on connections between HAdV and not infectious complications of transplant procedures, such as allograft rejection and loss, and GvHD, could benefit from acquisition of new serological data [5, 7].
The specific associations between adenovirus species or individual types and single diseases is also not clear [2, 4]. New serological data can add information on the most frequent serotypes, the relative neutralizing antibodies and their possible cross-protective activity, on serotypes connected with graft’s complications, with different localizations and with high case fatality.
CONFLICT OF INTEREST
The author confirms that this article content has no conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Carrigan DR. Adenovirus infections in immunocompromised patients. Am J Med 1997; 102(3A): 71-4.
[2] Guo L, Wu C, Zhou H, et al. Identification of a nonstructural DNA-binding protein (DBP) as an antigen with diagnostic potential for human adenovirus. PLoS One 2013; 8(3): e56708.
[3] Garnett CT, Talekar G, Mahr JA, et al. Latent species C adenoviruses in human tonsil tissues. J Virol 2009; 83(6): 2417-28.
[4] Kajon AE, Lamson D, Shudt M, et al. Identification of a novel intertypic recombinant species D human adenovirus in a pediatric stem cell transplant recipient. J Clin Virol 2014; 61(4): 496-502.
[5] Hoffman JA. Adenovirus infections in solid organ transplant recipients. Curr Opin Organ Transplant 2009; 14(6): 625-33.
[6] Echavarría M. Adenoviruses in immunocompromised hosts. Clin Microbiol Rev 2008; 21(4): 704-15.
[7] Koneru B, Atchison R, Jaffe R, Cassavilla A, Van Thiel DH, Starzl TE. Serological studies of adenoviral hepatitis following pediatric liver transplantation. Transplant Proc 1990; 22(4): 1547-8.
[8] Chakrabarti S, Mautner V, Osman H, et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood 2002; 100(5): 1619-27.
[9] Chakrabarti S. Adenovirus infections after hematopoietic stem cell transplantation: still unravelling the story. Clin Infect Dis 2007; 45(8): 966-8.
[10] Casadevall A, Pirofski LA. What is a host? Incorporating the microbiota into the damage-response framework. Infect Immun 2015; 83(1): 2-7.
[11] Rubin RH. The pathogenesis and clinical management of cytomegalovirus infection in the organ transplant recipient: the end of the ‘silo hypothesis’. Curr Opin Infect Dis 2007; 20(4): 399-407.
[12] George B, Pati N, Gilroy N, et al. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis 2010; 12(4): 322-9.
[13] Kullberg-Lindh C, Mellgren K, Friman V, et al. Opportunistic virus DNA levels after pediatric stem cell transplantation: serostatus matching, anti-thymocyte globulin, and total body irradiation are additive risk factors. Transpl Infect Dis 2011; 13(2): 122-30.
[14] Hiwarkar P, Gaspar HB, Gilmour K, et al. Impact of viral reactivations in the era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients. Bone Marrow Transplant 2013; 48(6): 803-8.
[15] Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009; 15(10): 1143-238.
[16] Sive JI, Thomson KJ, Morris EC, Ward KN, Peggs KS. Adenoviremia has limited clinical impact in the majority of patients following alemtuzumab-based allogeneic stem cell transplantation in adults. Clin Infect Dis 2012; 55(10): 1362-70.
[17] Soriano G, Perales MA. Adenovirus viremia and infection after reduced-intensity allogeneic hematopoietic stem cell transplant: should we institute a routine screening program? Clin Infect Dis 2012; 55(10): 1371-2.
[18] Lion T, Kosulin K, Landlinger C, et al. Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation. Leukemia 2010; 24(4): 706-14.
[19] Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood 2010; 116(25): 5476-85.
[20] Veltrop-Duits LA, van Vreeswijk T, Heemskerk B, et al. High titers of pre-existing adenovirus serotype-specific neutralizing antibodies in the host predict viral reactivation after allogeneic stem cell transplantation in children. Clin Infect Dis 2011; 52(12): 1405-13.
[21] de Pagter AP, Haveman LM, Schuurman R, Schutten M, Bierings M, Boelens JJ. Adenovirus DNA positivity in nasopharyngeal aspirate preceding hematopoietic stem cell transplantation: a very strong risk factor for adenovirus DNAemia in pediatric patients. Clin Infect Dis 2009; 49(10): 1536-9.
[22] Runde V, Ross S, Trenschel R, et al. Adenoviral infection after allogeneic stem cell transplantation (SCT): report on 130 patients from a single SCT unit involved in a prospective multi center surveillance study. Bone Marrow Transplant 2001; 28(1): 51-7.
[23] Muñoz-Cobo B, Solano C, Nieto J, et al. Surveillance for adenovirus DNAemia early after transplantation in adult recipients of unrelated-donor allogeneic stem cell transplants in the absence of clinically suspected infection. Bone Marrow Transplant 2011; 46(11): 1484-6.
[24] Anderson EJ, Guzman-Cottrill JA, Kletzel M, et al. High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy. Pediatr Transplant 2008; 12(2): 219-27.
[25] Ishibashi K, Tokumoto T, Shirakawa H, et al. Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors. Transpl Infect Dis 2011; 13(3): 318-23.
[26] Boppana SB, Rivera LB, Fowler KB, Mach M, Britt WJ. Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001; 344(18): 1366-71.
[27] Ishibashi K, Tokumoto T, Shirakawa H, et al. Strain-specific seroepidemiology and reinfection of cytomegalovirus. Microbes Infect 2008; 10(12-13): 1363-9.
[28] Kajon AE, de Jong JC, Dickson LM, et al. Molecular and serological characterization of species B2 adenovirus strains isolated from children hospitalized with acute respiratory disease in Buenos Aires, Argentina. J Clin Virol 2013; 58(1): 4-10.
[29] Sili U, Leen AM, Vera JF, et al. Production of good manufacturing practice-grade cytotoxic T lymphocytes specific for Epstein-Barr virus, cytomegalovirus and adenovirus to prevent or treat viral infections post-allogeneic hematopoietic stem cell transplant. Cytotherapy 2012; 14(1): 7-11.
[30] Gerdemann U, Vera JF, Rooney CM, Leen AM. Generation of multivirus-specific T cells to prevent/treat viral infections after allogeneic hematopoietic stem cell transplant. J Vis Exp 2011; 27(51): 2736.
[31] Veltrop-Duits LA, Heemskerk B, Sombroek CC, et al. Human CD4+ T cells stimulated by conserved adenovirus 5 hexon peptides recognize cells infected with different species of human adenovirus. Eur J Immunol 2006; 36(9): 2410-23.
[32] Tischer S, Priesner C, Heuft HG, et al. Rapid generation of clinical-grade antiviral T cells: selection of suitable T-cell donors and GMP-compliant manufacturing of antiviral T cells. J Transl Med 2014; 12: 336.
[33] Sukdolak C, Tischer S, Dieks D, et al. CMV-, EBV- and ADV-specific T cell immunity: screening and monitoring of potential third-party donors to improve post-transplantation outcome. Biol Blood Marrow Transplant 2013; 19(10): 1480-92.
[34] Miller JR, Barrett RE, Britton CB, et al. Progressive multifocal leukoencephalopathy in a male homosexual with T-cell immune deficiency. N Engl J Med 1982; 307(23): 1436-8.
[35] Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010; 68(3): 295-303.
[36] Johnson EM, Wortman MJ, Dagdanova AV, Lundberg P, Daniel D. Polyomavirus JC in the context of immunosuppression: a series of adaptive, DNA replication-driven recombination events in the development of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013: 197807 ; 2013;
[37] Sunyaev SR, Lugovskoy A, Simon K, Gorelik L. Adaptive mutations in the JC virus protein capsid are associated with progressive multifocal leukoencephalopathy (PML). PLoS Genet 2009; 5(2): e1000368.
[38] Watanabe A, Carraro E, Camargo C, et al. Human adenovirus detection among immunocompetent and immunocompromised patients presenting acute respiratory infection. Rev Soc Bras Med Trop 2013; 46(2): 161-5.
[39] George B, Kerridge IH, Gilroy N, et al. A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group. Transpl Infect Dis 2012; 14(2): 141-8.
[40] Rynans S, Dzieciątkowski T, Przybylski M, et al. Incidence of adenoviral DNAemia in Polish adults undergoing allogeneic haematopoietic stem cell transplantation. Arch Immunol Ther Exp (Warsz) 2015; 63(1): 79-84.
[41] Calkoen FG, Vervat C, van Halteren AG, et al. Mesenchymal stromal cell therapy is associated with increased adenovirus-associated but not cytomegalovirus-associated mortality in children with severe acute graft-versus-host disease. Stem Cells Transl Med 2014; 3(8): 899-910. | {
"url": "https://openmicrobiologyjournal.com/VOLUME/10/PAGE/4/",
"source_domain": "openmicrobiologyjournal.com",
"snapshot_id": "CC-MAIN-2024-10",
"warc_metadata": {
"Content-Length": "106303",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:N64EVJWIPB5H6NTONANJG7INNY2R4DAS",
"WARC-Concurrent-To": "<urn:uuid:6f8c44c1-5daa-4c48-97e9-dc6a71b3ee0a>",
"WARC-Date": "2024-03-02T23:48:39",
"WARC-IP-Address": "52.7.175.180",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:JDUIHMGVZQ2ZS6MJRPCRCMZ4H55UXIFU",
"WARC-Record-ID": "<urn:uuid:99a45cb0-ff90-43bb-9fd9-099c6c4c9339>",
"WARC-Target-URI": "https://openmicrobiologyjournal.com/VOLUME/10/PAGE/4/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:5a53d440-ea69-4684-b76c-7c021b80e1f4>"
},
"warc_info": "isPartOf: CC-MAIN-2024-10\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for February/March 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-154\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
17,
18,
19,
91,
92,
93,
94,
118,
220,
283,
284,
285,
301,
302,
322,
324,
342,
343,
370,
396,
415,
435,
463,
482,
483,
510,
536,
555,
575,
603,
604,
605,
606,
631,
674,
675,
1041,
1042,
1251,
1252,
1253,
1262,
1263,
2481,
2482,
2616,
2617,
2618,
2619,
2632,
2633,
3716,
3717,
4811,
4812,
5366,
5367,
6177,
6178,
6528,
6529,
6589,
6590,
7402,
7403,
8016,
8017,
9627,
9628,
9707,
9708,
10526,
10527,
11154,
11155,
11722,
11723,
13059,
13060,
13484,
13485,
14437,
14438,
14500,
14501,
16336,
16337,
16410,
16411,
17201,
17202,
19349,
19350,
19435,
19436,
21457,
21458,
21469,
21470,
22253,
22254,
23107,
23108,
24113,
24114,
25099,
25100,
25484,
25485,
25506,
25507,
25582,
25583,
25600,
25601,
25616,
25617,
25628,
25629,
25729,
25912,
26040,
26238,
26362,
26461,
26659,
26901,
27054,
27198,
27395,
27689,
27955,
28189,
28413,
28653,
28872,
29115,
29258,
29533,
29827,
30087,
30363,
30596,
30913,
31103,
31263,
31512,
31806,
32012,
32244,
32461,
32700,
32878,
33022,
33310,
33513,
33721,
34051,
34268
],
"line_end_idx": [
17,
18,
19,
91,
92,
93,
94,
118,
220,
283,
284,
285,
301,
302,
322,
324,
342,
343,
370,
396,
415,
435,
463,
482,
483,
510,
536,
555,
575,
603,
604,
605,
606,
631,
674,
675,
1041,
1042,
1251,
1252,
1253,
1262,
1263,
2481,
2482,
2616,
2617,
2618,
2619,
2632,
2633,
3716,
3717,
4811,
4812,
5366,
5367,
6177,
6178,
6528,
6529,
6589,
6590,
7402,
7403,
8016,
8017,
9627,
9628,
9707,
9708,
10526,
10527,
11154,
11155,
11722,
11723,
13059,
13060,
13484,
13485,
14437,
14438,
14500,
14501,
16336,
16337,
16410,
16411,
17201,
17202,
19349,
19350,
19435,
19436,
21457,
21458,
21469,
21470,
22253,
22254,
23107,
23108,
24113,
24114,
25099,
25100,
25484,
25485,
25506,
25507,
25582,
25583,
25600,
25601,
25616,
25617,
25628,
25629,
25729,
25912,
26040,
26238,
26362,
26461,
26659,
26901,
27054,
27198,
27395,
27689,
27955,
28189,
28413,
28653,
28872,
29115,
29258,
29533,
29827,
30087,
30363,
30596,
30913,
31103,
31263,
31512,
31806,
32012,
32244,
32461,
32700,
32878,
33022,
33310,
33513,
33721,
34051,
34268,
34547
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 34547,
"ccnet_original_nlines": 159,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2607666850090027,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.04921912029385567,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.24641111493110657,
"rps_doc_frac_unique_words": 0.30693677067756653,
"rps_doc_mean_word_length": 5.7921013832092285,
"rps_doc_num_sentences": 257,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 6.272983074188232,
"rps_doc_word_count": 4887,
"rps_doc_frac_chars_dupe_10grams": 0.005935139954090118,
"rps_doc_frac_chars_dupe_5grams": 0.04953012987971306,
"rps_doc_frac_chars_dupe_6grams": 0.022115450352430344,
"rps_doc_frac_chars_dupe_7grams": 0.018582630902528763,
"rps_doc_frac_chars_dupe_8grams": 0.011446340009570122,
"rps_doc_frac_chars_dupe_9grams": 0.005935139954090118,
"rps_doc_frac_chars_top_2gram": 0.006712359841912985,
"rps_doc_frac_chars_top_3gram": 0.009750580415129662,
"rps_doc_frac_chars_top_4gram": 0.006994979921728373,
"rps_doc_books_importance": -2493.875,
"rps_doc_books_importance_length_correction": -2493.875,
"rps_doc_openwebtext_importance": -1247.3475341796875,
"rps_doc_openwebtext_importance_length_correction": -1247.3475341796875,
"rps_doc_wikipedia_importance": -879.575439453125,
"rps_doc_wikipedia_importance_length_correction": -879.575439453125
},
"fasttext": {
"dclm": 0.04287397861480713,
"english": 0.8779768347740173,
"fineweb_edu_approx": 2.780151605606079,
"eai_general_math": 0.37392836809158325,
"eai_open_web_math": 0.39865487813949585,
"eai_web_code": 0.021938560530543327
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.994072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.994",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
3,365,823,381,482,727,400 | Top
10
Doctor insights on: Impaired Social Interaction
Share
Dr. Paul Bohn
28 doctors shared insights
Impaired Social Interaction (Overview)
Impaired social interaction is a clinical finding in which a person has poor interpersonal behaviors, such as inappropriate content or actions, difficulty engaging with others, or impaired communication skills.
1
1
What is meant by “impaired social interaction”?
What is meant by “impaired social interaction”?
Impaired ?: Means he does not socialize enough, either because he is depressed or anxious or can't have friends ...! ...Read more
See 1 more doctor answer
Dr. Paul Bohn
28 doctors shared insights
Impaired Social Interaction (Overview)
Impaired social interaction is a clinical finding in which a person has poor interpersonal behaviors, such as inappropriate content or actions, difficulty engaging with others, or impaired communication skills.
2
2
What is meant by “impaired social interaction”?
Impaired ?: Means he does not socialize enough, either because he is depressed or anxious or can't have friends ...! ...Read more
See 1 more doctor answer
3
3
Could there be a bad interaction with these 2 meds?
Unfortunately: It's not apparent, or possible to view, which to medications you are referring to. Can you repost the two medications you are concerned about in your question. ...Read more
See 1 more doctor answer
6
6
How concerned should I be about potential medication interactions?
Discuss: With your doctors. They will let you know if there should be concern and if so, what else can be done. ...Read more
7
7
Zeolit have any interaction whit letrozol ?
See the detailed : Here is a comprehensive answer: http://www.Drugs.Com/drug-interactions/letrozole, femara.Html. ...Read more
See 1 more doctor answer
8
8
Will stopping masturbating help social interaction?
Will stopping masturbating help social interaction?
Possibly: When masterbation becomes an addiction, which it can, then it can be desocializing in that the motivation to meet others and interact sexually is reduced. On the other hand, built up desire from avoiding masterbation can also be desocializing as the desire to have sex can be overwhelming. Balance is the key. ...Read more
9
9
For a teenager with not too much social interaction?
For a teenager with not too much social interaction?
Interaction is good: Adequate social interaction is important for everyone, especially teens. But, people have varying needs and preferences for social interaction. A therapist who specializes in working with adolescents might be helpful in evaluating the situation and providing treatment if needed. ...Read more
10
10
What is the definition or description of: drug interaction?
What is the definition or description of: drug interaction?
Bad combination: When the combination of two agents cause an effect, intended or unintended, that would not have otherwise occured if taken seperately. ...Read more
See 1 more doctor answer | {
"url": "https://www.healthtap.com/topics/impaired-social-interaction",
"source_domain": "www.healthtap.com",
"snapshot_id": "crawl=CC-MAIN-2017-13",
"warc_metadata": {
"Content-Length": "72362",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:UJQB777DXVYKYBLU6YMO3B6EDKU7ILIU",
"WARC-Concurrent-To": "<urn:uuid:73704357-0846-412d-b7a5-52d5d36698dd>",
"WARC-Date": "2017-03-24T15:29:17",
"WARC-IP-Address": "50.18.53.35",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:SJFKOUDWIM5HN5G5XHAF7IUTGONMNJOB",
"WARC-Record-ID": "<urn:uuid:10a03256-b70b-4d9e-b1ad-173660d610f5>",
"WARC-Target-URI": "https://www.healthtap.com/topics/impaired-social-interaction",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:768027b9-47d3-40eb-9a23-852819f92f03>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-233-31-227.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-13\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for March 2017\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
4,
7,
55,
56,
62,
76,
103,
104,
143,
144,
355,
356,
357,
359,
360,
362,
410,
411,
459,
460,
590,
591,
616,
630,
657,
658,
697,
698,
909,
910,
911,
913,
914,
916,
964,
965,
1095,
1096,
1121,
1123,
1124,
1126,
1178,
1179,
1367,
1368,
1393,
1395,
1396,
1398,
1465,
1466,
1591,
1592,
1594,
1595,
1597,
1641,
1642,
1769,
1770,
1795,
1797,
1798,
1800,
1852,
1853,
1905,
1906,
2239,
2240,
2242,
2243,
2245,
2298,
2299,
2352,
2353,
2667,
2668,
2671,
2672,
2675,
2735,
2736,
2796,
2797,
2962,
2963
],
"line_end_idx": [
4,
7,
55,
56,
62,
76,
103,
104,
143,
144,
355,
356,
357,
359,
360,
362,
410,
411,
459,
460,
590,
591,
616,
630,
657,
658,
697,
698,
909,
910,
911,
913,
914,
916,
964,
965,
1095,
1096,
1121,
1123,
1124,
1126,
1178,
1179,
1367,
1368,
1393,
1395,
1396,
1398,
1465,
1466,
1591,
1592,
1594,
1595,
1597,
1641,
1642,
1769,
1770,
1795,
1797,
1798,
1800,
1852,
1853,
1905,
1906,
2239,
2240,
2242,
2243,
2245,
2298,
2299,
2352,
2353,
2667,
2668,
2671,
2672,
2675,
2735,
2736,
2796,
2797,
2962,
2963,
2987
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2987,
"ccnet_original_nlines": 89,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 4,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3636363744735718,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0036363599356263876,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.20181818306446075,
"rps_doc_frac_unique_words": 0.41850221157073975,
"rps_doc_mean_word_length": 5.2466959953308105,
"rps_doc_num_sentences": 36,
"rps_doc_symbol_to_word_ratio": 0.01818181946873665,
"rps_doc_unigram_entropy": 4.887442588806152,
"rps_doc_word_count": 454,
"rps_doc_frac_chars_dupe_10grams": 0.33669185638427734,
"rps_doc_frac_chars_dupe_5grams": 0.503778338432312,
"rps_doc_frac_chars_dupe_6grams": 0.503778338432312,
"rps_doc_frac_chars_dupe_7grams": 0.4659949541091919,
"rps_doc_frac_chars_dupe_8grams": 0.41393786668777466,
"rps_doc_frac_chars_dupe_9grams": 0.41393786668777466,
"rps_doc_frac_chars_top_2gram": 0.07850545644760132,
"rps_doc_frac_chars_top_3gram": 0.0524769090116024,
"rps_doc_frac_chars_top_4gram": 0.02518891915678978,
"rps_doc_books_importance": -294.2768859863281,
"rps_doc_books_importance_length_correction": -294.2768859863281,
"rps_doc_openwebtext_importance": -166.58631896972656,
"rps_doc_openwebtext_importance_length_correction": -166.58631896972656,
"rps_doc_wikipedia_importance": -136.3419952392578,
"rps_doc_wikipedia_importance_length_correction": -136.3419952392578
},
"fasttext": {
"dclm": 0.5335420966148376,
"english": 0.9183815121650696,
"fineweb_edu_approx": 2.8349649906158447,
"eai_general_math": 0.1253373622894287,
"eai_open_web_math": 0.3627058267593384,
"eai_web_code": 0.0042020701803267
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.89",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "615.19",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "2",
"label": "Click Here References"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
8,056,594,047,343,268,000 | Skip to main content
by Dr. C.H. Weaver M.D. updated 11/2022
Stage IIIB and IV non-small cell lung cancers (NSCLC) are considered advanced and may be found in both lungs, in the fluid that surrounds the lungs or heart, or have spread to other parts of the body such as the liver, brain, or bones.
Lung CancerConnect 490
Rarely some patients with advanced NSCLC will have cancer that can be treated with surgery or radiation therapy however systemic therapy with precision cancer medicines, immunotherapy or chemotherapy is the mainstay of treatment for most patients.
Advanced NSCLC has historically not been considered to be curable, however recent advances in genomics leading to the development of precision cancer medicine and immunotherapy have led to improved survival in selected patients well beyond what was expected just a few years ago.
Advances in the use of newer precision cancer medicines and immunotherapy is rapid and ALL individuals with NSCLC should undergo genomic testing for biomarkers to determine if they can benefit from these newer drugs. Testing can be done on tissue or from blood.1-4
General Treatment Guidelines
• A liquid biopsy should be performed upon initial evaluation of NSCLC because it may better help identify treatable mutations than tissue biopsy alone.
• Initial treatment of NSCLC in individuals with an identified genomic cancer driving mutation that can be targeted with a precision cancer medicine.
• Individuals with high levels of PD-1 or PD-L1 are treated with checkpoint inhibitor immunotherapy with or without chemotherapy.
• Individuals with low levels of PD-1 or PD-L1 are treated with chemotherapy plus checkpoint inhibitor immunotherapy.4
• Starting checkpoint inhibitor immunotherapy before knowing whether a cancer is positive for EGFR is dangerous - EGFR + patients who receive a checkpoint inhibitor can develop immune mediated lung inflammation (pneumonitis) which is associated with significant mortality.
Precision Cancer Medicines & Immuno-oncology
Precision immunotherapy treatment of NSCLC has progressed considerably over the past few decades and treatment with a "checkpoint inhibitor" has now become a standard initial treatment for patients without a "driver" mutation that can be targeted.
The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.
Checkpoint inhibitors are one kind of immunotherapy that has improved the treatment of NSCLC and become the initial standard treatment for individuals without an identifiable mutation. Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. Checkpoint inhibitors block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.2
Overall two thirds of lung cancer patients have some expression of PD-L1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1. A diagnostic test to measure the level of PD-L1 is available.1-8
NSCLC Treatment in Individuals with High PD-L1 and No Driver Mutation
Keytruda® (pembrolizumab) and other checkpoint inhibitors have been demonstrated to be superior to chemotherapy treatment when used as single agents in patients with advanced NSCLC and higher levels of the PD-L1 ligand. Five year survival rates of 23% have been achieved with Keytruda used as a single agent.1 The average patients experiences a response to Keytruda in about 2 months.
The combination of a checkpoint inhibitor + chemotherapy also prolongs survival compared to treatment with chemotherapy alone. Keytruda in combination with Alimta (pemetrexed) and cisplatin or carboplatin chemotherapy improves the response rate from 19% to 48%, delays cancer progression, and prolongs survival compared to treatment with chemotherapy alone.2
Lung Newsletter 490
There are several checkpoint inhibitors available for the treatment of NSCLC, typically in combination with platinum chemotherapy.
Currently available checkpoint inhibitors:
NSCLC Treatment in Individuals with Low PD-L1 and No Driver Mutation
Chemotherapy drugs are a systemic therapy that kills rapidly dividing cells, a hallmark of cancer. Chemotherapy has been the main treatment for advanced NSCLC for many years. Unlike precision cancer medicines chemotherapy doesn’t target specific cancer cells. It may affect normal cells leading to many side effects of treatment.
Patients with advanced NSCLC are treated with chemotherapy to alleviate the symptoms of their disease and prolong their duration of survival. Most treatments involve a combination (regimen) of two chemotherapy drugs. The most commonly used regimens include either cisplatin or carboplatin; combined with one of several other drugs approved for the treatment of NSCLC; Alimta® (pemetrexed), Taxol® (paclitaxel), Taxotere® (docetaxel), Gemzar® (gemcitabine), Camptosar® (irinotecan), or Navelbine® (vinorelbine).17
The combination of chemotherapy and a checkpoint inhibitor is the standard initial treatment for NSCLC with low PD-L1 and no driver mutations that can be targeted because the combination improves survival compared to treatment with chemotherapy alone.17-20 Keytruda and Tecentriq when combined with chemotherapy have been shown to prolong survival compared to treatment with chemotherapy alone.
Avastin® (bevacizumab): Avastin® is a type of targeted therapy that slows or stops the growth of blood vessels that deliver blood to the cancer, effectively starving the cancer of the oxygen and nutrients it requires to survive and grow. Avastin, in combination with the chemotherapy drugs paclitaxel and carboplatin, is FDA-approved for the treatment of advanced, non-squamous NSCLC.21
Targeting Specific "Driver" Mutations
Testing for EGFR, ALK, ROS1, BRAF, MET, RET, TRK, KRAS and other "driver" mutations is essential because precision cancer medicines have been developed to target each of these mutations.4
Epidermal growth factor receptor (EGFR): The EGFR pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. EGFR-targeted drugs that have been shown to benefit selected patients with NSCLC belong to a class of drugs known as tyrosine kinase inhibitors (TKIs). The drugs enter the cell and interfere with EGFR from within. There are several TKI's approved for the treatment of EGFR positive NSCLC and more in development.
Anaplastic Lymphoma Kinase (ALK) gene: Approximately 5% of all NSCLC’s have an ALK mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ NSCLC can be treated with precision cancer medicines that target this abnormality. Recent studies have suggested that Alcensa (alectinib) may produce better outcomes.3,9,11,13
Learn more about ALK + NSCLC treatment...
ROS-1+ Lung Cancer: The ROS-1 mutation is an uncommon mutation found in only 1% of individuals with NSCLC. Research has indicated that the ROS-1 mutation plays a role in the development and progression of some lung cancers, and patient characteristics are similar to those who have ALK+ NSCLC and can be targeted with Xalkori.10
BRAF & MEK Kinase Inhibitors: The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Lung cancers may carry the BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Another mutation known as V600K may also be present. BRAF and MEK inhibitors are precision cancer medicines that block the activity of the V600E and V600K mutations respectively.11
Scroll to Continue
Recommended Articles
• Zelboraf® (vemurafenib) BRAF V600E kinase inhibitor
• Tafinlar® (dabrafenib) BRAF V600E kinase inhibitor
MEK Inhibitors
• Mekinist® (trametinib) MEK V600 kinase inhibitor
• Cotellic® (cobimetinib) MEK V600 kinase inhibitor
RET + Lung Cancer: Genetic alternations in the RET ( rearranged during transfection) receptor tyrosine kinase are present in 1-2% of NSCLC's and drive their development and growth.14
• Vandatenib
• Cabozantinib
• BLU-667
• LOXO-292
TRK + Lung Cancer: Tropomyosin receptor kinases (TRK) fusions are rare chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. (15,16)
• Vitrakvi (larotrectinib)
• Entrectinib
KRAS: KRAS mutations are detected in approximately 15% to 30% of lung adenocarcinomas and analyses of clinical trials shows that immunotherapy alone or combined with chemotherapy is more effective than chemotherapy for treating NSCLC with KRAS including G12C mutations. Precision cancer medicines targeting KRAS and G12C specifically are also now available.31,32,35
Treatment of Older Individuals
Many NSCLC cases occur in people over the age of 70, but there is limited information about how best to treat older patients. As a result of the limited information and concern that elderly patients will not be able to tolerate aggressive treatment, older patients may be treated with single-agent chemotherapy rather than the combination chemotherapy that is commonly used in younger patients. Studies have suggested, however, that although combination chemotherapy increases side effects, it also improves survival among elderly patients.13
A study presented at the 2021 World Conference on Lung Cancer suggests age does not negatively impact survival benefit from Checkpoint Inhibitors with stage IV NSCLC. Researchers analyzed 86,173 patients with stage IV NSCLC--24,136 patients were age 75 and older and 62,037 patients were under age 75 and confirmed the survival benefit from ICIs for patients 75 years of age and older and that chronological age does not appear to impact the survival benefit of ICIs in stage IV NSCLC.34
Maintenance Therapy
Maintenance therapy refers to treatment that is given after initial treatment but before cancer progression. It is a relatively new approach to lung cancer treatment. Drugs that have been approved for maintenance therapy in selected patients include Alimta® and Tarceva® (erlotinib). For patients who are candidates for maintenance therapy, the approach has been shown to delay cancer progression and improve overall survival.9,23 Learn more...
Managing Bone Complications
NSCLC cells commonly spread to the bone, causing bone metastases. Bone metastases may cause pain, bone loss, increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.
Preventing or delaying these skeletal-related events (SREs) can preserve quality of life and reduce healthcare costs. Bisphosphonate drugs such as Zometa® (zoledronic acid) and Xgeva® (denosumab) can be used to reduce the risk of complications from bone metastases.
Xgeva® has been directly compared to Zometa® for the treatment of bone metastases in 702 individuals with NSCLC and 109 with small-cell lung cancer (SCLC). Xgeva® was found to be associated with a decrease in SREs and improved overall survival when directly compared with Zometa.24
Managing Brain Metastases
When NSCLC spreads to the brain, it can cause symptoms such as headaches and seizures. Depending on the number, size, and location of the tumors in the brain, treatment may involve radiation, surgery or medication. Some but not all systemic therapies cross the "blood-brain" barrier and can shrink the cancer. About 30% of NSCLC's that express PD-1 respond to Keytruda treatment.33
Managing Pleural Effusion
In some patients with advanced NSCLC, fluid collects in the space around the lungs. This is called pleural effusion. The fluid can compress the lung and make it difficult to breath. If a patient is experiencing symptoms due to pleural effusion, the fluid may be drained using a catheter.
Strategies to Improve Treatment
The progress that has been made in the treatment of NSCLC has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of NSCLC.
Identification of Driver Mutations: Researchers have already identified several genetic mutations that "drive" the growth of lung cancer. Specific medications have been developed to target the EGFR, ALK, ROS1, BRAF, MET, RET, TRK "driver" mutations. Researchers continue to look for new mutations that can be targeted and several targeted therapies are being evaluated in clinical trials to determine their effectiveness.
Refining the use of Checkpoint Inhibitors: There is ongoing research to determine how best to use checkpoint inhibitors for the treatment of NSCLC. Checkpoint inhibitors may work better in some PD-L1 positive cancers that others. For example the tumor mutational burden (TMB) is a measurement of the mutations carried by tumor cells and a higher TMB is associated with greater response to treatment.30
The Lung-MAP Trial for Squamous Cell Carcinoma
In Lung-MAP (Lung-MAP.org), researchers with several public institutions, including the National Cancer Institute (NCI), are working with pharmaceutical companies to study treatment for advanced squamous cell lung cancer. Though only a fraction (about a quarter) of all lung cancer diagnoses as squamous cell, it’s an important area of research, as there are few treatment options for these patients.
Lung-MAP will evaluate several investigational treatments and match patients with the therapy most likely to benefit them. Participants will undergo genomic profiling—a type of testing that provides information about all the genes in an organism, including variation, gene expression, and the way genes interact with each other and the environment. The drugs studied in Lung-MAP are designed to target genomic alterations involved in the growth of cancer, and researchers will use genomic profiling to match patients with the therapy designed to target the particular genomic alterations that their cancer expresses.
This more comprehensive approach marks a change in the typical clinical trial model for targeted therapies, in which separate studies for the same disease focus on particular genomic abnormalities and treatments. Potential participants are tested for that genomic biomarker (a molecule that is a sign of a normal or abnormal process or of a condition or disease), and only individuals who test positive are enrolled in the study. As a result, many patients are left out of each trial and—with multiple, separate trials—overall progress in treatment development is made less efficient.
In Lung-MAP, however, everyone who’s tested will be eligible for a therapy. And several treatments for advanced squamous cell lung cancer will be evaluated under one protocol in an effort to accelerate safe drug development.
References:
1. Reck M, et al "Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non -- small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater" J Clin Oncol 2019; DOI: 10.1200/JCO.18.00149.
2. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New England Journal of Medicine. 2015;372(21):2018-20. Abstract. doi: 10.1056/ NEJMoa1501824.
3. Merck’s KEYTRUDA(R) (pembrolizumab) Significantly Improved Overall Survival and Progression-Free Survival as First-Line Treatment in Combination with Pemetrexed and Platinum Chemotherapy for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (KEYNOTE-189)
4. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Journal of Clinical Oncology. 2014;32(32):3673-79. Available here. Accessed September 30, 2016.
5. oncolife.com.ua/doc/nccn/Non-Small_Cell_Lung_Cancer.pdf
6. Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. New England Journal of Medicine. 2015;373(2):123-35. Abstract. doi: 10.1056/NEJMoa1504627.
7. Borghaei H, Paz-Arez L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. New England Journal of Medicine. 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643.
8. Bristol-Myers Squibb Announces Top-Line Results from CheckMate -026, a Phase 3 Study of Opdivo (Nivolumab) in Treatment-Naïve Patients with Advanced Non-small Cell Lung Cancer [news release]. Bristol-Myers Squibb website. Available at: investor.bms.com/investors/news-and-events/press-releases/press-release-details/2016/Bristol-Myers-Squibb-Announces-Top-Line-Results-from-CheckMate–026-a-Phase-3-Study-of-Opdivo-nivolumab-in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer/default.aspx. August 5, 2016.
9. Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.
10. OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: investor.osip.com/releasedetail.cfm?ReleaseID=460783. Accessed April 19, 2010.
11. United States Food and Drug Administration (FDA). FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Available at: . Accessed March 11, 2016.
12. FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation
13. Solomon, B., et al. (2014). First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer New England Journal of Medicine, 371 (23), 2167-2177 DOI: 10.1056/NEJMoa1408440
14. Kwak EL, Bang Y-J, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine. 2010;363:1693-1703.
15. Gainor JF, et al. Abstract 9008. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
16. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children
17. Entrectinib Granted Priority Review by FDA for NTRK+ Tumors and ROS1+ NSCLC
18. Chemotherapy for non small cell lung cancer
19. Lancet Oncol. 2019 May 20. Epub ahead of print.
20. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) as First-Line Combination Therapy with Pemetrexed and Carboplatin for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC), Irrespective of PD-L1 Expression
21. Abstract LBA1_PR ‘Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)‘ will be presented by Martin Reck during the Proffered Paper session ‘Combining immune checkpoint inhibitors and VEGF targeted therapies in cancer treatment’ on Thursday, 7 December, 18:15 to 19:15 (CET) in Room A. Annals of Oncology, Volume 28, 2017 Supplement 11.
22. Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in First-Line Non-Squamous, Non-Small Cell Lung Cancer. Available here.
23. Quoix E, Zalcman G, Oster J-P et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. The Lancet. Early online publication August 9, 2011.
24. Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncology. 2010;11:521-529.
25. Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: Subgroup analysis from a randomized phase 3 study. Journal of Thoracic Oncology. 2012; 7(12): 1823-1829.
26. abstracts.asco.org/199/AbstView_199_181148.html
27. Horn L, Infante J, Blumenshcein G, et al. A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 8030)
28. Ramalingam SS, Goss GD, Andric ZG et al. A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract CRA8007.
29. Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The Lancet Oncology. 2014; 15(2): 143-155.
30. Ramalingam S. Abstract CT078. Presented at American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
31. LBA4 - Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042.
32. Gadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC.
33. Lancet Oncol. 2020 May;21[5]:655-663).
34. https://www.iaslc.org/iaslc-news/press-release/immune-checkpoint-inhibitors-convey-survival-benefit-elderly-patients
35. Nakajima EC, Ren Y, Vallejo JJ, et al. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. Presented at ASCO 2022; June 3-7, 2022. Abstract 9001.
36. FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. News release. FDA. November 10, 2022. Accessed November 10, 2022. http://bit.ly/3Ej7yIx
37. Imjudo (tremelimumab-actl). Prescribing information; AstraZeneca Pharmaceuticals; 2022. Accessed November 10, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761270s000lbl.pdf | {
"url": "https://news.cancerconnect.com/lung-cancer/treatment-of-stage-iii-b-iv-non-small-cell-lung-cancer",
"source_domain": "news.cancerconnect.com",
"snapshot_id": "crawl=CC-MAIN-2022-49",
"warc_metadata": {
"Content-Length": "713772",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ONERSBQBCELSZDZZWGSTY7PLI5WRUEML",
"WARC-Concurrent-To": "<urn:uuid:2b51aed2-97c3-42f7-be38-bcb8072ed8ac>",
"WARC-Date": "2022-12-04T22:45:58",
"WARC-IP-Address": "151.101.66.98",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:YYXMGIK52VZV4CCPATF4H6HA7BNV2E2N",
"WARC-Record-ID": "<urn:uuid:4a878ae7-6a6c-4424-8549-22658cfd41ba>",
"WARC-Target-URI": "https://news.cancerconnect.com/lung-cancer/treatment-of-stage-iii-b-iv-non-small-cell-lung-cancer",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:ad48255e-1914-44bb-ae76-0405d41e505d>"
},
"warc_info": "isPartOf: CC-MAIN-2022-49\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November/December 2022\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-71\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
21,
22,
62,
63,
299,
300,
323,
324,
572,
573,
853,
854,
1119,
1120,
1149,
1150,
1305,
1457,
1589,
1710,
1985,
1986,
2031,
2032,
2280,
2281,
2796,
2797,
3605,
3606,
3834,
3835,
3905,
3906,
4291,
4292,
4651,
4652,
4672,
4673,
4804,
4805,
4848,
4849,
4918,
4919,
5249,
5250,
5763,
5764,
6159,
6160,
6547,
6548,
6586,
6587,
6775,
6776,
7396,
7397,
7764,
7765,
7807,
7808,
8137,
8138,
8631,
8632,
8651,
8652,
8673,
8674,
8730,
8785,
8786,
8801,
8802,
8855,
8909,
8910,
9093,
9094,
9109,
9126,
9138,
9151,
9152,
9478,
9479,
9508,
9524,
9525,
9891,
9892,
9923,
9924,
10467,
10468,
10956,
10957,
10977,
10978,
11423,
11424,
11452,
11453,
11701,
11702,
11968,
11969,
12251,
12252,
12278,
12279,
12661,
12662,
12688,
12689,
12977,
12978,
13010,
13011,
13229,
13230,
13652,
13653,
14055,
14056,
14103,
14104,
14505,
14506,
15123,
15124,
15709,
15710,
15935,
15936,
15948,
15949,
16193,
16389,
16663,
17156,
17217,
17432,
17638,
18165,
18465,
18672,
18855,
18976,
19160,
19325,
19429,
19515,
19597,
19647,
19701,
19930,
20407,
20578,
20854,
21072,
21348,
21402,
21584,
21947,
22224,
22358,
22583,
22815,
22860,
22983,
23275,
23276,
23502,
23503
],
"line_end_idx": [
21,
22,
62,
63,
299,
300,
323,
324,
572,
573,
853,
854,
1119,
1120,
1149,
1150,
1305,
1457,
1589,
1710,
1985,
1986,
2031,
2032,
2280,
2281,
2796,
2797,
3605,
3606,
3834,
3835,
3905,
3906,
4291,
4292,
4651,
4652,
4672,
4673,
4804,
4805,
4848,
4849,
4918,
4919,
5249,
5250,
5763,
5764,
6159,
6160,
6547,
6548,
6586,
6587,
6775,
6776,
7396,
7397,
7764,
7765,
7807,
7808,
8137,
8138,
8631,
8632,
8651,
8652,
8673,
8674,
8730,
8785,
8786,
8801,
8802,
8855,
8909,
8910,
9093,
9094,
9109,
9126,
9138,
9151,
9152,
9478,
9479,
9508,
9524,
9525,
9891,
9892,
9923,
9924,
10467,
10468,
10956,
10957,
10977,
10978,
11423,
11424,
11452,
11453,
11701,
11702,
11968,
11969,
12251,
12252,
12278,
12279,
12661,
12662,
12688,
12689,
12977,
12978,
13010,
13011,
13229,
13230,
13652,
13653,
14055,
14056,
14103,
14104,
14505,
14506,
15123,
15124,
15709,
15710,
15935,
15936,
15948,
15949,
16193,
16389,
16663,
17156,
17217,
17432,
17638,
18165,
18465,
18672,
18855,
18976,
19160,
19325,
19429,
19515,
19597,
19647,
19701,
19930,
20407,
20578,
20854,
21072,
21348,
21402,
21584,
21947,
22224,
22358,
22583,
22815,
22860,
22983,
23275,
23276,
23502,
23503,
23700
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 23700,
"ccnet_original_nlines": 178,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.2618475556373596,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.06355098634958267,
"rps_doc_frac_lines_end_with_ellipsis": 0.011173180304467678,
"rps_doc_frac_no_alph_words": 0.2518016993999481,
"rps_doc_frac_unique_words": 0.31596091389656067,
"rps_doc_mean_word_length": 5.694995403289795,
"rps_doc_num_sentences": 277,
"rps_doc_symbol_to_word_ratio": 0.0004367800138425082,
"rps_doc_unigram_entropy": 6.0045905113220215,
"rps_doc_word_count": 3377,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.08927828818559647,
"rps_doc_frac_chars_dupe_6grams": 0.05163269862532616,
"rps_doc_frac_chars_dupe_7grams": 0.040245421230793,
"rps_doc_frac_chars_dupe_8grams": 0.0195507500320673,
"rps_doc_frac_chars_dupe_9grams": 0.006031610071659088,
"rps_doc_frac_chars_top_2gram": 0.016638940200209618,
"rps_doc_frac_chars_top_3gram": 0.007279530167579651,
"rps_doc_frac_chars_top_4gram": 0.0061876000836491585,
"rps_doc_books_importance": -1971.381103515625,
"rps_doc_books_importance_length_correction": -1971.381103515625,
"rps_doc_openwebtext_importance": -1005.324951171875,
"rps_doc_openwebtext_importance_length_correction": -1005.324951171875,
"rps_doc_wikipedia_importance": -766.2908935546875,
"rps_doc_wikipedia_importance_length_correction": -766.2908935546875
},
"fasttext": {
"dclm": 0.020237920805811882,
"english": 0.881112277507782,
"fineweb_edu_approx": 2.334932565689087,
"eai_general_math": 0.0663151666522026,
"eai_open_web_math": 0.3675105571746826,
"eai_web_code": 0.0021123900078237057
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.99442072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.99442",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
2,383,994,927,070,548,500 | logo retina consultants os austin
Macular Degeneration
Vitreo-Retinal Surgeons & Specialists located in Austin, Round Rock, Marble Falls, and
Lakeway, TX
Macular Degeneration
Macular Degeneration
About 11 million Americans have macular degeneration, a disease that can affect your central vision. At Retina Consultants of Austin, with offices in Austin, Lakeway, Marble Falls, and Round Rock, Texas, the macular degeneration specialists offer leading treatments to prevent the development and progression of the disease. They’re also actively involved in clinical research, providing the opportunity to try the newest treatments before they’re widely available. Call the nearest office or schedule an appointment online today to learn more.
Macular Degeneration Q & A
What is macular degeneration?
Macular degeneration is an eye disease that causes progressive vision loss and, if untreated, blindness. The condition mainly affects adults over the age of 55, so it’s commonly called age-related macular degeneration.
There are two main types of macular degeneration: the dry form, in which deposits form under the retina, and the wet form, in which abnormal blood vessels grow underneath the retina.
Both dry and wet macular degeneration can cause vision issues.
What are the symptoms of macular degeneration?
Dry macular degeneration may occur in early or intermediate stages. You might not have any symptoms in either stage, although some people experience minor symptoms like blurrier eyesight or an increased difficulty seeing in low-light conditions.
Advanced (late-stage) macular degeneration can be either dry or wet. Wet macular degeneration is always advanced.
In advanced macular degeneration, it’s common to experience symptoms like straight lines looking wavy, blurry spots in your vision, or faded-looking colors.
Macular degeneration can lead to central vision loss, but there are ways to slow its progression.
How is macular degeneration treated?
Retina Consultants of Austin specializes in the treatment and management of macular degeneration.
Your treatment depends on whether you have dry or wet macular degeneration:
Dry macular degeneration
There’s no treatment for dry macular degeneration, but some may help, including adding foods like fish, dark leafy greens, and yellow and red fruits and veggies.
A specific combination of supplements (oral vitamins and minerals) may slow macular degeneration progression. If you smoke, it’s critical to quit because smoking progresses the disease faster.
You need eye exams at least once a year to monitor your condition, which allows you to start treatment right away if your disease progresses to the wet form.
Wet macular degeneration
Wet macular degeneration often responds positively to anti-VEGF injections, which prevents the growth of new blood vessels in your retina. Anti-VEGF injections given every four to six weeks can help you regain some lost vision and prevent further vision loss.
Port delivery systems (ocular implants that deliver medication over time) are another option for wet macular degeneration. The implants can eliminate the need for frequent injections in some cases.
The providers also offer the latest techniques and are actively involved in clinical research trials, allowing their patients access to the newest macular degeneration treatments before they’re widely available.
For macular degeneration help, call Retina Consultants of Austin or schedule an appointment online today. | {
"url": "https://www.retinaconsultantsofaustin.com/service/macular-degeneration",
"source_domain": "www.retinaconsultantsofaustin.com",
"snapshot_id": "CC-MAIN-2024-33",
"warc_metadata": {
"Content-Length": "347325",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:D245G6PID4N3P7BI5STXE5LYEPCACRAE",
"WARC-Concurrent-To": "<urn:uuid:378ee6da-1b94-46b6-9355-3547658b49e8>",
"WARC-Date": "2024-08-16T03:11:52",
"WARC-IP-Address": "108.138.64.127",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:U4DI3WTUHZNIUYABMKL6DVFM3OE4UFKP",
"WARC-Record-ID": "<urn:uuid:cd93d870-16d5-43b7-9a73-a082d908987f>",
"WARC-Target-URI": "https://www.retinaconsultantsofaustin.com/service/macular-degeneration",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:e130da03-c171-4b0a-87f3-8499021ed88f>"
},
"warc_info": "isPartOf: CC-MAIN-2024-33\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-252\r\nsoftware: Apache Nutch 1.20 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
34,
35,
56,
57,
144,
156,
157,
178,
179,
200,
201,
747,
748,
775,
776,
806,
807,
1027,
1028,
1212,
1213,
1277,
1278,
1325,
1326,
1573,
1574,
1689,
1690,
1848,
1849,
1948,
1949,
1986,
1987,
2086,
2087,
2164,
2165,
2191,
2192,
2355,
2356,
2549,
2550,
2709,
2710,
2735,
2736,
2997,
2998,
3197,
3198,
3411,
3412
],
"line_end_idx": [
34,
35,
56,
57,
144,
156,
157,
178,
179,
200,
201,
747,
748,
775,
776,
806,
807,
1027,
1028,
1212,
1213,
1277,
1278,
1325,
1326,
1573,
1574,
1689,
1690,
1848,
1849,
1948,
1949,
1986,
1987,
2086,
2087,
2164,
2165,
2191,
2192,
2355,
2356,
2549,
2550,
2709,
2710,
2735,
2736,
2997,
2998,
3197,
3198,
3411,
3412,
3519
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 3519,
"ccnet_original_nlines": 55,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.32459014654159546,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.009836070239543915,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.14098361134529114,
"rps_doc_frac_unique_words": 0.4609375,
"rps_doc_mean_word_length": 5.6328125,
"rps_doc_num_sentences": 28,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.935613632202148,
"rps_doc_word_count": 512,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.10194174945354462,
"rps_doc_frac_chars_dupe_6grams": 0.023578360676765442,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.18446601927280426,
"rps_doc_frac_chars_top_3gram": 0.04576975852251053,
"rps_doc_frac_chars_top_4gram": 0.026005549356341362,
"rps_doc_books_importance": -226.79183959960938,
"rps_doc_books_importance_length_correction": -226.79183959960938,
"rps_doc_openwebtext_importance": -130.477294921875,
"rps_doc_openwebtext_importance_length_correction": -130.477294921875,
"rps_doc_wikipedia_importance": -94.97053527832031,
"rps_doc_wikipedia_importance_length_correction": -94.97053527832031
},
"fasttext": {
"dclm": 0.03874117136001587,
"english": 0.8698298335075378,
"fineweb_edu_approx": 2.594632148742676,
"eai_general_math": 0.003466069931164384,
"eai_open_web_math": 0.05657767876982689,
"eai_web_code": 0.0008795899921096861
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.722",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-5,550,125,612,735,138,000 | Skip to main content
Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network
Abstract
Background
Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome-wide overview of the gene regulatory network in chondrogenesis has not been achieved.
Results
In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage-selective genes.
Conclusions
Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders.
Background
Chondrogenesis is the earliest stage of skeletal development and begins during embryogenesis with the proliferation and condensation of mesenchymal cells, followed by lineage commitment and differentiation, to yield the chondrocytes which populate and synthesize the scaffold for patterning the early skeletal elements. Subsequently, growth and mineralization of endochondral bones proceeds by establishment of the growth plates followed by the ordered differentiation, proliferation and hypertrophy of growth plate chondrocytes. Most of the terminally differentiated hypertrophic chondrocytes undergo apoptosis, while a subset can transdifferentiate to osteoblasts [1, 2]. Finally, the cartilage matrix is mineralized to form bone. This highly dynamic developmental process is regulated by transcription factors that include SOX9, RUNX2 and the GLI family of proteins, with synergistic regulation by multiple cell signaling pathways including the fibroblast growth factor (FGF), hedgehog, bone morphogenetic protein (BMP), transforming growth factor beta (TGF-beta) and WNT signaling pathways [3, 4]. Disruption of the genes that participate in chondrogenesis can lead to inherited skeletal disorders, as observed in humans and mice, which are characterized by abnormalities in the formation, linear growth and/or maintenance of the skeleton. The skeletal disorders comprise a broad range of severity from embryonic lethal phenotypes with extensive skeletal abnormalities to mild disorders in which short stature and early onset osteoarthritis are the main manifestations [5, 6].
Systematic identification of genes expressed in cartilage can uncover gene regulatory networks that are important for chondrogenesis and chondrocyte biology, providing fundamental insight into cartilage development and function. Indeed high-throughput gene expression profiling followed by data mining has been used to identify tissue-specific/selective genes in multiple human tissues, including cartilage [7,8,9,10,11]. Studies in cartilage have discovered genes that are highly and/or primarily expressed in chondrocytes and have been used as markers to investigate the differentiation potential of mesenchymal stem cells toward chondrocytes and other cell lineages [12]. Not surprisingly, a large number of the genes selectively expressed in chondrocytes are associated with human skeletal disorders [7], and the published gene expression data have been used as a resource to facilitate studies that have led to identification of additional genes associated with human skeletal phenotypes. For example, TRPV4, COL11A1 and ACAN gene mutations were identified as the causes of autosomal dominant brachyolmia, fibrochondrogenesis and an autosomal recessive form of spondyloepimetaphyseal dysplasia, respectively, based in part on their cartilage-selective (CS) expression patterns [13,14,15].
Microarray technology has been widely used for the high-throughput detection of gene expression. However, microarray gene expression applications are limited by low signal-to-noise ratios for genes expressed at low levels, signal saturation for highly expressed genes, and detection restricted to a predefined gene set. The development of high throughput sequencing methods has facilitated measuring most cellular transcript levels by RNA sequencing (RNA-Seq) [16]. In contrast to microarray technology, RNA-seq provides more sensitive and accurate measurement of gene expression, and is able to discover novel transcripts and genes. To provide a deeper measure of both quantitative and qualitative gene expression in human growth plate chondrocytes, we used RNA-seq to acquire a comprehensive gene expression profile of the tissue. These data were complemented by publically available RNA-Seq and ChIP-seq data sets, also generated on high throughput sequencing platforms, to reveal regulatory mechanisms that underlie chondrogenesis and linear growth. The data have provided a comprehensive understanding of the transcriptional network in chondrocytes and suggested novel regulatory networks and mechanisms underlying chondrogenesis and skeletal development.
Results
Identification of cartilage-selective (CS) genes in human fetal cartilage
We sought to identify CS genes using RNA-seq data from human tissues and cells. Cartilage gene expression profiles were generated from 14 to 18 week distal femur growth plate chondrocytes. RNA-seq data from other tissues/cells were generated by previously described studies [17,18,19,20,21,22,23] and accessed from public databases as detailed in Methods. There were 111 RNA-seq gene expression datasets representing 22 tissues or cell types in the comparison data set (Additional file 1: Dataset S1). With the exception of the data from CD4+ and CD8+ primary cells, which were obtained from adults, the remaining data were generated from human fetal tissues/cells. Therefore, the gene expression data mainly reflected human fetal transcription. Data quality were assessed by calculating the Pearson’s correlation coefficients between datasets, requiring that gene expression patterns be similar in the same or closely related tissues, which would be reflected by high Pearson’s correlation coefficients. As shown in Additional file 2: Figure S1, tissues/cells with same origins had high Pearson’s correlation coefficients and formed unique clusters, indicating that the data were of high quality and therefore represented the intrinsic gene expression properties of the tissues/cells studied.
Using the PaGeFinder algorithm, we identified 403 transcripts, representing 332 protein coding genes, which were selectively expressed in cartilage (Additional file 3: Dataset S2). A boxplot of the selective gene expression showed that there was a set of genes that were highly expressed in cartilage as compared with other tissues/cells (Additional file 2: Figure S2). Many well-studied cartilage marker genes were identified and listed as top CS genes with high specificity measure (SPM) values, such as the known CS genes encoding types II, IX and XI collagens, aggrecan and matrix metalloproteinase 13 (Additional file 3: Dataset S2). We found that 63 (42%) of the CS genes previously discovered in our similar microarray-based study [7] were also identified as CS in the current study (Additional file 4: Dataset S3). Another 25 genes from the previous study [7] had high SPM values (between 0.7 and 0.9) in the current study, indicating they were preferentially, but not selectively, expressed in cartilage. This comparison indicates that the RNA-seq approach was capable of recapitulating the prior findings [7] and able to reveal known and newly identified genes selectively expressed in human fetal cartilage. There were also 57 CS genes from the microarray study that showed expression in non-cartilage samples in the RNA-seq dataset, reflecting the differences between the microarray and RNA-seq techniques. RNA-seq has a broader dynamic range that is able to better detect low-abundance transcripts [24]. Thus genes expressed at low levels on microarrays have signals close to background and are set as non-expressed while by RNA-seq the low level expression can be measured, revealing that they may not be selectively expressed.
GO and KEGG pathway analysis indicated that the cartilage-selective gene set was enriched for genes known to participate in skeletal system development. These included selectively expressed genes involved in cellular processes necessary for chondrogenesis, such as regulation of cell proliferation and apoptosis, cellular biosynthesis, cell adhesion, blood vessel morphogenesis, transcriptional regulation and TGFβ signaling (Fig. 1a, b).
Fig. 1
figure 1
Cartilage-selective genes are required for proper bone formation. a Gene ontology (GO) analysis of cartilage-selective (CS) genes. b KEGG pathway analysis of cartilage-selective genes. The number of genes in each GO term is indicated. c CS genes associated with skeletal phenotypes in gene targeted mice
Cartilage-selective genes are required for skeletal development
As the GO analysis of the CS genes indicated that they have roles in skeletal development, it would be expected that disruption of their functions in mice and/or humans would lead to skeletal abnormalities. To assess this, we retrieved mouse phenotypes from the Mouse Genome Informatics Database (MGI, http://www.informatics.jax.org/) and found that mutations in 153/332 (46%) of the CS genes were associated with mouse skeletal defects (Fig. 1c; Additional file 3: Dataset S2). Using the MGI descriptors, the 153 genes were represented across a number of overlapping categories, with 128 genes associated with growth/size/body phenotypes, 92 genes associated with skeletal phenotypes, 52 genes associated with craniofacial phenotypes, and 60 genes associated with limb/digit/tail phenotypes. For the remaining 179 genes, 94 genes were not present in the MGI phenotype list and 85 genes did not show a skeletal phenotype when targeted in mice. Despite the latter observation, a review of the literature revealed that many of these genes do have roles in skeletogenesis, including human skeletal disorders due to mutations in SHOX, FBLN7 and VIT as examples [25,26,27]. In addition, although knockout mutations targeting Trpv4 or Comp do not show skeletal phenotypes in mice, dominant negative structural mutations in these genes result in skeletal disorders in humans [14, 28,29,30]. In this context, we compared the CS genes with the genes associated with human genetic skeletal disorders, expecting that many of the genes would be associated with skeletal dysplasias [5]. There were 32 of the CS genes (Additional file 3: Dataset S2) associated with a broad spectrum of 62 human skeletal disorders, 26 of which were also associated with mouse skeletal phenotypes. The human and mouse skeletal phenotypes highlight the essential roles of the CS genes in skeletal development but also reveal that loss-of-function mouse models do not identify the essential roles of all genes important for skeletogenesis.
Cartilage-selective gene products interact
To decipher relationships among the proteins encoded by the selective genes, a protein-protein interaction network was built with Cytoscape [31]. As shown in Fig. 2, proteins encoded by the genes showed extensive physical interactions and formed a large interaction network. Matrix metallopeptidases had complex interactions with extracellular matrix proteins, such as CS collagens and aggrecan, consistent with their central roles in processing these proteins and regulating bone mineralization. TGFβ family signaling molecules including BMP2/6, ACVR1 and GDF5 also showed physical interactions (Fig. 2), in agreement with their regulatory functions in chondrogenesis and bone formation [32]. Thus the proteins specified by the CS genes comprise a functional cartilage interactome.
Fig. 2
figure 2
Protein-protein interaction network for the CS genes. CS proteins are represented as colored nodes. Node colors represent three GO groups as noted
Transcriptional regulation of cartilage-selective genes
We expected that CS transcription factors could function as master regulatory molecules to control downstream expression of additional selectively expressed genes. By comparing the CS genes with the transcription factor genes annotated in the Animal Transcription Factor Database (AnimalTFDB) [33], 34 selectively expressed cartilage transcription factors were identified [Figs. 1a, 2; Additional file 5: Dataset S4]. These transcription factors are known or now predicted to participate in multiple cellular activities that regulate chondrocyte development (Fig. 3a). To determine if these factors control CS gene transcription, we searched for transcription factor binding motifs in the promoter regions of the CS genes. As shown in Fig. 3b, the promoters were enriched in consensus-binding sites for transcription factors that were selectively expressed in cartilage, including SOX6, CREB3L2, EGR2/3/4, GLIS3, PLAGL1, RELB and SNAI1/2, all of which have been shown to play important roles in skeletal development [34,35,36,37,38,39]. Although RUNX2 was not identified as a CS gene, since it was also expressed in lymphocytes (Additional file 2: Figure S3), its binding motif was also enriched among the CS promoters (Fig. 3b), consistent with its known transcriptional regulatory role in chondrogenesis. These data suggest that expression of the selective genes might be directly regulated by a group of transcription factors that are uniquely expressed in cartilage.
Fig. 3
figure 3
Cartilage-selective transcription factors and DNA binding motif analysis. a ClueGO network analysis for enrichment biological process modules within transcription factors. GO terms are represented as large nodes and genes are represented as small nodes. Node colors represent GO groups. b Transcription factor DNA binding motif analysis shows enrichment of motifs in cartilage-selective gene promoters. All P values for motif enrichment are less than 10−10
The binding motif of SOX6 was also enriched among the CS gene promoters, and SOX6 cooperates with SOX5 to secure SOX9 binding to CS enhancers in chondrocytes [40]. SOX9 is expressed in skeletogenic mesenchymal cells at early embryonic stages and regulates chondrogenesis through transcriptional activation of target genes [41, 42]. SOX9 mutations in humans produce campomelic dysplasia, a generally lethal osteochondrodysplasia with distinctive abnormalities in cartilage and bone [43, 44]. As has been previously observed in animal models, SOX9 is selectively expressed in cartilage and is required for expression of CS genes in chondrocytes [41, 42, 45]. In our analysis, 247 (74.4%) CS genes had SOX9 binding sites in their promoter regions (±2 kb of TSS). These CS genes included 25 transcription factor genes which by ChIP-seq had SOX9 bound to their TSS (Fig. 4a), with 13 of them showing strong SOX9 binding intensity (>25% quantile of all SOX9 binding sites). For instance, SOX9 strongly binds to the TSS of transcription factor genes Egr2 and Fosl1 (Fig. 4b, c), which are essential for skeletogenesis in mice [36, 46]. Because both SOX9 and EGR2 are highly expressed and regulate gene expression in mesenchymal stem cells (MSC) [41, 42, 47, 48], it is plausible to speculate that SOX9 controls chondrogenesis through functions as an upstream transcription factor that directly activates expression of downstream transcription factors.
Fig. 4
figure 4
Sox9 binds to the cartilage-selective transcription factor gene promoters in mouse chondrocytes. a Average binding profile of Sox9 at the CS transcription factor gene TSS. The distance on the plot is measured in base pairs. b, c Genome browser views of Sox9 peaks along the Egr2 b and Fosl1 c loci
Cartilage-selective genes are regulated by active enhancers
Spatiotemporal gene expression is modulated by both transcription factors and epigenetic mechanisms such as enhancers [49]. Enhancers are distinct genomic regions bound by transcriptional activators and are marked by histone modifications such as histone H3 lysine 4 monomethylation (H3K4me1) and lysine 27 acetylation (H3K27ac) [50, 51]. Activation of tissue-specific enhancers provides a molecular mechanism that turns on gene expression in a cell type-specific manner [49]. Genome-wide studies in chondrocytes have identified a set of genes involved in chondrogenesis that are regulated by enhancers [52,53,54], so we asked whether CS gene expression might be activated by enhancers. Active enhancers in human chondrocytes were predicted by mapping the genome-wide distribution of H3K27ac [55], revealing 31,235 active chondrocyte enhancer regions marked by this chromatin modification (Additional file 6: Dataset S5). By comparing these data with enhancers across seven fetal tissues, we identified a subset of 11,334 enhancers that were uniquely present in chondrocytes. These enhancers were specifically enriched at CS gene loci including COL10A1, COL2A1 and COL11A1 (Fig. 5a and Additional file 2: Figure S4). Similar to other tissues, the chondrocyte enhancers were predominantly bound by H3K4me1 and H3K27ac (Fig. 5b, c). To predict enhancer target genes, we examined genome-wide enhancer-gene associations in chondrocytes with GREAT [56]. As shown in Fig. 6a, the chondrocyte unique enhancers were associated with genes involved in skeletal developmental processes including bone morphogenesis, chondrocyte differentiation, cellular carbohydrate biosynthesis, polysaccharide biosynthesis and endochondral ossification. 176 (53%) of the CS genes had active chondrocyte unique enhancers flanking their loci, suggesting that these genes are potentially enhancer regulated.
Fig. 5
figure 5
Identification of active enhancers in chondrocytes. a Genome browser views of H3K4me1 and H3K27ac peaks along the COL10A1 locus on chromosome 6. Chromosome coordinates are shown as black bars on top. Black arrows indicate the direction of transcription on a diagram of the gene below. CH, chondrocytes. AG, adrenal gland. LI, large intestine. SI, small intestine. MU, muscle. SC, spinal cord. ST, stomach. TH, thymus. b and c Genome-wide average of b H3K4me1 and c H3K27ac enrichment at chondrocyte enhancers in human fetal tissues and cells. The distance on the plot is measured in base pairs
Fig. 6
figure 6
GO and DNA binding motif analysis of chondrocyte-unique enhancers. a GO analysis of chondrocyte enhancers. The number of genes in each GO term is indicated. b Enrichment of transcription factor DNA binding motifs on chondrocyte enhancers. All P values for motif enrichment are less than 10−10
With DNA motif analysis, we found that the chondrocyte unique enhancers were enriched for consensus-binding sites for transcription factors that have pivotal roles in chondrogenesis, including RUNX2, SOX8/9, SMAD3, STAT1/4 and FOSL1 (Fig. 6b), in agreement with the fact that they regulate transcription in part through binding to enhancers [52, 54, 57,58,59,60]. Furthermore, binding sites for additional transcription factors were also found to be enriched among the chondrocyte unique enhancers, suggesting roles in transcriptional regulation in chondrocytes that could be further explored experimentally (Additional file 6: Dataset S5).
Identification of cartilage-selective lncRNAs
LncRNAs are emerging as transcriptional regulators that participate in skeletogenesis through regulation of chondrocyte and osteoblast differentiation and homeostasis [61]. Since most lncRNAs are polyadenylated, and therefore can be measured by mRNA-seq, we analyzed the RNA-seq data and identified 34 lncRNAs genes selectively expressed in cartilage. LncRNAs have been shown to act as cis-regulators that modulate expression of neighboring genes [62, 63]. To identify potential regulatory targets, we used GREAT analysis to reveal protein coding genes neighboring the cartilage selective lncRNAs (Additional file 7: Dataset S6). Eight lncRNAs were adjacent to genes known to be involved in skeletal development including SOX9, GLI2, FOXA2, UMPS, SOD2, BHLHE41 and RAB11FIP4. Three lncRNAs (LINC00673, AC058791.1 and RP11–261P24.2) were embedded in active enhancer regions that were marked by H3K27ac and H3K4me1 in chondrocytes (Fig. 7a; Additional file 2: Figure S5), suggesting the lncRNA expression and enhancer activity might be functionally related. Among these, we were particularly interested in LINC00673 (annotated as a fusion gene with LINC00511 by ENSEMBL) because it is transcribed from a locus on human chromosome 17 that is ~280 kb downstream of SOX9. In human chondrocytes, LINC00673 was highly expressed and its promoter was enriched in H3K4me3, a marker for active transcription. The active enhancers at the LINC00673 gene locus span a ~0.5 Mb region downstream of SOX9. This region and the upstream region of SOX9 were marked with H3K27ac and shown to interact with the SOX9 promoter in melanoma cells that express SOX9 [64]. These data suggest that the LINC00673 locus might function as an enhancer to regulate SOX9 transcription (Fig. 7a).
Fig. 7
figure 7
LINC00673 is co-expressed with SOX9. a Genome browser views of H3K4me1, H3K4me3, H3K27ac peaks and RNA expression track along SOX9 and LINC00673 loci on chromosome 17 in human chondrocytes. b Bar graphs showing SOX9 and LINC00673 expression in human tissues. Red bars indicate cartilage samples and blue bars indicate non-cartilage samples, respectively. Gene expression levels are shown as FPKM values. c Correlation between SOX9 and LINC00673 expression (Log2FPKM) in human tissues. Scatter plot of SOX9 against LINC00673 with regression lines showing a correlation between the two genes using the Pearson’s correlation coefficient. Red and blue dots indicates the tissues with SOX9 Log2FPKM value greater or less than 1, respectively. Cartilage samples are highlighted as purple dots. The blue regression line was generated with data from all tissues. The red regression line was generated with data from the tissues that have SOX9 FPKM value ≥1. The Pearson’s correlation coefficient for each regression line is shown
LINC00673 and SOX9 were highly expressed in chondrocytes, and also had low expression in brain, kidney, intestine, lung, spinal cord and stomach (Fig. 7b). Among all tissues, the expression levels of LINC00673 and SOX9 were positively correlated with each other, yielding a Pearson’s correlation coefficient 0.66. When we only considered the tissues/cells that express SOX9 (FPKM > 1), the Pearson’s correlation coefficient reached 0.8, indicating LINC00673 and SOX9 have orchestrated expression patterns across tissues (Fig. 7c). To validate the finding, we analyzed gene expression data using the UCLA Gene Expression Tool (UGET) [65], which reported the Pearson’s correlation coefficient for every pair of 54,675 probe sets on Affymetrix HG U133 Plus 2.0 arrays from the 12,000 human expression profiles. Among the 38,500 genes detected by the Affymetrix arrays, SOX9 was ranked as the gene with the second highest correlation with LINC00673 expression (the most highly correlated gene was LINC00673 itself), with a Pearson’s correlation coefficient 0.43. Reciprocally, LINC00673 was ranked as the gene that had the nineteenth highest correlation with SOX9 expression, with a Pearson’s correlation coefficient 0.39. The high Pearson’s correlation coefficients suggest a gene expression co-regulatory mechanism between SOX9 and LINC00673 (Additional file 7: Dataset S6).
Because SOX9 positively regulates transcription through binding to gene promoters and enhancers [54], we also considered the possibility that SOX9 could directly bind to LINC00673 and activate its transcription. To assess this, we examined SOX9 binding sites in mouse chondrocytes [52] and found that SOX9 bound to the promoter and structural gene for 2610035D17Rik, the orthologue of LINC00673 in mice, strongly suggesting that expression of the gene is regulated by SOX9 (Additional file 2: Figure S6). Because LINC00673 was selectively expressed in chondrocytes and was embedded in the enhancer region downstream of SOX9 gene, it is also possible that there is reciprocal regulation in which LINC00673 could work with enhancers to activate SOX9 and possibly other genes, and therefore participate in regulation of chondrogenesis.
Discussion
Organogenesis is a process of proliferation and differentiation of progenitor cells into diverse types of cells with distinct functions. Their unique functions are largely acquired through expression of tissue-specific/selective genes. Studies of gene expression patterns and regulatory mechanisms in particular tissues thus inform our understanding of tissue development and mechanisms of disease. Tissue-specificity refers to genes whose expression is restricted to one particular tissue or cell type, while tissue-selective expression includes genes that are expressed in one or a few generally biologically similar tissue types [66]. The data presented in this study described 332 cartilage-selective genes expressed in human fetal cartilage, providing unique insights into chondrocyte gene expression and regulation.
The significance of cartilage-selective gene identification
High expression of the CS genes in chondrocytes suggests they may have essential roles in skeletal development and skeletal disorders. In support of this hypothesis, 32 CS genes were linked to human skeletal disorders that result from mutations in these genes. Gene-targeting mice for 153 genes showed skeletal development defects. Among the list, there were well-known genes whose products have pivotal roles in chondrogenesis, such as cartilage collagens, cell signaling molecules and transcription factors. Base on this observation, we suggest that some of the newly identified CS genes may be good candidate genes for skeletal disorders in which the associated genes have yet to be identified. As new skeletal dysplasia loci are defined, the candidate genes can be compared with the CS genes to promote rapid identification of the mutated gene. Gene network analysis revealed complex interactions of CS gene products, data compatible with the hypothesis that CS genes are functionally related in the initiation and progression of complex diseases such as osteoarthritis. It may thus be useful to correlate gene mutations and dysregulation of gene expression among the chondrodysplasias with the CS gene interactome for further understanding of the pathogenesis of cartilage disorders [67]. In addition, we identified 94 genes that are less studied and for which knockout mice phenotypes have not been annotated by MGI (Additional file 3: Dataset S2). According to GO analysis, 39 of these genes are involved in cell signaling pathways and 27 genes encode secreted proteins. Their unique cartilage expression pattern suggests the genes might participate in chondrogenesis. For example, C2orf82 is highly expressed in human cartilage with an average FPKM value >1500 and encodes a type I single-pass transmembrane chondroitin sulfate proteoglycan. The gene showed a CS expression pattern with the highest expression in proliferating and prehypertrophic zones in embryonic and postnatal growth plate. Its expression was restricted to the uncalcified zone in adult articular cartilage, including chondrocyte clusters in human osteoarthritic cartilage. Its expression pattern was similar to the highly expressed CS genes Sox9, Acan and Col2a1, and could be induced by BMP-2, suggesting its functions may be associated with the development and maintenance of the chondrocyte phenotype [68]. As a second example, zinc-finger 385 family genes including ZNF385B/C/D were also selectively expressed in cartilage and another family member, ZNF385A, was also highly expressed in the tissue (Additional file 3: Dataset S2). Fluorescence-labeled Znf385C protein was highly expressed in maturing chondrocytes in the pharyngeal arches as well as in the cartilage associated with the ear and ventral fins in zebrafish [69]. Loss of Znf385C in zebrafish led to craniofacial defects and premature ossification of the Meckel’s cartilage, potentially through disturbance of p53-dependent cell cycle regulation [69]. Therefore, targeting some of the 94 understudied CS genes is likely to reveal new biology related to cartilage function.
Regulation of chondrogenesis by epigenetic mechanisms
Epigenetic mechanisms such as histone modifications and enhancers regulate transcription in skeletal development and disease [70, 71]. Genome-wide profiling of SOX9 indicated that it functions in part by binding to enhancers. Disruption of upstream distal intergenic regions especially the regions between -50 kb and -350 kb 5′ of SOX9 by deletion/translocation/inversion are associated with severe campomelic dysplasia [72, 73]. Systematically screening the 350 kb region upstream of SOX9 using histone modification markers and DNase I hypersensitivity assays identified ten potential enhancers, with three enhancers primarily active in chondrocytes and that activate SOX9 expression in the chondrocyte lineage [74]. SOX9, in complex with SOX5 and SOX6, reciprocally activate the enhancers, which provides a potential mechanism for autoregulation of its own expression in chondrocytes [74]. In the current study, genome-wide mapping of histone marks led to identification of 11,334 enhancers that were uniquely active in chondrocytes and associated with 176 of the CS genes. The identified active enhancers could be used as a resource to explore epigenetic regulation and higher-order chromatin organization in chondrocytes. The data also indicated that these enhancers were enriched in the consensus binding motifs for well-known transcription factors such as SOX9 and RUNX2, suggesting that transcription factor-bound enhancers contribute to the selective gene expression pattern in chondrocytes.
lncRNAs and chondrogenesis
lncRNAs are non-protein coding transcripts with lengths of more than 200 nucleotides, which are proposed to regulate transcription through both trans- and cis-regulatory mechanisms. Some lncRNAs tether to their target gene loci and affect transcriptional activity of neighboring genes through association with regulatory proteins. They could also bind to regions on other chromosomes and also control gene activity through recruiting regulatory proteins [75]. The roles for lncRNAs in skeletal development are emerging with a growing number of lncRNAs identified that participate in skeletal development and disease [61]. In our study, 34 lncRNAs were identified to be selectively expressed in human cartilage. Eight lncRNAs are adjacent to loci of protein coding genes that participate in skeletal development, suggesting the cartilage-selective lncRNAs may be involved in chondrogenesis through regulation of protein coding genes. We found that LINC00673 and SOX9 are co-regulated in human tissues, and that LINC00673 is embedded within a potential enhancer region for SOX9, suggesting LINC00673 may regulate SOX9 expression through a distal enhancer. In support of this hypothesis, by Circularized Chromosome Conformation Capture sequencing (4C–seq), the LINC00673 locus was found to be involved in long-range enhancer-promoter interactions at the SOX9 locus in SOX9-expressed melanoma cells but not in SOX9-inactive cells, consistent with the enhancer-promoter interactions driving SOX9 activation [64]. In addition, LINC00673 regulates target gene expression in gastric cancer cells by recruiting histone methyltransferase EZH2 and demethylase LSD1 to target gene promoters, suggesting that it can function as a transcriptional regulator through epigenetic mechanisms [76]. While the exact role of LINC00673 in SOX9 gene regulation is unknown, loss- and gain-of-function experiments could be used to directly address this question.
Cartilage-selective genes and mouse phenotypes
There were 85 CS genes that did not show a skeletal phenotype when targeted in mice (Figure 1C). Some of these genes may have overlapping functions with paralogous genes. For example, NKX3.1 is a transcription factor selectively expressed in cartilage. Inactivation of the Nkx3.1 gene produced no apparent skeletal phenotype, while knockout of its paralogue Nkx3.2 in mice led to a lethal skeletal dysplasia, with abnormalities of the vertebral column and craniofacial bones [77,78,79,80]. Nkx3.1 and Nkx3.2 double knockout mice showed enhanced vertebral defects compared with Nkx3.2 knockout mice, suggesting that Nkx3.1 and Nkx3.2 regulate skeletal development coordinately [81]. In addition, although knockout of some CS genes did not produce skeletal defects in mice, such mutations in humans produced skeletal disorders. As an example, knockout of Wisp3 in mice did not yield skeletal abnormalities, while human loss-of-function mutations in WISP3 produce the autosomal recessive skeletal disease progressive pseudorheumatoid dysplasia in humans (OMIM 208230). Depletion of the gene in zebrafish affected mandibular and pharyngeal cartilage development and over-expression Wisp3 in zebrafish indicated that it might function as a BMP and Wnt signaling modulator [82, 83]. As another example, COMP encodes a noncollagenous extracellular matrix protein that interacts with cartilage collagens and promotes formation of well-defined collagen fibrils [84]. In contrast to COMP knockout mice, which showed normal skeletal development, dominant missense mutations of human COMP result in autosomal dominant pseudoachondroplasia and multiple epiphyseal dysplasia type 1 [29, 85, 86]. Furthermore, pseudoachondroplasia knock-in mice carrying the COMP p.Thr583Met mutation that causes a skeletal phenotype in humans exhibited short-limb dwarfism and severe degeneration of articular cartilage [87]. COMP p.Asp469del knock-in mice developed a progressive short-limb dwarfism and hip dysplasia, with disorganized growth plate [88]. Finally, dominant structural mutations in TRPV4, which encodes a Ca2+ permeable ion channel that responds to chemical and physical stimuli, result in a broad spectrum of inherited skeletal disorders in humans [14, 28, 89,90,91]. Trpv4 knockout mice showed bladder dysfunction and hearing loss without obvious skeletal defects [92]. However, Trpv4 transgenic mice expressing the known pathogenic missense mutation p.Arg594His showed a severe skeletal dysplasia that recapitulated abnormalities of metatropic dysplasia in humans [93]. In the latter examples, dominant negative or gain-of-function mutations interrupt normal chondrocyte activities and lead to abnormal skeletal phenotypes that mouse knockouts did not reveal.
Limitations and future directions
The goal of this study was to identify key genes and transcriptional regulatory mechanisms in chondrogenesis using total RNA isolated from fetal distal femur cartilage, including all types of chondrocytes from the growth plate. As a consequence, we were not able to determine if the selective genes are uniformly expressed throughout the growth plate or are preferentially expressed in certain chondrocyte cell type(s). For example, it is known that SOX9 is expressed in reserve and proliferating chondrocytes and COL10A1 is expressed in hypertrophic chondrocytes [94, 95]. Laser capture microdissection followed by RNA-seq could further define the expression patterns of the cartilage-selective genes. In addition, due the limited number of tissue types and samples used in this study, and objective but arbitrary criteria for identifying cartilage selectivity, the CS gene list could change if the criteria for identifying CS selective genes are changed, or as additional fetal tissue expression profiles are added. Curation of additional RNA-seq data from human tissues and developmental stages will help to better define tissue selective genes and promote functional studies at spatial and temporal scales.
Conclusions
In summary, the current study identified 332 protein coding genes and 34 lncRNA genes that are selectively expressed in human fetal cartilage. Proteins transcribed from the cartilage-selective genes formed a complex interaction network and participate in multiple processes in skeletal development. The data further indicate that transcription factors, enhancers and lncRNAs work cooperatively to mediate transcriptional regulation in cartilage. In addition to known regulatory molecules, our study also discovered novel protein coding genes and lncRNAs that are likely to regulate chondrogenesis. Together, these findings help us to better understand the mechanisms underlying chondrogenesis and will be instrumental in further dissecting gene regulatory mechanisms in skeletal pattern formation, endochondral ossification and chondrocyte function.
Methods
Cartilage specimen collection and RNA isolation
Under a UCLA IRB-approved human subjects protocol, five independent 14–18 week distal human femur growth plate cartilage samples were obtained with informed consent. RNA was isolated and purified from the tissue as previously described [96]. Briefly, the fetal cartilage was digested in 0.3% bacterial collagenase, the chondrocytes were collected by centrifugation and total RNA was isolated with TRIZol (Thermo Fisher Scientific). Genomic DNA contamination was removed by DNase I (Thermo Fisher Scientific) digestion and the RNA was further purified with the RNeasy Mini Kit (Qiagen). All of the RNA samples had RIN (RNA Integrity Number) ≥8 (measured with the Agilent 2100 BioAnalyzer).
Gene expression analysis
PolyA-tailed mRNA was isolated from total RNA and used as the input for sequencing library construction with the TruSeq RNA Preparation Kit (Illumina). Sequencing was performed on the Illumina HiSeq 2000 instrument (Additional file 1: Dataset S1). The sequencing data analysis pipeline was described previously [97]. Briefly, RNA-seq reads were mapped to the human genome (hg19) using TopHat (v2.0.9), allowing up to 2-bp mismatches per read [98]. The mapped reads were analyzed using the Cufflinks (v2.2.1) package [99]. The transcript abundance in each sample was quantified with Cuffquant. The Cuffquant outputs for all samples were then joined and normalized with Cuffnorm. Gene expression level is represented as FPKM (fragments per kilobase of exon per million fragments mapped) values. Refseq gene annotation was obtained from the UCSC genome website (https://genome.ucsc.edu/). LncRNA gene annotation was downloaded from GENCODE [100]. Low abundance genes with FPKM values less than 1 were filtered before downstream analysis.
Identification of cartilage-selective (CS) genes
The PaGeFinder program has been used to define gene expression patterns from high-throughput transcriptomic data, which applies cosine similarity measurements to discover housekeeping and tissue-specific/selective genes [101]. The specificity measure (SPM) value produced by PaGeFinder was used as a criterion to estimate the relative expression specificity of a gene in a given sample. To identify CS genes, gene expression FPKM values from multiple samples within the same tissue/cell type were averaged, yielding a table with average FPKM values for all measured genes. The data were then processed with PaGeFinder and SPM values were generated. CS genes were defined as the subset of genes with average FPKM values ≥1 and SPM ≥0.9 in cartilage samples. For the cartilage-selective lncRNAs, to eliminate false-positives, lncRNAs that had sense strand exonic overlap with expressed protein-coding genes or that were embedded in gene introns for which there was intron-retention, were excluded from the cartilage-selective lncRNA list.
External data sources
The data used in this study are summarized in Additional file 1: Dataset S1. Some of the RNA-seq data from normal human tissues/cells have been reported by others [17,18,19,20,21,22,23]. Histone modification ChIP-seq data were downloaded from the NCBI epigenome roadmap project (http://www.ncbi.nlm.nih.gov/geo/roadmap/epigenomics/) [20]. Processed alignment files for histone ChIP-seq in human fetal tissues were also downloaded from the epigenome roadmap project website (http://egg2.wustl.edu/roadmap/data/byFileType/alignments/consolidated/). Genome-wide SOX9 binding data in mouse chondrocytes were described previously [52]. All downloaded data were processed using the UCSC hg19 build.
ChIP-seq data processing
Bowtie 0.12.7 was used to align sequenced reads to the human (hg19, for histone modifications) and murine genomes (mm9, for SOX9 ChIP-seq). Reads that aligned to more than one genomic location or that had more than 2 mismatches were discarded. The human genome was divided into 100 bp windows and peak calling was performed with MACS (v1.3.7.1) using its default P-value [102].
Prediction of active enhancers
Active enhancers were predicted based on H3K27ac ChIP-seq peaks that were >3 kb away from gene transcription start sites (TSS) and H3K4me3 peaks (a marker for active promoters) [55]. Enhancers within 1 kb of each other were merged. Chondrocyte-unique enhancers were defined as the enhancers only detected in chondrocytes in comparison with other tissues.
Gene ontology (GO) and network analysis
CS genes were submitted to DAVID for GO and KEGG pathway analysis [103]. GO analysis for chondrocyte-unique enhancers was performed with the Genomic Regions Enrichment of Annotations Tool (GREAT) using default settings [56]. Genome coordinates for CS lncRNAs were submitted to GREAT and protein coding genes flanking lncRNA loci were identified. Gene network analysis was performed with Cytoscape 3.2.1, using plug-ins ClueGO and GeneMANIA [31, 104, 105].
Motif analysis
Enrichment analysis of known transcription factor binding motifs was performed with SeqPos [106] using DNA sequences from gene promoter regions (±2 kb from TSS) or enhancers.
Data processing and visualization
Heatmaps, boxplots and scatter plots were generated with R. Sequencing data were visualized with the Integrated Genome Browser [107].
References
1. Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 2014;10(12):e1004820.
Article PubMed PubMed Central Google Scholar
2. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A. 2014;111(33):12097–102.
Article CAS PubMed PubMed Central Google Scholar
3. Goldring MB, Tsuchimochi K, Ijiri K. The control of chondrogenesis. J Cell Biochem. 2006;97(1):33–44.
Article CAS PubMed Google Scholar
4. Kozhemyakina E, Lassar AB, Zelzer E. A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015;142(5):817–31.
Article CAS PubMed PubMed Central Google Scholar
5. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. 2015;167A(12):2869–92.
Article PubMed CAS Google Scholar
6. Krakow D. Skeletal dysplasias. Clin Perinatol. 2015;42(2):301–19. viii
Article PubMed PubMed Central Google Scholar
7. Funari VA, Day A, Krakow D, Cohn ZA, Chen Z, Nelson SF, Cohn DH. Cartilage-selective genes identified in genome-scale analysis of non-cartilage and cartilage gene expression. BMC Genomics. 2007;8:165.
Article PubMed PubMed Central CAS Google Scholar
8. Edqvist PH, Fagerberg L, Hallstrom BM, Danielsson A, Edlund K, Uhlen M, Ponten F. Expression of human skin-specific genes defined by transcriptomics and antibody-based profiling. J Histochem Cytochem. 2015;63(2):129–41.
Article PubMed CAS Google Scholar
9. Megy K, Audic S, Claverie JM. Heart-specific genes revealed by expressed sequence tag (EST) sampling. Genome Biol. 2002;3(12):Research0074.
Article PubMed PubMed Central Google Scholar
10. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929–47.
Article CAS PubMed PubMed Central Google Scholar
11. Pogue R, Sebald E, King L, Kronstadt E, Krakow D, Cohn DH. A transcriptional profile of human fetal cartilage. Matrix Biol. 2004;23(5):299–307.
Article CAS PubMed Google Scholar
12. Freeman BT, Jung JP, Ogle BM. Single-cell RNA-Seq of bone marrow-derived Mesenchymal stem cells reveals unique profiles of lineage priming. PLoS One. 2015;10(9):e0136199.
Article PubMed PubMed Central CAS Google Scholar
13. Tompson SW, Bacino CA, Safina NP, Bober MB, Proud VK, Funari T, Wangler MF, Nevarez L, Ala-Kokko L, Wilcox WR, et al. Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene. Am J Hum Genet. 2010;87(5):708–12.
Article CAS PubMed PubMed Central Google Scholar
14. Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008;40(8):999–1003.
Article CAS PubMed PubMed Central Google Scholar
15. Tompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, Nelson SF, Briggs MD, Cohn DH, Krakow D. A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. Am J Hum Genet. 2009;84(1):72–9.
Article CAS PubMed PubMed Central Google Scholar
16. Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1):57–63.
Article CAS PubMed PubMed Central Google Scholar
17. Gkountela S, Zhang KX, Shafiq TA, Liao WW, Hargan-Calvopina J, Chen PY, Clark AT. DNA Demethylation dynamics in the human prenatal Germline. Cell. 2015;161(6):1425–36.
Article CAS PubMed PubMed Central Google Scholar
18. Yan L, Guo H, Hu B, Li R, Yong J, Zhao Y, Zhi X, Fan X, Guo F, Wang X, et al. Epigenomic landscape of human fetal brain, heart, and liver. J Biol Chem. 2016;291(9):4386–98.
Article CAS PubMed Google Scholar
19. Jin S, Lee YK, Lim YC, Zheng Z, Lin XM, Ng DP, Holbrook JD, Law HY, Kwek KY, Yeo GS, et al. Global DNA hypermethylation in down syndrome placenta. PLoS Genet. 2013;9(6):e1003515.
Article CAS PubMed PubMed Central Google Scholar
20. Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–30.
Article CAS Google Scholar
21. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR, et al. The NIH roadmap Epigenomics mapping consortium. Nat Biotechnol. 2010;28(10):1045–8.
Article CAS PubMed PubMed Central Google Scholar
22. Gkountela S, Li Z, Vincent JJ, Zhang KX, Chen A, Pellegrini M, Clark AT. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat Cell Biol. 2013;15(1):113–22.
Article CAS PubMed Google Scholar
23. Consortium F. The RP, Clst, Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassmann T et al: a promoter-level mammalian expression atlas. Nature. 2014;507(7493):462–70.
Article CAS Google Scholar
24. Zhao S, Fung-Leung WP, Bittner A, Ngo K, Liu X. Comparison of RNA-Seq and microarray in transcriptome profiling of activated T cells. PLoS One. 2014;9(1):e78644.
Article PubMed PubMed Central CAS Google Scholar
25. Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, Scambler PJ, Winter RM. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet. 1998;19(1):70–3.
Article CAS PubMed Google Scholar
26. Russell MW, Raeker MO, Geisler SB, Thomas PE, Simmons TA, Bernat JA, Thorsson T, Innis JW. Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations. Hum Mol Genet. 2014;23(16):4272–84.
Article CAS PubMed Google Scholar
27. Wilson R, Norris EL, Brachvogel B, Angelucci C, Zivkovic S, Gordon L, Bernardo BC, Stermann J, Sekiguchi K, Gorman JJ, et al. Changes in the chondrocyte and extracellular matrix proteome during post-natal mouse cartilage development. Mol Cell Proteomics. 2012;11(1):M111 014159.
Article PubMed CAS Google Scholar
28. Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009;84(3):307–15.
Article CAS PubMed PubMed Central Google Scholar
29. Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FF, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M, et al. Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet. 1995;10(3):325–9.
Article CAS PubMed Google Scholar
30. Briggs MD, Mortier GR, Cole WG, King LM, Golik SS, Bonaventure J, Nuytinck L, De Paepe A, Leroy JG, Biesecker L, et al. Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet. 1998;62(2):311–9.
Article CAS PubMed PubMed Central Google Scholar
31. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.
Article CAS PubMed PubMed Central Google Scholar
32. Wu M, Chen G, Li YP. TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone research. 2016;4:16009.
Article PubMed PubMed Central Google Scholar
33. Zhang HM, Chen H, Liu W, Liu H, Gong J, Wang H, Guo AY. AnimalTFDB: a comprehensive animal transcription factor database. Nucleic Acids Res. 2012;40(Database issue):D144–9.
Article CAS PubMed Google Scholar
34. Saito A, Kanemoto S, Zhang Y, Asada R, Hino K, Imaizumi K. Chondrocyte proliferation regulated by secreted luminal domain of ER stress transducer BBF2H7/CREB3L2. Mol Cell. 2014;53(1):127–39.
Article CAS PubMed Google Scholar
35. Chen Y, Gridley T. Compensatory regulation of the Snai1 and Snai2 genes during chondrogenesis. J Bone Miner Res. 2013;28(6):1412–21.
Article CAS PubMed PubMed Central Google Scholar
36. Levi G, Topilko P, Schneider-Maunoury S, Lasagna M, Mantero S, Cancedda R, Charnay P. Defective bone formation in Krox-20 mutant mice. Development. 1996;122(1):113–20.
CAS PubMed Google Scholar
37. Dimitri P, De Franco E, Habeb AM, Gurbuz F, Moussa K, Taha D, Wales JK, Hogue J, Slavotinek A, Shetty A, et al. An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3). Am J Med Genet A. 2016;170(7):1918–23.
Article CAS PubMed Google Scholar
38. Tourtellotte WG, Milbrandt J. Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. Nat Genet. 1998;20(1):87–91.
Article CAS PubMed Google Scholar
39. Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C, Severac D, Chotard L, Kahli M, Le Digarcher A, et al. Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell. 2006;11(5):711–22.
Article CAS PubMed Google Scholar
40. Han Y, Lefebvre V. L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer. Mol Cell Biol. 2008;28(16):4999–5013.
Article CAS PubMed PubMed Central Google Scholar
41. Lee YH, Saint-Jeannet JP. Sox9 function in craniofacial development and disease. Genesis. 2011;49(4):200–8.
Article CAS PubMed PubMed Central Google Scholar
42. Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002;16(21):2813–28.
Article CAS PubMed PubMed Central Google Scholar
43. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79(6):1111–20.
Article CAS PubMed Google Scholar
44. Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994;372(6506):525–30.
Article CAS PubMed Google Scholar
45. Healy C, Uwanogho D, Sharpe PT. Regulation and role of Sox9 in cartilage formation. Dev Dyn. 1999;215(1):69–78.
Article CAS PubMed Google Scholar
46. Eferl R, Hoebertz A, Schilling AF, Rath M, Karreth F, Kenner L, Amling M, Wagner EF. The Fos-related antigen Fra-1 is an activator of bone matrix formation. EMBO J. 2004;23(14):2789–99.
Article CAS PubMed PubMed Central Google Scholar
47. Tamama K, Barbeau DJ. Early growth response genes signaling supports strong paracrine capability of mesenchymal stem cells. Stem Cells Int. 2012;2012:428403.
Article PubMed PubMed Central CAS Google Scholar
48. Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. 1999;22(1):85–9.
Article CAS PubMed Google Scholar
49. Smallwood A, Ren B. Genome organization and long-range regulation of gene expression by enhancers. Curr Opin Cell Biol. 2013;25(3):387–94.
Article CAS PubMed PubMed Central Google Scholar
50. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna J, Lodato MA, Frampton GM, Sharp PA, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010;107(50):21931–6.
Article CAS PubMed PubMed Central Google Scholar
51. Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011;470(7333):279–83.
Article CAS PubMed Google Scholar
52. Ohba S, He X, Hojo H, McMahon AP. Distinct transcriptional programs underlie Sox9 regulation of the mammalian Chondrocyte. Cell Rep. 2015;12(2):229–43.
Article CAS PubMed PubMed Central Google Scholar
53. Herlofsen SR, Bryne JC, Hoiby T, Wang L, Issner R, Zhang X, Coyne MJ, Boyle P, Gu H, Meza-Zepeda LA, et al. Genome-wide map of quantified epigenetic changes during in vitro chondrogenic differentiation of primary human mesenchymal stem cells. BMC Genomics. 2013;14:105.
Article CAS PubMed PubMed Central Google Scholar
54. Liu CF, Lefebvre V. The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis. Nucleic Acids Res. 2015;43(17):8183–203.
Article CAS PubMed PubMed Central Google Scholar
55. Wang A, Yue F, Li Y, Xie R, Harper T, Patel NA, Muth K, Palmer J, Qiu Y, Wang J, et al. Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates. Cell Stem Cell. 2015;16(4):386–99.
Article CAS PubMed PubMed Central Google Scholar
56. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28(5):495–501.
Article CAS PubMed PubMed Central Google Scholar
57. Meyer MB, Benkusky NA, Pike JW. The RUNX2 cistrome in osteoblasts: characterization, down-regulation following differentiation, and relationship to gene expression. J Biol Chem. 2014;289(23):16016–31.
Article CAS PubMed PubMed Central Google Scholar
58. Mullen AC, Orlando DA, Newman JJ, Loven J, Kumar RM, Bilodeau S, Reddy J, Guenther MG, DeKoter RP, Young RA. Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell. 2011;147(3):565–76.
Article CAS PubMed PubMed Central Google Scholar
59. Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G. Latent enhancers activated by stimulation in differentiated cells. Cell. 2013;152(1–2):157–71.
Article CAS PubMed Google Scholar
60. Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L. Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. EMBO J. 2007;26(5):1292–302.
Article CAS PubMed PubMed Central Google Scholar
61. Huynh NP, Anderson BA, Guilak F, McAlinden A. Emerging roles for long noncoding RNAs in skeletal biology and disease. Connect Tissue Res. 2017;58(1):116–141.
62. Guil S, Esteller M. Cis-acting noncoding RNAs: friends and foes. Nat Struct Mol Biol. 2012;19(11):1068–75.
Article CAS PubMed Google Scholar
63. Engreitz JM, Haines JE, Perez EM, Munson G, Chen J, Kane M, McDonel PE, Guttman M, Lander ES. Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature. 2016;539(7629):452–5.
Article CAS PubMed Google Scholar
64. Verfaillie A, Imrichova H, Atak ZK, Dewaele M, Rambow F, Hulselmans G, Christiaens V, Svetlichnyy D, Luciani F, Van den Mooter L, et al. Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nat Commun. 2015;6:6683.
Article CAS PubMed PubMed Central Google Scholar
65. Day A, Dong J, Funari VA, Harry B, Strom SP, Cohn DH, Nelson SF. Disease gene characterization through large-scale co-expression analysis. PLoS One. 2009;4(12):e8491.
Article PubMed PubMed Central CAS Google Scholar
66. Liang S, Li Y, Be X, Howes S, Liu W. Detecting and profiling tissue-selective genes. Physiol Genomics. 2006;26(2):158–62.
Article CAS PubMed Google Scholar
67. Reginato AM, Olsen BR. The role of structural genes in the pathogenesis of osteoarthritic disorders. Arthritis Res. 2002;4(6):337–45.
Article PubMed PubMed Central Google Scholar
68. Heinonen J, Taipaleenmaki H, Roering P, Takatalo M, Harkness L, Sandholm J, Uusitalo-Jarvinen H, Kassem M, Kiviranta I, Laitala-Leinonen T, et al. Snorc is a novel cartilage specific small membrane proteoglycan expressed in differentiating and articular chondrocytes. Osteoarthr Cartil. 2011;19(8):1026–35.
Article CAS PubMed Google Scholar
69. Hochgreb-Hagele T, Koo DE, Bronner ME. Znf385C mediates a novel p53-dependent transcriptional switch to control timing of facial bone formation. Dev Biol. 2015;400(1):23–32.
Article CAS PubMed Google Scholar
70. Birnbaum RY, Clowney EJ, Agamy O, Kim MJ, Zhao J, Yamanaka T, Pappalardo Z, Clarke SL, Wenger AM, Nguyen L, et al. Coding exons function as tissue-specific enhancers of nearby genes. Genome Res. 2012;22(6):1059–68.
Article CAS PubMed PubMed Central Google Scholar
71. Yang L, Lawson KA, Teteak CJ, Zou J, Hacquebord J, Patterson D, Ghatan AC, Mei Q, Zielinska-Kwiatkowska A, Bain SD, et al. ESET histone methyltransferase is essential to hypertrophic differentiation of growth plate chondrocytes and formation of epiphyseal plates. Dev Biol. 2013;380(1):99–110.
Article CAS PubMed Google Scholar
72. Velagaleti GV, Bien-Willner GA, Northup JK, Lockhart LH, Hawkins JC, Jalal SM, Withers M, Lupski JR, Stankiewicz P. Position effects due to chromosome breakpoints that map approximately 900 kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet. 2005;76(4):652–62.
Article CAS PubMed PubMed Central Google Scholar
73. Leipoldt M, Erdel M, Bien-Willner GA, Smyk M, Theurl M, Yatsenko SA, Lupski JR, Lane AH, Shanske AL, Stankiewicz P, et al. Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia. Clin Genet. 2007;71(1):67–75.
Article CAS PubMed Google Scholar
74. Yao B, Wang Q, Liu CF, Bhattaram P, Li W, Mead TJ, Crish JF, Lefebvre V. The SOX9 upstream region prone to chromosomal aberrations causing campomelic dysplasia contains multiple cartilage enhancers. Nucleic Acids Res. 2015;43(11):5394–408.
Article CAS PubMed PubMed Central Google Scholar
75. Guttman M, Rinn JL. Modular regulatory principles of large non-coding RNAs. Nature. 2012;482(7385):339–46.
Article CAS PubMed PubMed Central Google Scholar
76. Huang M, Hou J, Wang Y, Xie M, Wei C, Nie F, Wang Z, Sun M. Long noncoding RNA LINC00673 is activated by SP1 and exerts Oncogenic properties by interacting with LSD1 and EZH2 in gastric cancer. Mol Ther. 2017;
77. Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mech Dev. 2000;95(1–2):163–74.
Article CAS PubMed Google Scholar
78. Lettice LA, Purdie LA, Carlson GJ, Kilanowski F, Dorin J, Hill RE. The mouse bagpipe gene controls development of axial skeleton, skull, and spleen. Proc Natl Acad Sci U S A. 1999;96(17):9695–700.
Article CAS PubMed PubMed Central Google Scholar
79. Tribioli C, Lufkin T. The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development. 1999;126(24):5699–711.
CAS PubMed Google Scholar
80. Akazawa H, Komuro I, Sugitani Y, Yazaki Y, Nagai R, Noda T. Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation. Genes to cells: devoted to molecular & cellular mechanisms. 2000;5(6):499–513.
Article CAS Google Scholar
81. Herbrand H, Pabst O, Hill R, Arnold HH. Transcription factors Nkx3.1 and Nkx3.2 (Bapx1) play an overlapping role in sclerotomal development of the mouse. Mech Dev. 2002;117(1–2):217–24.
Article CAS PubMed Google Scholar
82. Nakamura Y, Weidinger G, Liang JO, Aquilina-Beck A, Tamai K, Moon RT, Warman ML. The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling. J Clin Invest. 2007;117(10):3075–86.
Article CAS PubMed PubMed Central Google Scholar
83. Kutz WE, Gong Y, Warman ML. WISP3, the gene responsible for the human skeletal disease progressive pseudorheumatoid dysplasia, is not essential for skeletal function in mice. Mol Cell Biol. 2005;25(1):414–21.
Article CAS PubMed PubMed Central Google Scholar
84. Halasz K, Kassner A, Morgelin M, Heinegard D. COMP acts as a catalyst in collagen fibrillogenesis. J Biol Chem. 2007;282(43):31166–73.
Article CAS PubMed Google Scholar
85. Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES, et al. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet. 1995;10(3):330–6.
Article CAS PubMed Google Scholar
86. Svensson L, Aszodi A, Heinegard D, Hunziker EB, Reinholt FP, Fassler R, Oldberg A. Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. Mol Cell Biol. 2002;22(12):4366–71.
Article CAS PubMed PubMed Central Google Scholar
87. Pirog-Garcia KA, Meadows RS, Knowles L, Heinegard D, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet. 2007;16(17):2072–88.
Article CAS PubMed PubMed Central Google Scholar
88. Suleman F, Gualeni B, Gregson HJ, Leighton MP, Pirog KA, Edwards S, Holden P, Boot-Handford RP, Briggs MD. A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Hum Mutat. 2012;33(1):218–31.
Article CAS PubMed Google Scholar
89. Camacho N, Krakow D, Johnykutty S, Katzman PJ, Pepkowitz S, Vriens J, Nilius B, Boyce BF, Cohn DH. Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am J Med Genet A. 2010;152A(5):1169–77.
Article CAS PubMed Google Scholar
90. Nishimura G, Dai J, Lausch E, Unger S, Megarbane A, Kitoh H, Kim OH, Cho TJ, Bedeschi F, Benedicenti F, et al. Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am J Med Genet A. 2010;152a(6):1443–9.
PubMed Google Scholar
91. Lamande SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, Little CB, Botzenhart E, Zerres K, Amor DJ, et al. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet. 2011;43(11):1142–6.
Article CAS PubMed Google Scholar
92. Tabuchi K, Suzuki M, Mizuno A, Hara A. Hearing impairment in TRPV4 knockout mice. Neurosci Lett. 2005;382(3):304–8.
Article CAS PubMed Google Scholar
93. Weinstein MM, Tompson SW, Chen Y, Lee B, Cohn DH. Mice expressing mutant Trpv4 recapitulate the human TRPV4 disorders. J Bone Miner Res. 2014;29(8):1815–22.
Article CAS PubMed PubMed Central Google Scholar
94. Lefebvre V, Li P, de Crombrugghe B. A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J. 1998;17(19):5718–33.
Article CAS PubMed PubMed Central Google Scholar
95. de Frutos CA, Vega S, Manzanares M, Flores JM, Huertas H, Martinez-Frias ML, Nieto MA. Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. Dev Cell. 2007;13(6):872–83.
Article CAS PubMed Google Scholar
96. Krakow D, Sebald ET, Pogue R, Rimoin LP, King L, Cohn DH. Analysis of clones from a human cartilage cDNA library provides insight into chondrocyte gene expression and identifies novel candidate genes for the osteochondrodysplasias. Mol Genet Metab. 2003;79(1):34–42.
Article CAS PubMed Google Scholar
97. Marques F, Tenney J, Duran I, Martin J, Nevarez L, Pogue R, Krakow D, Cohn DH, Li B. Altered mRNA splicing, Chondrocyte gene expression and abnormal skeletal development due to SF3B4 mutations in Rodriguez Acrofacial Dysostosis. PLoS Genet. 2016;12(9):e1006307.
Article PubMed PubMed Central CAS Google Scholar
98. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009;25(9):1105–11.
Article CAS PubMed PubMed Central Google Scholar
99. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, Salzberg SL, Wold BJ, Pachter L. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28(5):511–5.
Article CAS PubMed PubMed Central Google Scholar
100. Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, Aken BL, Barrell D, Zadissa A, Searle S, et al. GENCODE: the reference human genome annotation for the ENCODE project. Genome Res. 2012;22(9):1760–74.
Article CAS PubMed PubMed Central Google Scholar
101. Pan JB, Hu SC, Wang H, Zou Q, Ji ZL. PaGeFinder: quantitative identification of spatiotemporal pattern genes. Bioinformatics. 2012;28(11):1544–5.
Article CAS PubMed PubMed Central Google Scholar
102. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):R137.
Article PubMed PubMed Central CAS Google Scholar
103. da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.
Article PubMed CAS Google Scholar
104. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25(8):1091–3.
Article CAS PubMed PubMed Central Google Scholar
105. Mostafavi S, Ray D, Warde-Farley D, Grouios C, Morris Q. GeneMANIA: a real-time multiple association network integration algorithm for predicting gene function. Genome Biol. 2008;9(Suppl 1):S4.
Article PubMed PubMed Central CAS Google Scholar
106. Liu T, Ortiz JA, Taing L, Meyer CA, Lee B, Zhang Y, Shin H, Wong SS, Ma J, Lei Y, et al. Cistrome: an integrative platform for transcriptional regulation studies. Genome Biol. 2011;12(8):R83.
Article CAS PubMed PubMed Central Google Scholar
107. Nicol JW, Helt GA, Blanchard SG Jr, Raja A, Loraine AE. The integrated genome browser: free software for distribution and exploration of genome-scale datasets. Bioinformatics. 2009;25(20):2730–1.
Article CAS PubMed PubMed Central Google Scholar
Download references
Acknowledgements
We thank Min Chen, Jer-Young Lin and Bob Goldberg (UCLA) for their assistance with the RNA-seq experiment.
Funding
This study was supported in part by NIH grants RO1AR062651 and RO1AR066124.
Availability of data and materials
The RNA-seq data sets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession GSE107649.
Author information
Authors and Affiliations
Authors
Contributions
BL performed most of the experiments and analyses including data generation, computational analysis, methodological application and writing the original draft; KB participated in data generation, as well as review and editing of the manuscript; DK participated in conceptualizing the project, supervising the work, and reviewing and editing of the manuscript; DHC participated in conceptualizing the project, supervising the work, and reviewing and editing of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Correspondence to Daniel H. Cohn.
Ethics declarations
Ethics approval and consent to participate
Under a UCLA IRB-approved human subjects protocol, five independent 14-18 week distal human femur growth plate cartilage samples were obtained with informed consent. (Protocol ID: IRB#14-000177).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional files
Additional file 1:
Supplementary Dataset S1. Data used in the study. (XLSX 17 kb)
Additional file 2: Figure S1.
Dendrogram and heatmap of the Pearson’s correlation coefficient for human tissue gene expression (Log2FPKM). Only genes with FPKM > 1 in at least one sample were used for analysis. The cartilage samples are highlighted with a red frame. Figure S2. Box plots showing cartilage-selective gene expression in cartilage (red) and non-cartilage (blue) tissues. The thick horizontal line in each box represents the median gene expression value. Figure S3. Bar graph showing RUNX2 expression in human tissues. Red bars indicate cartilage samples and blue bars indicate non-cartilage samples, respectively. Gene expression levels are shown as FPKM values. Figure S4. Genome browser views of H3K4me1 and H3K27ac peaks along a COL2A1 and b COL11A1 loci. Chromosome coordinates are shown as black bars on top. Black arrows indicate the direction of transcription on a diagram of each gene below. CH, chondrocytes. AG, adrenal gland. LI, large intestine. SI, small intestine. MU, muscle. SC, spinal cord. ST, stomach. TH, thymus. Figure S5. Genome browser views of H3K4me1, H3K4me3, H3K27ac peaks and RNA expression track along lncRNA loci (A) AC058791.1 and (B) RP11–261P24.2 in human chondrocytes. Figure S6. Sox9 binds to the lncRNA 2610035D17Rik promoter and gene body in mouse rib chondrocytes. a Genome browser view of Sox9 binding along Sox9 and 2610035D17Rik loci on chromosome 11. b Shaded region in a was enlarged for a close view of Sox9 binding at the 2610035D17Rik promoter and first intron. (PDF 912 kb)
Additional file 3:
Supplementary Dataset S2. Cartilage-selective genes. (XLSX 45110 kb)
Additional file 4:
Supplementary Dataset S3. Data comparison between microarray and RNA-seq platforms. (XLSX 8 kb)
Additional file 5:
Supplementary Dataset S4. Cartilage-selective transcription factors and motif analysis. (XLSX 26 kb)
Additional file 6:
Supplementary Dataset S5. GO analysis of cartilage-unique enhancers. (XLSX 1028 kb)
Additional file 7:
Supplementary Dataset S6. Cartilage selective lncRNAs. (XLSX 17845 kb)
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Reprints and Permissions
About this article
Verify currency and authenticity via CrossMark
Cite this article
Li, B., Balasubramanian, K., Krakow, D. et al. Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network. BMC Genomics 18, 983 (2017). https://doi.org/10.1186/s12864-017-4378-y
Download citation
• Received:
• Accepted:
• Published:
• DOI: https://doi.org/10.1186/s12864-017-4378-y
Keywords
• Cartilage
• Chondrocyte
• RNA-seq
• lncRNA
• Skeletal dysplasia
• Gene expression
• Human | {
"url": "https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4378-y",
"source_domain": "bmcgenomics.biomedcentral.com",
"snapshot_id": "CC-MAIN-2023-06",
"warc_metadata": {
"Content-Length": "570158",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:QL6OYWCQASQVR4QODM6YTFPKGVP66JQ3",
"WARC-Concurrent-To": "<urn:uuid:fb2d2c24-fd65-4f04-b8c4-6994d249dfd5>",
"WARC-Date": "2023-01-29T16:23:24",
"WARC-IP-Address": "146.75.32.95",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:7C2MXQJ63VDIDIS7YLKVW4AJYTDJDPAR",
"WARC-Record-ID": "<urn:uuid:fee0d2b6-de26-4d5e-abfd-d21539da27fc>",
"WARC-Target-URI": "https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4378-y",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:1bfa81a9-4566-41ff-b474-6b1dfb3ad508>"
},
"warc_info": "isPartOf: CC-MAIN-2023-06\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for January/February 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-47\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
21,
22,
120,
121,
130,
131,
142,
143,
615,
616,
624,
625,
1401,
1402,
1414,
1415,
1740,
1741,
1752,
1753,
3334,
3335,
4629,
4630,
5891,
5892,
5900,
5901,
5975,
5976,
7270,
7271,
9013,
9014,
9453,
9454,
9461,
9470,
9471,
9775,
9776,
9840,
9841,
11847,
11848,
11891,
11892,
12675,
12676,
12683,
12692,
12693,
12840,
12841,
12897,
12898,
14369,
14370,
14377,
14386,
14387,
14844,
14845,
16290,
16291,
16298,
16307,
16308,
16606,
16607,
16667,
16668,
18548,
18549,
18556,
18565,
18566,
19160,
19161,
19168,
19177,
19178,
19471,
19472,
20113,
20114,
20160,
20161,
21922,
21923,
21930,
21939,
21940,
22962,
22963,
24336,
24337,
25170,
25171,
25182,
25183,
26005,
26006,
26066,
26067,
29187,
29188,
29242,
29243,
30743,
30744,
30771,
30772,
32709,
32710,
32757,
32758,
35507,
35508,
35542,
35543,
36754,
36755,
36767,
36768,
37618,
37619,
37627,
37628,
37676,
37677,
38366,
38367,
38392,
38393,
39428,
39429,
39478,
39479,
40516,
40517,
40539,
40540,
41233,
41234,
41259,
41260,
41638,
41639,
41670,
41671,
42026,
42027,
42067,
42068,
42524,
42525,
42540,
42541,
42716,
42717,
42751,
42752,
42886,
42887,
42898,
42899,
43145,
43146,
43199,
43200,
43396,
43397,
43455,
43456,
43563,
43564,
43606,
43607,
43799,
43800,
43858,
43859,
44107,
44108,
44150,
44151,
44227,
44228,
44281,
44282,
44488,
44489,
44547,
44548,
44773,
44774,
44816,
44817,
44962,
44963,
45016,
45017,
45291,
45292,
45350,
45351,
45501,
45502,
45544,
45545,
45722,
45723,
45781,
45782,
46022,
46023,
46081,
46082,
46310,
46311,
46369,
46370,
46653,
46654,
46712,
46713,
46833,
46834,
46892,
46893,
47067,
47068,
47126,
47127,
47306,
47307,
47349,
47350,
47535,
47536,
47594,
47595,
47818,
47819,
47853,
47854,
48079,
48080,
48138,
48139,
48407,
48408,
48450,
48451,
48645,
48646,
48680,
48681,
48849,
48850,
48908,
48909,
49131,
49132,
49174,
49175,
49482,
49483,
49525,
49526,
49811,
49812,
49854,
49855,
50156,
50157,
50215,
50216,
50463,
50464,
50506,
50507,
50813,
50814,
50872,
50873,
51101,
51102,
51160,
51161,
51326,
51327,
51380,
51381,
51560,
51561,
51603,
51604,
51801,
51802,
51844,
51845,
51984,
51985,
52043,
52044,
52218,
52219,
52252,
52253,
52509,
52510,
52552,
52553,
52708,
52709,
52751,
52752,
53006,
53007,
53049,
53050,
53236,
53237,
53295,
53296,
53410,
53411,
53469,
53470,
53736,
53737,
53795,
53796,
54051,
54052,
54094,
54095,
54359,
54360,
54402,
54403,
54521,
54522,
54564,
54565,
54757,
54758,
54816,
54817,
54981,
54982,
55040,
55041,
55173,
55174,
55216,
55217,
55362,
55363,
55421,
55422,
55685,
55686,
55744,
55745,
55932,
55933,
55975,
55976,
56134,
56135,
56193,
56194,
56470,
56471,
56529,
56530,
56713,
56714,
56772,
56773,
57018,
57019,
57077,
57078,
57274,
57275,
57333,
57334,
57541,
57542,
57600,
57601,
57833,
57834,
57892,
57893,
58111,
58112,
58154,
58155,
58406,
58407,
58465,
58466,
58630,
58631,
58744,
58745,
58787,
58788,
59003,
59004,
59046,
59047,
59317,
59318,
59376,
59377,
59550,
59551,
59609,
59610,
59738,
59739,
59781,
59782,
59922,
59923,
59976,
59977,
60290,
60291,
60333,
60334,
60514,
60515,
60557,
60558,
60779,
60780,
60838,
60839,
61139,
61140,
61182,
61183,
61513,
61514,
61572,
61573,
61878,
61879,
61921,
61922,
62168,
62169,
62227,
62228,
62341,
62342,
62400,
62401,
62617,
62618,
62861,
62862,
62904,
62905,
63108,
63109,
63167,
63168,
63344,
63345,
63378,
63379,
63671,
63672,
63706,
63707,
63899,
63900,
63942,
63943,
64179,
64180,
64238,
64239,
64454,
64455,
64513,
64514,
64655,
64656,
64698,
64699,
64976,
64977,
65019,
65020,
65230,
65231,
65289,
65290,
65636,
65637,
65695,
65696,
65936,
65937,
65979,
65980,
66196,
66197,
66239,
66240,
66536,
66537,
66565,
66566,
66797,
66798,
66840,
66841,
66963,
66964,
67006,
67007,
67170,
67171,
67229,
67230,
67437,
67438,
67496,
67497,
67718,
67719,
67761,
67762,
68035,
68036,
68078,
68079,
68347,
68348,
68406,
68407,
68536,
68537,
68595,
68596,
68872,
68873,
68931,
68932,
69163,
69164,
69222,
69223,
69376,
69377,
69435,
69436,
69621,
69622,
69680,
69681,
69848,
69849,
69891,
69892,
70157,
70158,
70216,
70217,
70418,
70419,
70477,
70478,
70677,
70678,
70736,
70737,
70940,
70941,
70999,
71000,
71020,
71021,
71038,
71039,
71146,
71147,
71155,
71156,
71232,
71233,
71268,
71269,
71399,
71400,
71419,
71420,
71445,
71446,
71454,
71455,
71469,
71470,
71998,
71999,
72020,
72021,
72055,
72056,
72076,
72077,
72120,
72121,
72317,
72318,
72342,
72343,
72358,
72359,
72379,
72380,
72439,
72440,
72457,
72458,
72577,
72578,
72595,
72596,
72615,
72616,
72679,
72680,
72710,
72711,
74216,
74217,
74236,
74237,
74306,
74307,
74326,
74327,
74423,
74424,
74443,
74444,
74545,
74546,
74565,
74566,
74650,
74651,
74670,
74671,
74742,
74743,
74766,
74767,
75354,
75355,
75380,
75381,
75400,
75401,
75448,
75449,
75467,
75468,
75685,
75686,
75704,
75705,
75719,
75720,
75734,
75735,
75750,
75751,
75802,
75803,
75812,
75813,
75827,
75843,
75855,
75866,
75889,
75909
],
"line_end_idx": [
21,
22,
120,
121,
130,
131,
142,
143,
615,
616,
624,
625,
1401,
1402,
1414,
1415,
1740,
1741,
1752,
1753,
3334,
3335,
4629,
4630,
5891,
5892,
5900,
5901,
5975,
5976,
7270,
7271,
9013,
9014,
9453,
9454,
9461,
9470,
9471,
9775,
9776,
9840,
9841,
11847,
11848,
11891,
11892,
12675,
12676,
12683,
12692,
12693,
12840,
12841,
12897,
12898,
14369,
14370,
14377,
14386,
14387,
14844,
14845,
16290,
16291,
16298,
16307,
16308,
16606,
16607,
16667,
16668,
18548,
18549,
18556,
18565,
18566,
19160,
19161,
19168,
19177,
19178,
19471,
19472,
20113,
20114,
20160,
20161,
21922,
21923,
21930,
21939,
21940,
22962,
22963,
24336,
24337,
25170,
25171,
25182,
25183,
26005,
26006,
26066,
26067,
29187,
29188,
29242,
29243,
30743,
30744,
30771,
30772,
32709,
32710,
32757,
32758,
35507,
35508,
35542,
35543,
36754,
36755,
36767,
36768,
37618,
37619,
37627,
37628,
37676,
37677,
38366,
38367,
38392,
38393,
39428,
39429,
39478,
39479,
40516,
40517,
40539,
40540,
41233,
41234,
41259,
41260,
41638,
41639,
41670,
41671,
42026,
42027,
42067,
42068,
42524,
42525,
42540,
42541,
42716,
42717,
42751,
42752,
42886,
42887,
42898,
42899,
43145,
43146,
43199,
43200,
43396,
43397,
43455,
43456,
43563,
43564,
43606,
43607,
43799,
43800,
43858,
43859,
44107,
44108,
44150,
44151,
44227,
44228,
44281,
44282,
44488,
44489,
44547,
44548,
44773,
44774,
44816,
44817,
44962,
44963,
45016,
45017,
45291,
45292,
45350,
45351,
45501,
45502,
45544,
45545,
45722,
45723,
45781,
45782,
46022,
46023,
46081,
46082,
46310,
46311,
46369,
46370,
46653,
46654,
46712,
46713,
46833,
46834,
46892,
46893,
47067,
47068,
47126,
47127,
47306,
47307,
47349,
47350,
47535,
47536,
47594,
47595,
47818,
47819,
47853,
47854,
48079,
48080,
48138,
48139,
48407,
48408,
48450,
48451,
48645,
48646,
48680,
48681,
48849,
48850,
48908,
48909,
49131,
49132,
49174,
49175,
49482,
49483,
49525,
49526,
49811,
49812,
49854,
49855,
50156,
50157,
50215,
50216,
50463,
50464,
50506,
50507,
50813,
50814,
50872,
50873,
51101,
51102,
51160,
51161,
51326,
51327,
51380,
51381,
51560,
51561,
51603,
51604,
51801,
51802,
51844,
51845,
51984,
51985,
52043,
52044,
52218,
52219,
52252,
52253,
52509,
52510,
52552,
52553,
52708,
52709,
52751,
52752,
53006,
53007,
53049,
53050,
53236,
53237,
53295,
53296,
53410,
53411,
53469,
53470,
53736,
53737,
53795,
53796,
54051,
54052,
54094,
54095,
54359,
54360,
54402,
54403,
54521,
54522,
54564,
54565,
54757,
54758,
54816,
54817,
54981,
54982,
55040,
55041,
55173,
55174,
55216,
55217,
55362,
55363,
55421,
55422,
55685,
55686,
55744,
55745,
55932,
55933,
55975,
55976,
56134,
56135,
56193,
56194,
56470,
56471,
56529,
56530,
56713,
56714,
56772,
56773,
57018,
57019,
57077,
57078,
57274,
57275,
57333,
57334,
57541,
57542,
57600,
57601,
57833,
57834,
57892,
57893,
58111,
58112,
58154,
58155,
58406,
58407,
58465,
58466,
58630,
58631,
58744,
58745,
58787,
58788,
59003,
59004,
59046,
59047,
59317,
59318,
59376,
59377,
59550,
59551,
59609,
59610,
59738,
59739,
59781,
59782,
59922,
59923,
59976,
59977,
60290,
60291,
60333,
60334,
60514,
60515,
60557,
60558,
60779,
60780,
60838,
60839,
61139,
61140,
61182,
61183,
61513,
61514,
61572,
61573,
61878,
61879,
61921,
61922,
62168,
62169,
62227,
62228,
62341,
62342,
62400,
62401,
62617,
62618,
62861,
62862,
62904,
62905,
63108,
63109,
63167,
63168,
63344,
63345,
63378,
63379,
63671,
63672,
63706,
63707,
63899,
63900,
63942,
63943,
64179,
64180,
64238,
64239,
64454,
64455,
64513,
64514,
64655,
64656,
64698,
64699,
64976,
64977,
65019,
65020,
65230,
65231,
65289,
65290,
65636,
65637,
65695,
65696,
65936,
65937,
65979,
65980,
66196,
66197,
66239,
66240,
66536,
66537,
66565,
66566,
66797,
66798,
66840,
66841,
66963,
66964,
67006,
67007,
67170,
67171,
67229,
67230,
67437,
67438,
67496,
67497,
67718,
67719,
67761,
67762,
68035,
68036,
68078,
68079,
68347,
68348,
68406,
68407,
68536,
68537,
68595,
68596,
68872,
68873,
68931,
68932,
69163,
69164,
69222,
69223,
69376,
69377,
69435,
69436,
69621,
69622,
69680,
69681,
69848,
69849,
69891,
69892,
70157,
70158,
70216,
70217,
70418,
70419,
70477,
70478,
70677,
70678,
70736,
70737,
70940,
70941,
70999,
71000,
71020,
71021,
71038,
71039,
71146,
71147,
71155,
71156,
71232,
71233,
71268,
71269,
71399,
71400,
71419,
71420,
71445,
71446,
71454,
71455,
71469,
71470,
71998,
71999,
72020,
72021,
72055,
72056,
72076,
72077,
72120,
72121,
72317,
72318,
72342,
72343,
72358,
72359,
72379,
72380,
72439,
72440,
72457,
72458,
72577,
72578,
72595,
72596,
72615,
72616,
72679,
72680,
72710,
72711,
74216,
74217,
74236,
74237,
74306,
74307,
74326,
74327,
74423,
74424,
74443,
74444,
74545,
74546,
74565,
74566,
74650,
74651,
74670,
74671,
74742,
74743,
74766,
74767,
75354,
75355,
75380,
75381,
75400,
75401,
75448,
75449,
75467,
75468,
75685,
75686,
75704,
75705,
75719,
75720,
75734,
75735,
75750,
75751,
75802,
75803,
75812,
75813,
75827,
75843,
75855,
75866,
75889,
75909,
75918
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 75918,
"ccnet_original_nlines": 699,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 2,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.18776096403598785,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.09261413663625717,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.27503594756126404,
"rps_doc_frac_unique_words": 0.252554327249527,
"rps_doc_mean_word_length": 5.621865272521973,
"rps_doc_num_sentences": 943,
"rps_doc_symbol_to_word_ratio": 0.00006844999734312296,
"rps_doc_unigram_entropy": 6.591824531555176,
"rps_doc_word_count": 10766,
"rps_doc_frac_chars_dupe_10grams": 0.030367620289325714,
"rps_doc_frac_chars_dupe_5grams": 0.14174307882785797,
"rps_doc_frac_chars_dupe_6grams": 0.08634448796510696,
"rps_doc_frac_chars_dupe_7grams": 0.07679470628499985,
"rps_doc_frac_chars_dupe_8grams": 0.033804211765527725,
"rps_doc_frac_chars_dupe_9grams": 0.033804211765527725,
"rps_doc_frac_chars_top_2gram": 0.02255265973508358,
"rps_doc_frac_chars_top_3gram": 0.021676989272236824,
"rps_doc_frac_chars_top_4gram": 0.02147872932255268,
"rps_doc_books_importance": -5175.59619140625,
"rps_doc_books_importance_length_correction": -5175.59619140625,
"rps_doc_openwebtext_importance": -2634.881103515625,
"rps_doc_openwebtext_importance_length_correction": -2634.881103515625,
"rps_doc_wikipedia_importance": -1208.043212890625,
"rps_doc_wikipedia_importance_length_correction": -1208.043212890625
},
"fasttext": {
"dclm": 0.09924154728651047,
"english": 0.8209125995635986,
"fineweb_edu_approx": 2.665654182434082,
"eai_general_math": 0.1077728271484375,
"eai_open_web_math": 0.3509368300437927,
"eai_web_code": 0.027449609711766243
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "572.888",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Biology and Anthropology",
"level_3": "Anthropology"
}
},
"secondary": {
"code": "612.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Physiology"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
370,744,720,157,876,900 | • Large Print
Add To Favorites In PHR
Adenomatous Polyps
Adenomatous Polyps
Adenomatous polyps are a type of abnormal growth in the colon. While most colon polyps do not cause any problems, adenomatous polyps are thought to be the source of most colorectal cancer.
Adenomatous polyps usually grow very slowly. It may be years before they turn into cancer, if they ever do. They usually are discovered during a routine sigmoidoscopy or colonoscopy and are removed. Having adenomatous polyps in the colon means that you will need to be screened for colorectal cancer more often than a person who has no polyps.
Processing...
Driving Walking/Biking Public Transit Get Directions | {
"url": "http://mahoning.oh.networkofcare.org/ph/library/article.aspx?hwid=zx1061",
"source_domain": "mahoning.oh.networkofcare.org",
"snapshot_id": "crawl=CC-MAIN-2019-26",
"warc_metadata": {
"Content-Length": "23604",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:77K5FQJCOGZ2T6WN6O7ITY7TEXOTMEAY",
"WARC-Concurrent-To": "<urn:uuid:b7a9b831-6c7b-4e62-a8b3-7bea7d7f0804>",
"WARC-Date": "2019-06-25T09:25:38",
"WARC-IP-Address": "72.5.171.242",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:ULALU3E653TGDIEHXAORBEG5TY36EFYJ",
"WARC-Record-ID": "<urn:uuid:5fe2c4c5-16a2-40cb-870a-9cc9e41544a4>",
"WARC-Target-URI": "http://mahoning.oh.networkofcare.org/ph/library/article.aspx?hwid=zx1061",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:b6dd2e51-8871-4a54-8883-ef5668ab5732>"
},
"warc_info": "isPartOf: CC-MAIN-2019-26\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for June 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-63-23-226.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
16,
17,
41,
42,
61,
62,
81,
82,
271,
272,
616,
617,
619,
633,
634,
635
],
"line_end_idx": [
16,
17,
41,
42,
61,
62,
81,
82,
271,
272,
616,
617,
619,
633,
634,
635,
688
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 688,
"ccnet_original_nlines": 16,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4166666567325592,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.008333330042660236,
"rps_doc_frac_lines_end_with_ellipsis": 0.05882352963089943,
"rps_doc_frac_no_alph_words": 0.09166666865348816,
"rps_doc_frac_unique_words": 0.6697247624397278,
"rps_doc_mean_word_length": 5.091742992401123,
"rps_doc_num_sentences": 8,
"rps_doc_symbol_to_word_ratio": 0.008333330042660236,
"rps_doc_unigram_entropy": 4.083738327026367,
"rps_doc_word_count": 109,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.18378378450870514,
"rps_doc_frac_chars_top_3gram": 0.10090090334415436,
"rps_doc_frac_chars_top_4gram": 0.1225225180387497,
"rps_doc_books_importance": -46.81242752075195,
"rps_doc_books_importance_length_correction": -50.60765838623047,
"rps_doc_openwebtext_importance": -21.265762329101562,
"rps_doc_openwebtext_importance_length_correction": -25.060991287231445,
"rps_doc_wikipedia_importance": -17.39866065979004,
"rps_doc_wikipedia_importance_length_correction": -21.193889617919922
},
"fasttext": {
"dclm": 0.24463117122650146,
"english": 0.9151318669319153,
"fineweb_edu_approx": 3.1240715980529785,
"eai_general_math": 0.0008152099908329546,
"eai_open_web_math": 0.5275396108627319,
"eai_web_code": 0.00016837999282870442
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.22",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "1",
"label": "About (Org.)"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
2,307,668,854,401,913,300 | Essential Elements for Health
English: Healthy nutrition pyramid with 7 to 9...
English: Healthy nutrition pyramid with 7 to 9 servings of fruits and vegetables to get precious phytonutrients to feed your body at the cellular level. (Photo credit: Wikipedia)
Essential elements for healthy body
Even though the subject matter of this series is juice diet, it is essential to discuss certain essential elements which are themselves the main body building blocks necessary for good health.
We consume food to keep our body active and healthy. One thing we ought to realize is that man can select proper diet only when he knows what constituents of food are necessary for healthy body. Then one should eat only that food, the constituents of which are congenial to one.
These constituents should rejuvenate the body besides maintaining health. Diseases are caused because of deficiencies of some of these essential constituents. If we know this, we shall never eat dispensable food.
We need to cultivate this kind of understanding of and view-point on the system and substance of diet.
With a view to making our lives happy, with healthy and active body, our daily diet should normally consist of the following constituents:
1. Carbohydrates : The most important function of the carbohydrates is to provide fuel and energy to the body. The carbohydrates include sugar and starch. This constituent of food is available from all kinds of food grains (cereals). Flour devoid of husk, polished rice, white sugar etc., retain their carbohydrates but loose most of the vitamins and minerals. Processed carbohydrates (if taken in excess) reduce the power of digestion and place unnecessary pressure on other organs of the body. Therefore we should try to reduce from our diet the quantum of processed food except few substances containing natural carbohydrates.
2. Fat : Fat provides heat to the body. Vegetable fats (oil seeds, edible oil) are preferable, because they are better digested and comparatively harmless, in comparison to animal fats (milk, meat, etc). Animal fats have saturated fatty acids cause accumulation of bad cholesterol in the arteries, narrowing the path of blood. In such situation diseases like high blood pressure and heart disease can occur. You are therefore advised to take food with less fats or food prepared with vegetable oils containing unsaturated fats.
3. Protein : Proteins are necessary for the growth, development and reconstruction of the body. It is therefore of great importance in our diet. Several types of amino acids constitute proteins. It is worth noting that our bodies produce some amino acids, while the rest are obtained from food.
4. Vitamins : Vitamins are organic chemical substances required in the body for the process of metabolism. Our bodies are not capable of producing these substances. Vitamins are named by coded letters like Vitamin ‘A’, Vitamin ‘B’, and so on. Description and use is better obtained from your physician.
5. Minerals : A mineral, according to Cyclopaedia Medical dictionary, is a solid inorganic element or compound occurring in nature. Minerals are essential for the formation of cells of the body. They are essential for maintaining optimal health. They play a very important role in the complex processes going on in the body. Again the use of minerals should be advised by your physician. It is especially important ll for the old people (over 50 years) to be particularly careful about minerals.
6. Enzymes : An enzyme is a catalyst produced in the live cells. Enzyme aids chemical changes in the body. In dictionaries, catalyst is described as a substance which causes or assists a chemical change in another substance without itself undergoing any permanent chemical change. Enzymes help in the digestion of foods. Please seek more explanations and advise from your physician.
If you find this article interesting, please donate.
Donations can be made via PayPal using the button below.
[serialposts]
Enhanced by Zemanta
Leave a Reply | {
"url": "http://fancywriter.com/essential-elements-health/",
"source_domain": "fancywriter.com",
"snapshot_id": "crawl=CC-MAIN-2017-26",
"warc_metadata": {
"Content-Length": "56799",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:RIQTR75742TKURPNVE7PSU55BQ5QXLIQ",
"WARC-Concurrent-To": "<urn:uuid:44bc3c9e-1298-4f4d-862d-5f9d127932ea>",
"WARC-Date": "2017-06-26T12:08:46",
"WARC-IP-Address": "199.26.85.247",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:AOXT3VBJBMBLW6U3RISZZMEXWCWGQBJ6",
"WARC-Record-ID": "<urn:uuid:028dec5f-d7ae-4b28-b0a5-befe65b9e10e>",
"WARC-Target-URI": "http://fancywriter.com/essential-elements-health/",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:e0afa523-dca9-4750-ad61-5c27fbbcbffa>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-145-147-87.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2017-26\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for June 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
30,
31,
81,
260,
261,
297,
298,
492,
493,
772,
773,
986,
987,
1090,
1091,
1230,
1231,
1865,
2396,
2693,
2998,
3497,
3883,
3884,
3937,
3938,
3995,
3996,
3998,
3999,
4013,
4033,
4034
],
"line_end_idx": [
30,
31,
81,
260,
261,
297,
298,
492,
493,
772,
773,
986,
987,
1090,
1091,
1230,
1231,
1865,
2396,
2693,
2998,
3497,
3883,
3884,
3937,
3938,
3995,
3996,
3998,
3999,
4013,
4033,
4034,
4047
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4047,
"ccnet_original_nlines": 33,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.39566394686698914,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.004065040033310652,
"rps_doc_frac_lines_end_with_ellipsis": 0.029411759227514267,
"rps_doc_frac_no_alph_words": 0.1436314433813095,
"rps_doc_frac_unique_words": 0.4968847334384918,
"rps_doc_mean_word_length": 5.09190034866333,
"rps_doc_num_sentences": 50,
"rps_doc_symbol_to_word_ratio": 0.001355009968392551,
"rps_doc_unigram_entropy": 5.230085849761963,
"rps_doc_word_count": 642,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.0232487004250288,
"rps_doc_frac_chars_dupe_6grams": 0.0232487004250288,
"rps_doc_frac_chars_dupe_7grams": 0.0232487004250288,
"rps_doc_frac_chars_dupe_8grams": 0.0232487004250288,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.01927194930613041,
"rps_doc_frac_chars_top_3gram": 0.008259410038590431,
"rps_doc_frac_chars_top_4gram": 0.01835424080491066,
"rps_doc_books_importance": -329.5854187011719,
"rps_doc_books_importance_length_correction": -329.5854187011719,
"rps_doc_openwebtext_importance": -185.96665954589844,
"rps_doc_openwebtext_importance_length_correction": -185.96665954589844,
"rps_doc_wikipedia_importance": -127.14906311035156,
"rps_doc_wikipedia_importance_length_correction": -127.14906311035156
},
"fasttext": {
"dclm": 0.07084798812866211,
"english": 0.932440996170044,
"fineweb_edu_approx": 2.9909634590148926,
"eai_general_math": 0.030277790501713753,
"eai_open_web_math": 0.2297755479812622,
"eai_web_code": 0.0005417499924078584
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
1,460,801,453,630,533,400 | Definition
clinical trial
Contributor(s): Corinne Bernstein and Megan Charles
A clinical trial, also known as a clinical research study, is a protocol to evaluate the effects and efficacy of experimental medical treatments or behavioral interventions on health outcomes. This type of study gathers data from volunteer human subjects and is typically funded by a medical institution, university or nonprofit group, or by pharmaceutical companies and government agencies.
A typical scenario for a clinical trial is that a patient who is already ill from a disease agrees to undergo experimental treatment in the hopes a new drug or medical device improves his or her condition.
The purpose of a clinical trial is to determine if a new treatment or test -- or a potential drug or medical device -- works and is safe. A clinical trial can determine which medical approach might work best to treat life-threatening diseases, such as cancer, diabetes, coronary heart disease and HIV/AIDS, along with other equally pernicious and debilitating conditions. Potential treatments include drugs, medical devices, vaccines, blood products or gene therapy.
Why clinical trials are important
Clinical trials are important because they improve medical research in terms of usefulness and safety. They teach investigators what does and does not work when analyzing new ways to detect, diagnose and treat disease.
Clinical research can determine whether a drug under review has the desired effect, how the drug is metabolized, how much of the drug should be administered to a patient and how often it should be administered. A clinical trial can also determine what side effects are associated with the drug; how to best manage these side effects; if the drug has any undesirable interactions with food, drink or other drugs; and how these effects can be avoided.
Regulation of clinical trials
In the United States, strict rules for conducting clinical studies have been put in place by the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Drugs intended for human use are evaluated by the FDA's Center for Drug Evaluation and Research (CDER) to ensure that the drugs marketed in the U.S. are safe and effective.
Potential treatments must meet acceptable safety standards and demonstrate efficacy before being approved. Therefore, these drugs and treatments undergo a series of phase trials to determine whether the product or protocol can offer benefits and to determine any possible side effects.
Other countries regulate clinical trials according to their local laws, although some -- such as the U.K. -- have rules similar to the U.S. In 2017, China announced new regulations that will affect clinical trials and promote innovation in drug research, according to contract research organization Pharmaceutical Product Development.
Clinical trial phases and how they're defined
In the U.S., clinical trials are divided into five stages of research.
Phase 0 -- also referred to as Early Phase I. This phase differs significantly from other phases of clinical trials as it is not a required part of testing for a new drug. However, the purpose of this phase is to expedite the drug approval process.
Phase 0 studies, also known as human micro-dosing studies, use only a small dose of the new drug in fewer than 15 patients over a short period of time. The goal is to determine if the new drug or agent behaves in human subjects as is expected based on preclinical studies.
Smaller doses mean less risk to the patient compared to the human subjects in later phase trials, but it can also mean the patient will not see the same benefits, if any, as those in phase II or phase III. In any of the trial phases, treatment can be halted if the side effects present a danger to the patient.
Clinical trial phases defined
Phase I. Researchers test an experimental drug or treatment with a small group of volunteers, from 15 to 30 patients, to determine the highest dose that can be administered while incurring the fewest side effects. Placebos are not administered during phase I clinical trials, as the goal is to see how the experimental drug interacts with a human subject. If the results look promising, the trial moves to the second phase.
Phase II. During this phase, the experimental drug or treatment is given to a larger group of volunteers, from 25 to 100 patients, to see if it is effective and to further evaluate its safety. While doses of the drug are akin to the levels administered in the first phase of the trial, some phase II participants can be assigned to different treatments groups in which they may receive different treatment protocols. Placebos are not typically used in this phase, either. Again, if the results look promising, the trial will continue to the next phase.
Phase III. Phase III clinical trials compare the safety and effectiveness of the new treatment against the current standard treatment. The experimental study drug or treatment is given to a larger group of volunteers -- 100 or more. Researchers monitor side effects and effectiveness while also comparing the experimental drug to the current standard of treatment.
To do this, researchers often employ a double-blind study approach during which neither the doctors nor the patients know which treatment protocol the patient is receiving -- the new one or the standard one. Human subjects are selected at random and assigned a protocol. The purpose of this kind of study is to eliminate the power of suggestion -- in other words, to eliminate subjective bias from the test results.
Placebos may be used in some phase III studies. If the experimental treatment is found to be effective and can be used safely, it is evaluated and potentially approved for use by the general population.
Phase IV. Once a drug or treatment has been approved for use by the general population, researchers will continue to gather data from the clinical trial participants.
On average, it can take about 10 years for a drug to go from preclinical development to approval in the U.S. The drug development process, from inception to approval, can cost pharmaceutical companies and research firms millions -- and in some cases billions -- of dollars.
Clinical trial vs. clinical study
A clinical study is research conducted with the intent of gaining medical knowledge. Observational and interventional are the two main types of clinical studies. A clinical trial is an interventional study.
In an interventional study, participants are put into groups and receive one or more interventions or treatments, a placebo -- or sugar pill, or no intervention. Participants receive specific treatment according to the research plan or protocol the researchers created.
Human subjects who volunteer to participate in these types of studies may receive diagnostic, therapeutic or other types of interventions. Researchers can then evaluate the effects of the assigned course of treatment on biomedical or health-related factors.
These interventions can include drugs, therapeutic agents, prophylactic agents, diagnostic agents, medical devices, procedures, vaccines and noninvasive approaches, such as modifying diet and exercise.
One example of an interventional study is a randomized control trial (RCT). During a randomized control trial, human subjects are chosen at random to receive an intervention. Generally, participants are arbitrarily placed into one of two groups: the experimental group receiving the intervention that is being tested, and a comparison group, or control group, which is receiving the standard practice of care, a placebo or no intervention at all. The goal of a randomized control trial is to quantitatively measure and compare the results following the interventions.
Observational studies differ from interventional studies in that, while participants may receive diagnostic, therapeutic or other types of interventions, researchers do not assign participants a specific course of treatment. Observational studies look to understand cause-and-effect relationships, drawing inferences from a sample group where variables are not under the control of the researchers.
Eliminating bias in clinical trials
Clinical trials are created to answer specific questions, and they often overlap. For example, a university trial may seek answers on how to detect a particular illness, while a government agency trial about the same illness might seek answers on how to prevent the illness from occurring. A pharmaceutical company's study may seek answers on how to treat the illness, while a medical institution's study might seek answers on how to prevent the illness from reoccurring.
Various strategies help to eliminate bias in clinical trials. One example is the use of comparison groups, in which one group receives the current standard treatment for a condition and another receives an experimental treatment. To eliminate bias, patients are randomly assigned to comparison groups. Additionally, the results of each group can be analyzed side-by-side, and no study participants are left without treatment.
Another way to avoid bias is masking, or blinding, which involves not telling the trial participants which treatment they will receive. Researchers may also be unaware of this information, although it can be made accessible in an emergency.
This was last updated in April 2018
Continue Reading About clinical trial
Dig Deeper on Clinical data analytics software and systems
Join the conversation
1 comment
Send me notifications when other members comment.
Please create a username to comment.
What is the most important aspect of a clinical trial that enables it to advance medical research and drug safety?
Cancel
-ADS BY GOOGLE
File Extensions and File Formats
Powered by:
SearchCompliance
SearchCIO
SearchCloudComputing
SearchMobileComputing
SearchSecurity
SearchStorage
Close | {
"url": "https://searchhealthit.techtarget.com/definition/clinical-trial",
"source_domain": "searchhealthit.techtarget.com",
"snapshot_id": "crawl=CC-MAIN-2019-43",
"warc_metadata": {
"Content-Length": "80891",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:JCARLAVIBLE2ROYCDOX6AX6LNCGJVSRI",
"WARC-Concurrent-To": "<urn:uuid:c98d3637-b4f9-453a-aaea-a7b96c7febab>",
"WARC-Date": "2019-10-22T17:28:52",
"WARC-IP-Address": "206.19.49.153",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:TJHEMGMKVWWUBWNCRAIPVIE7EM7Q6AWK",
"WARC-Record-ID": "<urn:uuid:ca6bb203-43a9-411a-962e-e4287293c5f4>",
"WARC-Target-URI": "https://searchhealthit.techtarget.com/definition/clinical-trial",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:c35496d6-98fe-4214-bb95-425f1436a6b9>"
},
"warc_info": "isPartOf: CC-MAIN-2019-43\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for October 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-28.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
11,
12,
27,
28,
80,
81,
473,
474,
680,
681,
1148,
1149,
1183,
1184,
1403,
1404,
1854,
1855,
1885,
1886,
2236,
2237,
2523,
2524,
2859,
2860,
2906,
2907,
2978,
2979,
3228,
3229,
3502,
3503,
3814,
3815,
3845,
3846,
4270,
4271,
4824,
4825,
5190,
5191,
5607,
5608,
5811,
5812,
5979,
5980,
6254,
6255,
6289,
6290,
6497,
6498,
6768,
6769,
7027,
7028,
7230,
7231,
7799,
7800,
8199,
8200,
8236,
8237,
8709,
8710,
9136,
9137,
9378,
9379,
9415,
9416,
9454,
9455,
9514,
9515,
9537,
9538,
9548,
9549,
9599,
9600,
9637,
9638,
9753,
9760,
9761,
9776,
9777,
9810,
9811,
9823,
9824,
9841,
9842,
9852,
9853,
9874,
9875,
9897,
9898,
9913,
9914,
9928,
9929
],
"line_end_idx": [
11,
12,
27,
28,
80,
81,
473,
474,
680,
681,
1148,
1149,
1183,
1184,
1403,
1404,
1854,
1855,
1885,
1886,
2236,
2237,
2523,
2524,
2859,
2860,
2906,
2907,
2978,
2979,
3228,
3229,
3502,
3503,
3814,
3815,
3845,
3846,
4270,
4271,
4824,
4825,
5190,
5191,
5607,
5608,
5811,
5812,
5979,
5980,
6254,
6255,
6289,
6290,
6497,
6498,
6768,
6769,
7027,
7028,
7230,
7231,
7799,
7800,
8199,
8200,
8236,
8237,
8709,
8710,
9136,
9137,
9378,
9379,
9415,
9416,
9454,
9455,
9514,
9515,
9537,
9538,
9548,
9549,
9599,
9600,
9637,
9638,
9753,
9760,
9761,
9776,
9777,
9810,
9811,
9823,
9824,
9841,
9842,
9852,
9853,
9874,
9875,
9897,
9898,
9913,
9914,
9928,
9929,
9934
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 9934,
"ccnet_original_nlines": 109,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40136054158210754,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.02154194936156273,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.11791382730007172,
"rps_doc_frac_unique_words": 0.31826984882354736,
"rps_doc_mean_word_length": 5.235635757446289,
"rps_doc_num_sentences": 82,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.362316608428955,
"rps_doc_word_count": 1549,
"rps_doc_frac_chars_dupe_10grams": 0.03970406949520111,
"rps_doc_frac_chars_dupe_5grams": 0.061898890882730484,
"rps_doc_frac_chars_dupe_6grams": 0.061898890882730484,
"rps_doc_frac_chars_dupe_7grams": 0.056720100343227386,
"rps_doc_frac_chars_dupe_8grams": 0.03970406949520111,
"rps_doc_frac_chars_dupe_9grams": 0.03970406949520111,
"rps_doc_frac_chars_top_2gram": 0.02083846926689148,
"rps_doc_frac_chars_top_3gram": 0.012083849869668484,
"rps_doc_frac_chars_top_4gram": 0.007891490124166012,
"rps_doc_books_importance": -855.0982666015625,
"rps_doc_books_importance_length_correction": -855.0982666015625,
"rps_doc_openwebtext_importance": -421.7676696777344,
"rps_doc_openwebtext_importance_length_correction": -421.7676696777344,
"rps_doc_wikipedia_importance": -301.6245422363281,
"rps_doc_wikipedia_importance_length_correction": -301.6245422363281
},
"fasttext": {
"dclm": 0.060768719762563705,
"english": 0.9392079710960388,
"fineweb_edu_approx": 2.832740068435669,
"eai_general_math": 0.1329447627067566,
"eai_open_web_math": 0.20871174335479736,
"eai_web_code": 0.0076753501780331135
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "610.73",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": ""
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
6,399,838,715,057,570,000 | top of page
Psychonutrition
"All diseases begin in the gut."
"Let food be thy medicine and medicine by thy food."
"Leave your drugs to the chemist's pot if you can heal the patient with food."
- Hippocrates 460 -370 BC
nutritional support, psychonutrition, mental health matters
Is it enough for modern psychotherapy to deal with just thoughts, emotions and behaviour nowadays? What if our body chemistry played a bigger part in how we think and feel?
A lack of good nutrients from our diet is now being shown to play a huge part in a person's mental health and well-being. Despite having what we might consider a healthy diet, stress is scientifically being proven to have consequences in our ability to absorb as many of the nutrients that we need to sustain optimum health.
I have been studying nutrition for mental health issues for over 8 years, and recommended that people take a look at their diets to support their emotional health.
The lack of nutrients our bodies absorb due to high levels of stress can have devastating long term effects on our nervous system which can lead to unhealthy emotional and mental states such as depression, panic disorder, anxiety disorder, weight gain, brain fog, low mood and mood swings, along with diabetes and auto-immune problems.
Whether you find it hard to believe right now, or not - toxicity, biochemical imbalances, gut dysbiosis, malabsorption, lack of nutrients, all can cause racing thoughts, anxious, depressing and negative beliefs about ourselves which would be considered emotional issues, but sleep disturbances, asthma, skin conditions, allergies and such, considered physical issues, can be symptoms of the above also.
Here’s a helpful link to get you started -
http://www.doctoryourself.com
Dr. Andrew W. Saul has 35 years' experience in natural health education.
Dr Saul is the author of "Doctor Yourself" and "Fire Your Doctor!". He has co-authored 7 books.
Call me on 07971 823033 to see if I can help you with this modern and cutting edge therapy model.
bottom of page | {
"url": "https://www.tanyadransfield.com/psychonutrition",
"source_domain": "www.tanyadransfield.com",
"snapshot_id": "CC-MAIN-2024-33",
"warc_metadata": {
"Content-Length": "582349",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:AHNCWBJQGNNVE3RIHKCYKIRYE5U7YAJL",
"WARC-Concurrent-To": "<urn:uuid:16345e2b-67bc-4983-b93d-feeb247288c8>",
"WARC-Date": "2024-08-03T09:41:24",
"WARC-IP-Address": "34.149.87.45",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:BXHAGFKHWPMM4Z3FV2ULD6C63ATDL5CV",
"WARC-Record-ID": "<urn:uuid:cb1d0dd6-fa14-48ee-a85e-35594a629985>",
"WARC-Target-URI": "https://www.tanyadransfield.com/psychonutrition",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:cd8f73c9-6a84-44c5-9c80-0ed0a155c9df>"
},
"warc_info": "isPartOf: CC-MAIN-2024-33\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-29\r\nsoftware: Apache Nutch 1.20 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
12,
13,
29,
30,
63,
64,
126,
127,
181,
182,
262,
263,
265,
266,
292,
293,
353,
354,
356,
357,
530,
531,
856,
857,
1022,
1023,
1359,
1360,
1763,
1764,
1808,
1809,
1840,
1841,
1914,
1915,
2011,
2012,
2014,
2015,
2017,
2018,
2020,
2021,
2129,
2130
],
"line_end_idx": [
12,
13,
29,
30,
63,
64,
126,
127,
181,
182,
262,
263,
265,
266,
292,
293,
353,
354,
356,
357,
530,
531,
856,
857,
1022,
1023,
1359,
1360,
1763,
1764,
1808,
1809,
1840,
1841,
1914,
1915,
2011,
2012,
2014,
2015,
2017,
2018,
2020,
2021,
2129,
2130,
2144
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2144,
"ccnet_original_nlines": 46,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.37128713726997375,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.012376240454614162,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.17079207301139832,
"rps_doc_frac_unique_words": 0.6216216087341309,
"rps_doc_mean_word_length": 4.930931091308594,
"rps_doc_num_sentences": 19,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.065237998962402,
"rps_doc_word_count": 333,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.02192448079586029,
"rps_doc_frac_chars_top_3gram": 0.018270399421453476,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -180.35455322265625,
"rps_doc_books_importance_length_correction": -180.35455322265625,
"rps_doc_openwebtext_importance": -116.27886199951172,
"rps_doc_openwebtext_importance_length_correction": -116.27886199951172,
"rps_doc_wikipedia_importance": -96.55024719238281,
"rps_doc_wikipedia_importance_length_correction": -96.55024719238281
},
"fasttext": {
"dclm": 0.1883563995361328,
"english": 0.9164590835571289,
"fineweb_edu_approx": 2.7335731983184814,
"eai_general_math": 0.00028032000409439206,
"eai_open_web_math": 0.22886979579925537,
"eai_web_code": 0.4834490418434143
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "6",
"label": "Promotional/Advertisement"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "2",
"label": "Partially Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
6,015,450,125,579,444,000 | Top
10
Doctor insights on: Antibiotics And Trying To Conceive
Share
1
1
Is it okay to take antibiotics while trying to conceive?
Is it okay to take antibiotics while trying to conceive?
Depends.: Some antibiotics (e.g. Doxycycline, levofloxacin) are potentially teratogenic so you should avoid them while trying to conceive - however most antibiotics are safe under your doctor's care. Take Folic Acid 1 mg daily and best of luck! ...Read more
Dr. Serena Chen
1,118 doctors shared insights
Trying To Conceive (Definition)
Trying to conceive means trying to get pregnant. Patients understand that the best to conceive is when the women is in the middle of her cycle day 12 to day 14 (with the first day of your ...Read more
2
2
Vaginal bacterial infection 7 day antibiotics done trying to conceive for two years Could the bacterial infection be the reason i wasn't getting preg?
Vaginal bacterial infection 7 day antibiotics done trying to conceive for two years Could the bacterial infection be the reason i wasn't getting preg?
Infertility: Yes. If the infection was an STD and caused PID or blocked fallopian tubes. But, you will not ever find the cause of your infertility on the internet. There are at least a dozen physical and chemical processes in conception in you and your male partner. All of these need to be studied by a good fertility specialist to determine how to fix you or help you get pregnant in the future. ...Read more
See 1 more doctor answer
3
3
I'm on antibiotics and I'm trying to conceive. Ovulating in few days. Is it safe?
I'm on antibiotics and I'm trying to conceive. Ovulating in few days. Is it safe?
Antibiotic/pregnancy: This depends upon which antibiotic. Penicillins and cephalosporins are likely to be quite safe, but you do not want to be on tetracyclines, fluorinated quinolones, or several other classes of antibiotics. If you are more specific could provide more definitive responses. ...Read more
7
7
Me and my fiancé have been trying to conceive. She had milky white discharge yesterday and vj has been itching all week..? What can that mean.?
May be yeast infect: Her symptoms resemble yeast infection, also called candida and monilia. Is she near her period? Has she been taking antibiotics? Does she have diabetes or high blood glucose ("sugar")? These factors can increase the chance for candida. This infection can improve with over-the-counter vagina creams or tablets. If no improvement, then see the medical provider. Hope that helps ...Read more
8
8
Does rephresh gel mask or treat bv? Is it safe to use while trying to conceive?
Does rephresh gel mask or treat bv? Is it safe to use while trying to conceive?
Tricky question: Most research shows that antibiotics are required for treatment of bv. But there is also some research that shows that improving the ph in the vagina and taking oral probiotics may reverse early BV changes or perhaps lower risk of it's return. The company says that it's product is safe for sperm. But there are no studies published by them about this. ...Read more
9
9
My pap smear test results are neg, but also says cervicitis my obg, says i repeat test in 6mths, should I have a 2nd opinion?As I am trying to conceive
My pap smear test results are neg, but also says cervicitis my obg, says i repeat test in 6mths, should I have a 2nd opinion?As I am trying to conceive
Yes: There is no need to repeat a pap smear unless it's abnormal. Cervicitis is treated with antibiotics and cervical infections can be evaluated for quickly without the need for waiting six months. First ask your doctor to explain the reasoning for their plan as they may provide informantion that would make it reasonable to wait. However if you are uncomfortable with the plan seek a second opinion. ...Read more
10
10
Painful passing urine...unable to empty bladder completely. LMP..26 jun..trying to conceive?
Painful passing urine...unable to empty bladder completely. LMP..26 jun..trying to conceive?
Painful urine: you might have Urinary tract infection, please see your doctor for a Urinalysis and possible Antibiotics treatment. ...Read more
See 2 more doctor answers
Dr. John Leander Po
1,118 doctors shared insights
Antibiotic (Definition)
An antibiotic is a medicine that slows, stops, or kills germs. The germs are usually bacteria causing an infection in a person, so the person uses antibiotics to help his body get ...Read more | {
"url": "https://www.healthtap.com/topics/antibiotics-and-trying-to-conceive",
"source_domain": "www.healthtap.com",
"snapshot_id": "crawl=CC-MAIN-2016-44",
"warc_metadata": {
"Content-Length": "78176",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:RA4MUZY2YGEB7G5HZ2JCYEEEQ3HXZLCK",
"WARC-Concurrent-To": "<urn:uuid:06f9bd68-0203-4332-acf9-21b6c4e62b12>",
"WARC-Date": "2016-10-25T12:10:48",
"WARC-IP-Address": "54.215.81.62",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:RUWTJO5XIRRG3X3WKJS6TALXO6QLDUFD",
"WARC-Record-ID": "<urn:uuid:f5378b0d-2fe6-4add-936c-563f40b94762>",
"WARC-Target-URI": "https://www.healthtap.com/topics/antibiotics-and-trying-to-conceive",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:a05fbe19-fff5-409b-9d73-44a112b131a5>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-171-6-4.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2016-44\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for October 2016\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
4,
7,
62,
63,
69,
71,
72,
74,
131,
132,
189,
190,
448,
449,
465,
495,
496,
528,
529,
730,
731,
732,
734,
735,
737,
888,
889,
1040,
1041,
1452,
1453,
1478,
1480,
1481,
1483,
1565,
1566,
1648,
1649,
1955,
1956,
1958,
1959,
1961,
2105,
2106,
2517,
2518,
2520,
2521,
2523,
2603,
2604,
2684,
2685,
3068,
3069,
3071,
3072,
3074,
3226,
3227,
3379,
3380,
3796,
3797,
3800,
3801,
3804,
3897,
3898,
3991,
3992,
4136,
4137,
4163,
4183,
4213,
4214,
4238,
4239
],
"line_end_idx": [
4,
7,
62,
63,
69,
71,
72,
74,
131,
132,
189,
190,
448,
449,
465,
495,
496,
528,
529,
730,
731,
732,
734,
735,
737,
888,
889,
1040,
1041,
1452,
1453,
1478,
1480,
1481,
1483,
1565,
1566,
1648,
1649,
1955,
1956,
1958,
1959,
1961,
2105,
2106,
2517,
2518,
2520,
2521,
2523,
2603,
2604,
2684,
2685,
3068,
3069,
3071,
3072,
3074,
3226,
3227,
3379,
3380,
3796,
3797,
3800,
3801,
3804,
3897,
3898,
3991,
3992,
4136,
4137,
4163,
4183,
4213,
4214,
4238,
4239,
4431
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4431,
"ccnet_original_nlines": 81,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 2,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40382450819015503,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.014623169787228107,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.16535432636737823,
"rps_doc_frac_unique_words": 0.41689008474349976,
"rps_doc_mean_word_length": 4.6916890144348145,
"rps_doc_num_sentences": 66,
"rps_doc_symbol_to_word_ratio": 0.012373450212180614,
"rps_doc_unigram_entropy": 5.252971649169922,
"rps_doc_word_count": 746,
"rps_doc_frac_chars_dupe_10grams": 0.27971428632736206,
"rps_doc_frac_chars_dupe_5grams": 0.27971428632736206,
"rps_doc_frac_chars_dupe_6grams": 0.27971428632736206,
"rps_doc_frac_chars_dupe_7grams": 0.27971428632736206,
"rps_doc_frac_chars_dupe_8grams": 0.27971428632736206,
"rps_doc_frac_chars_dupe_9grams": 0.27971428632736206,
"rps_doc_frac_chars_top_2gram": 0.051428571343421936,
"rps_doc_frac_chars_top_3gram": 0.06857143342494965,
"rps_doc_frac_chars_top_4gram": 0.029999999329447746,
"rps_doc_books_importance": -360.9337463378906,
"rps_doc_books_importance_length_correction": -360.9337463378906,
"rps_doc_openwebtext_importance": -238.599853515625,
"rps_doc_openwebtext_importance_length_correction": -238.599853515625,
"rps_doc_wikipedia_importance": -154.50718688964844,
"rps_doc_wikipedia_importance_length_correction": -154.50718688964844
},
"fasttext": {
"dclm": 0.09456723928451538,
"english": 0.9557598233222961,
"fineweb_edu_approx": 1.9494653940200806,
"eai_general_math": 0.0847020074725151,
"eai_open_web_math": 0.22699058055877686,
"eai_web_code": 0.07512140274047852
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "615.6",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-7,558,349,452,610,023,000 | What is atelectasis
What is atelectasis?
Atelectasis is reduced inflation of part or all of the lung and may be subsegmental, segmental, lobar, or whole lung in extent. Whereas subsegmental atelectasis is usually not clinically significant (despite being very common, particularly in the inpatient setting and after surgery), larger amounts of atelectasis can result in significantly decreased pulmonary gas exchange.
You cannot copy content of this page | {
"url": "https://www.seekhealthz.com/health/what-is-atelectasis/",
"source_domain": "www.seekhealthz.com",
"snapshot_id": "crawl=CC-MAIN-2020-45",
"warc_metadata": {
"Content-Length": "1049889",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:4PFDG7CMGMO444NYJUXRTAB5Y62F24F2",
"WARC-Concurrent-To": "<urn:uuid:d4623338-9177-4a31-a3c5-b0796cdd8b60>",
"WARC-Date": "2020-10-28T10:54:28",
"WARC-IP-Address": "104.28.1.144",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:K43HHXOPG5FFLVBVSOBZ5ZTQLMZG4LWM",
"WARC-Record-ID": "<urn:uuid:a79cdda4-0765-41ff-8e66-25a6a58014c0>",
"WARC-Target-URI": "https://www.seekhealthz.com/health/what-is-atelectasis/",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:390e935d-74aa-4268-bfad-7912549db57d>"
},
"warc_info": "isPartOf: CC-MAIN-2020-45\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for October 2020\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-201.ec2.internal\r\nsoftware: Apache Nutch 1.17 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
20,
21,
42,
43,
420,
421
],
"line_end_idx": [
20,
21,
42,
43,
420,
421,
457
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 457,
"ccnet_original_nlines": 6,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.40789473056793213,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1184210479259491,
"rps_doc_frac_unique_words": 0.7313432693481445,
"rps_doc_mean_word_length": 5.641790866851807,
"rps_doc_num_sentences": 4,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 3.745720386505127,
"rps_doc_word_count": 67,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.0317460298538208,
"rps_doc_frac_chars_top_3gram": 0.08994708955287933,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -29.782974243164062,
"rps_doc_books_importance_length_correction": -31.426780700683594,
"rps_doc_openwebtext_importance": -16.901599884033203,
"rps_doc_openwebtext_importance_length_correction": -18.5454044342041,
"rps_doc_wikipedia_importance": -9.69844913482666,
"rps_doc_wikipedia_importance_length_correction": -11.342253684997559
},
"fasttext": {
"dclm": 0.969588041305542,
"english": 0.9033293724060059,
"fineweb_edu_approx": 3.264869213104248,
"eai_general_math": 0.21059268712997437,
"eai_open_web_math": 0.4791375398635864,
"eai_web_code": 0.000010609999662847258
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.2",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.201",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "1",
"label": "Factual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
-1,904,191,923,294,166,800 | Top
30
Doctor insights on: Medicine For Primary Lateral Sclerosis
Share
1
1
What is primary lateral sclerosis?
What is primary lateral sclerosis?
Variation of ALS: Motor neuron disease or ALS presents in several variable forms, and is a disease of motor neuron degeneration in brain and spinal cord. In the primary lateral sclerosis variant (only 1-3% of all cases), the disorder affects the upper motor neuron only, and is focal on one side or the other. By definition, this form would be far less malignant. ...Read more
Dr. Ana Adelstein
25 Doctors shared insights
Primary Lateral Sclerosis (Definition)
Motor neuron disease or ALS presents in several variable forms, and is a disease of motor neuron degeneration in brain and spinal cord. In the primary lateral sclerosis variant (only 1-3% of all cases), the disorder affects the upper motor neuron only, and is focal on one side or the other. By definition, this form would ...Read more
2
2
What are the symptoms of primary lateral sclerosis?
What are the symptoms of primary lateral sclerosis?
Variant of ALS: Als affects motor nerve cells, but varies in presentation. Diagnosis of primary lateral sclerosis is challenging, as involves upper motor neuron cells and early on, an EMG test could well be non-diagnostic, as it tests the lower cells. Since this variation involves central corticospinal cells, there is unilateral weakness of arm and/or leg without sensory loss. Later, loss of muscle bulk maybe. ...Read more
3
3
Primary lateral sclerosis only 1 side, is this normal?
Primary lateral sclerosis only 1 side, is this normal?
Not unexpected: Not surprising but this may not stay unilateral, or this may be the ultimate outcome. Motor neuron disorders vary in expression, but require attentive followup with a neuromuscular specialist on an ongoing basis. Riluzole may be of value. ...Read more
4
4
What is the definition or description of: primary lateral sclerosis?
What is the definition or description of: primary lateral sclerosis?
Variation of ALS: Motor neuron disease or ALS presents in several variable forms, and is a disease of motor neuron degeneration in brain and spinal cord. In the primary lateral sclerosis variant (only 1-3% of all cases), the disorder affects the upper motor neuron only, and is focal on one side or the other. By definition, this form would be far less malignant. ...Read more
5
5
I am suffering from primary lateral sclerosis, is there a treatmnet?
Yes there is: Primary lateral sclerosis is a form of lou gehrig's disease, which affects the motor neuron cell, and may involve a slow chronic course. The drug Riluzole is the only product on the market so far, and has shown some potential to prevent tracheostomy. Part of the treatment involves supportive care, and prevention of infections, so work closely with a team of experienced physicians. ...Read more
6
6
Can you tell me if emg tests can be normal with primary lateral sclerosis?
Can you tell me if emg tests can be normal with primary lateral sclerosis?
Would be unlikely: If motor neuron disease exists, and could be in form of primary lateral sclerosis, there will usually be some degree of EMG pathology. A fully normal EMG would tend to rule against a diagnosis of any kind of motor neuron disease, but early on, findings might be very minimal and the test might need repetition in several months. ...Read more
7
7
Treatment for upper motor neuron sympathy for my diagnose of primary lateral sclerosis?
Treatment for upper motor neuron sympathy for my diagnose of primary lateral sclerosis?
Try this: Although no cure currently, the drug Riluzole has been used to slow down the process and prevent or delay tracheostomy. Some pts might benefit from other glutamate blockers, Gabapentin and memantine have been tried in addition. Some alternative health sites have mentioned anti-oxidant approaches, and you might check hsi (health science institute). Get second opinion at nearby medical schools. ...Read more
8
8
I have been diagnosed with primary lateral sclerosis by my neurologist here in savannah. What's the chance of mine changing to als? Really concerned.
Unlikely: Although primary lateral sclerosis can be disabling, it is no where near as bad as als. You shouldn't be thinking about that but how you can best follow your neuologists instructions to get better. ...Read more
9
9
How much time does it take to loose legs arms speaking if they tell ya primary lateral sclerosis?
How much time does it take to loose legs arms speaking if they tell ya primary lateral sclerosis?
Variable, but: Many pts succumb within 5-10 yrs at most. Others may rapidly lose function over just several months to 1 or 2 years. No magic formula, but Riluzole can delay deterioration for at least 6-9 months or more. ...Read more
10
10
My grandma has Amyotrophic lateral sclerosis and what medicine she should take for relieving the pain? Or preventing the further complications?
My grandma has Amyotrophic lateral sclerosis and what medicine she should take for relieving the pain? Or preventing the further complications?
Comments: Sole drug on market for ALS is riluzole, which can delay tracheotomy but does not enhance strength. Since it inhibits glutamate, maybe pain relief achieved by use of Lyrica (pregabalin) or gabapentin. Most of the approach in ALS is supportive and palliative. Have a family conference with her neurologist. ...Read more
11
11
What drugs would I take for multiple sclerosis?
What drugs would I take for multiple sclerosis?
DMT's: If you possess relapsing-remitting MS, you vitally need a "disease modifying agent", such as an interferon, Copaxone, Tysabri (natalizumab), (natalizumab) Gilenya, Aubrigio, or Tecfidera. But best usually to use a potent medication, such as Gilenya or Tysabri (natalizumab). A neurologist should be able to address your needs readily. ...Read more
12
12
Which multiple sclerosis drug is good to start with?
Which multiple sclerosis drug is good to start with?
New paradigm: People vary and may have different needs and symptoms, here is a generic approach. Young females desiring children might start with copaxone, and should never use augabio. If the MRI is showing many lesions, and relapses are frequent, choose either tysabri (natalizumab) or Gilenya if a blood test jcv is done. Tecfidera may be a good general starting item, but too early to judge. Older injectables less used. ...Read more
13
13
What do you consider primary symptoms of multiple sclerosis?
What do you consider primary symptoms of multiple sclerosis?
Classical: Loss of vision unilaterally, loss of balance and coordination, weakness of both legs, or focal arm/leg weakness, electrical shock sensation from neck downwards, unexplained fatigue or cognitive loss, problems with bladder control. All of this varies greatly from patient to patient as NO MS pt is similar to another. ...Read more
14
14
Could anyone know some medicine to cure multiple sclerosis?
Advice: No current cure, but we are close, and the med called lemtrada may stop the disease for years. However, those drugs on the market that have best potential to control disorder include tysabri, (natalizumab) gilenya, and possibly tecfidera. Forget the others if you desire potent control. Vitamin d supplements definitely help. ...Read more
15
15
Which type of medicine are you taking for your multiple sclerosis?
Which type of medicine are you taking for your multiple sclerosis?
Nonspecific question: Presume you are asking advice. The most potent meds in order are tysabri, (natalizumab) gilenya, tecfidera, rebif, betaseron, aubagio, copaxone, and least potent, avonex. Suggest strongly add vitamin d supplements. ...Read more
16
16
Is primary progessive multiple sclerosis always fatal?
Is primary progessive multiple sclerosis always fatal?
Not necessarily: Ms has been said to shorten life span, and untreated this is correct, but several studies have supported normal life if appropriate potent meds are employed. Primary progressive ms does not respond well to the usual meds, and mostly symptomatic interventions are used. There are many research projects nowadays, and best to contact a medical school and get involved. ...Read more
17
17
What is amyotrophic lateral sclerosis (als)?
Motor neuron disease: A disorder of misfolded proteins, attacking nerve cell bodies in spinal cord and brain. Tends to involve weakness not numbness, and can affect legs and arms with flickering of muscles, loss of muscle mass, and evenually problems with breathing and swallowing. Unfortunately, there is no cure, and it preserves awareness. Gratefully, it is relatively rare. ...Read more
18
18
Who first discovered amyotrophic lateral sclerosis?
Who first discovered amyotrophic lateral sclerosis?
Charcot: The French Neurologist Charcot is credited with the paper describing ALS as a distinct illness ...Read more
19
19
What are the tests for amyotrophic lateral sclerosis?
Diagnosis: Since we hope to find alternative problems instead of als, we search for possible other diagnoses. The testing includes blood studies, especially for hyperthyroidism, MRI tests of the neck and spinal cord, EMG studies, and even muscle biopsies on occasion. ...Read more
20
20
What sort of problem is amyotrophic lateral sclerosis?
Lou Gehrig's: Als also known as lou gehrig's disease is a disease of nerves. It is a progressive loss of muscle strength. Initial symptoms are usually muscle weakness or cramps followed by muscle paralysis in later stages. Difficulty breathing and swallowing are common due to the muscle weakness. There is no cure but there are medications to help with symptom management. ...Read more
21
21
What are the symptoms of amyotrophic lateral sclerosis?
What are the symptoms of amyotrophic lateral sclerosis?
See below: The main symptoms of ALS are weakness. The weakness often starts with one hand and then may progress to the other. The legs will often become weak as well. The muscles begin to get thinner. This is called atrophy. There may also be exaggerated reflexes and stiffness in the muscles called spasticity. The muscles that help us speak and swallow and breath can also be weakened. ...Read more
22
22
How is amyotrophic lateral sclerosis transmitted in humans?
It is not transmitte: It is not typically a heriditary or infectious disease. No one knows the exact cause. ...Read more
23
23
Hi doctors, was just wondering what is amyotrophic lateral sclerosis?
Lou Gehrig's disease: Als is a very nasty uncurable disease involving the motor neuron in brain and spinal cord, usually arising in middle to later years of life. It results in a steady deterioration of muscle, with atrophy and fasciculations, possibly eventuating in loss of ability to swallow and breathe. The sole medication on the market which may modestly help is riluzole. ...Read more
24
24
What is the treatment for amyotrophic lateral sclerosis?
What is the treatment for amyotrophic lateral sclerosis?
Not good: Lou gehrig's disease remains resistant to successful treatment or control. The drug Riluzole is on the market but is very disappointing, although may delay useage of a tracheostomy tube for a few months. We are learning about a misfolded protein, and this may point the way for future success. ...Read more
25
25
What chinese medicine can I use for lichen sclerosis?
What chinese medicine can I use for lichen sclerosis?
Variable: Sitz baths are important. Herbs such as sephora root and stemona root are the mainstays of treatment from an naturopathic viewpoint. Allopathic treatments include topical testosterone and topical steroids of moderate to intense strength under the direction of a physician. ...Read more
26
26
A friend of mine was recently diagnosed with primary progressive multiple sclerosis. Is this a fatal disease?
Cannot predict: Primary progressive ms is typically without rapid relapses, but also, without remission. Does not seem to respond well to meds employed in relapsing/remitting form. Most active therapy is symptomatic. However, research is ongoing with Gilenya (fingolimod) for ppms. Other drugs not yet on the market are being studied. Best bet is to get into one of these studies. Contact local medical school. Stay positive. ...Read more
27
27
What is amyotrophic lateral sclerosis?
Disease of nervecell: Amyotrophic lateral sclerosis, or als, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. Als does not affect the senses (sight, smell, taste, hearing, touch). It only rarely affects bladder or bowel function, or a person's ability to think or reason. The condition slowly gets worse and cause difficulty with breathing muscles. ...Read more
28
28
Could kids get amyotrophic lateral sclerosis?
Could kids get amyotrophic lateral sclerosis?
Similar: But most childhood illnesses which affect the motor neuron, like als, are quite rare, and more hereditary in origin. A variety of such disorders cause weakness in very young children, and adolescents and seem similar in outcome. Also, polio used to affect many children but is almost unknown in usa today. ...Read more
29
29
What exactly is amyotrophic lateral sclerosis?
What exactly is amyotrophic lateral sclerosis?
Lou Gehrig's disease: Als is a disease affecting the nerve cell body, causes weakness, muscle wasting, and fasciculations or fluttering of the muscles. It can affect mobility, swallowing, and breathing. There is no known cure to date, and the prognosis is often very poor. We believe it is a disorder of "misfolded proteins", similar in some ways to alzheimer's and parkinson's, but a far rarer condition, fortunately. ...Read more
30
30
What is amyotrophic lateral sclerosis (als)? Can it be treated?
Lou Gehrig's disease: Als is a disease affecting the nerve cell body, causes weakness, muscle wasting, and fasciculations or fluttering of the muscles. It can affect mobility, swallowing, and breathing. There is no known cure to date, and the prognosis is often very poor. We believe it is a disorder of "misfolded proteins", similar in some ways to alzheimer's and parkinson's, but a far rarer condition, fortunately. ...Read more
Dr. Theodore Davantzis
3 Doctors shared insights
Sclerosis (Definition)
We neurologists employ the term to describe localized damage involving the central nervous system, and sclerosis means scarring. If in many areas, might be multiple sclerosis. If affecting the motor nerve cell, ...Read more | {
"url": "https://www.healthtap.com/topics/medicine-for-primary-lateral-sclerosis",
"source_domain": "www.healthtap.com",
"snapshot_id": "crawl=CC-MAIN-2018-34",
"warc_metadata": {
"Content-Length": "158037",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:PQLN6CXV4N4GUPIGUXR4NCXSDYOM54LV",
"WARC-Concurrent-To": "<urn:uuid:4c79f92c-de66-4604-8066-d6a32cbafd07>",
"WARC-Date": "2018-08-20T20:37:33",
"WARC-IP-Address": "104.18.180.32",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:IRMPQTW2YLHTIWE7XRNYNZ4EWP6GXYNU",
"WARC-Record-ID": "<urn:uuid:822735c5-9d86-48a8-ac49-cf5ac22e003e>",
"WARC-Target-URI": "https://www.healthtap.com/topics/medicine-for-primary-lateral-sclerosis",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:30a85a8d-46b2-40f9-aceb-8a3b6d45595a>"
},
"warc_info": "isPartOf: CC-MAIN-2018-34\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for August 2018\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-142-246-207.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 0.11-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
4,
7,
66,
67,
73,
75,
76,
78,
113,
114,
149,
150,
527,
528,
546,
573,
574,
613,
614,
950,
951,
952,
954,
955,
957,
1009,
1010,
1062,
1063,
1490,
1491,
1493,
1494,
1496,
1551,
1552,
1607,
1608,
1876,
1877,
1879,
1880,
1882,
1951,
1952,
2021,
2022,
2399,
2400,
2402,
2403,
2405,
2474,
2475,
2886,
2887,
2889,
2890,
2892,
2967,
2968,
3043,
3044,
3405,
3406,
3408,
3409,
3411,
3499,
3500,
3588,
3589,
4008,
4009,
4011,
4012,
4014,
4164,
4165,
4386,
4387,
4389,
4390,
4392,
4490,
4491,
4589,
4590,
4823,
4824,
4827,
4828,
4831,
4975,
4976,
5120,
5121,
5450,
5451,
5454,
5455,
5458,
5506,
5507,
5555,
5556,
5911,
5912,
5915,
5916,
5919,
5972,
5973,
6026,
6027,
6465,
6466,
6469,
6470,
6473,
6534,
6535,
6596,
6597,
6938,
6939,
6942,
6943,
6946,
7006,
7007,
7354,
7355,
7358,
7359,
7362,
7429,
7430,
7497,
7498,
7748,
7749,
7752,
7753,
7756,
7811,
7812,
7867,
7868,
8265,
8266,
8269,
8270,
8273,
8320,
8321,
8712,
8713,
8716,
8717,
8720,
8772,
8773,
8825,
8826,
8943,
8944,
8947,
8948,
8951,
9005,
9006,
9287,
9288,
9291,
9292,
9295,
9350,
9351,
9738,
9739,
9742,
9743,
9746,
9802,
9803,
9859,
9860,
10261,
10262,
10265,
10266,
10269,
10329,
10330,
10451,
10452,
10455,
10456,
10459,
10529,
10530,
10922,
10923,
10926,
10927,
10930,
10987,
10988,
11045,
11046,
11363,
11364,
11367,
11368,
11371,
11425,
11426,
11480,
11481,
11777,
11778,
11781,
11782,
11785,
11895,
11896,
12335,
12336,
12339,
12340,
12343,
12382,
12383,
12797,
12798,
12801,
12802,
12805,
12851,
12852,
12898,
12899,
13227,
13228,
13231,
13232,
13235,
13282,
13283,
13330,
13331,
13763,
13764,
13767,
13768,
13771,
13835,
13836,
14268,
14269,
14292,
14318,
14319,
14342,
14343
],
"line_end_idx": [
4,
7,
66,
67,
73,
75,
76,
78,
113,
114,
149,
150,
527,
528,
546,
573,
574,
613,
614,
950,
951,
952,
954,
955,
957,
1009,
1010,
1062,
1063,
1490,
1491,
1493,
1494,
1496,
1551,
1552,
1607,
1608,
1876,
1877,
1879,
1880,
1882,
1951,
1952,
2021,
2022,
2399,
2400,
2402,
2403,
2405,
2474,
2475,
2886,
2887,
2889,
2890,
2892,
2967,
2968,
3043,
3044,
3405,
3406,
3408,
3409,
3411,
3499,
3500,
3588,
3589,
4008,
4009,
4011,
4012,
4014,
4164,
4165,
4386,
4387,
4389,
4390,
4392,
4490,
4491,
4589,
4590,
4823,
4824,
4827,
4828,
4831,
4975,
4976,
5120,
5121,
5450,
5451,
5454,
5455,
5458,
5506,
5507,
5555,
5556,
5911,
5912,
5915,
5916,
5919,
5972,
5973,
6026,
6027,
6465,
6466,
6469,
6470,
6473,
6534,
6535,
6596,
6597,
6938,
6939,
6942,
6943,
6946,
7006,
7007,
7354,
7355,
7358,
7359,
7362,
7429,
7430,
7497,
7498,
7748,
7749,
7752,
7753,
7756,
7811,
7812,
7867,
7868,
8265,
8266,
8269,
8270,
8273,
8320,
8321,
8712,
8713,
8716,
8717,
8720,
8772,
8773,
8825,
8826,
8943,
8944,
8947,
8948,
8951,
9005,
9006,
9287,
9288,
9291,
9292,
9295,
9350,
9351,
9738,
9739,
9742,
9743,
9746,
9802,
9803,
9859,
9860,
10261,
10262,
10265,
10266,
10269,
10329,
10330,
10451,
10452,
10455,
10456,
10459,
10529,
10530,
10922,
10923,
10926,
10927,
10930,
10987,
10988,
11045,
11046,
11363,
11364,
11367,
11368,
11371,
11425,
11426,
11480,
11481,
11777,
11778,
11781,
11782,
11785,
11895,
11896,
12335,
12336,
12339,
12340,
12343,
12382,
12383,
12797,
12798,
12801,
12802,
12805,
12851,
12852,
12898,
12899,
13227,
13228,
13231,
13232,
13235,
13282,
13283,
13330,
13331,
13763,
13764,
13767,
13768,
13771,
13835,
13836,
14268,
14269,
14292,
14318,
14319,
14342,
14343,
14566
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 14566,
"ccnet_original_nlines": 266,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.349511057138443,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.011227820068597794,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.17855848371982574,
"rps_doc_frac_unique_words": 0.29495471715927124,
"rps_doc_mean_word_length": 5.018542289733887,
"rps_doc_num_sentences": 168,
"rps_doc_symbol_to_word_ratio": 0.011590000241994858,
"rps_doc_unigram_entropy": 5.6584858894348145,
"rps_doc_word_count": 2319,
"rps_doc_frac_chars_dupe_10grams": 0.21730537712574005,
"rps_doc_frac_chars_dupe_5grams": 0.32574325799942017,
"rps_doc_frac_chars_dupe_6grams": 0.31543219089508057,
"rps_doc_frac_chars_dupe_7grams": 0.28707683086395264,
"rps_doc_frac_chars_dupe_8grams": 0.27899983525276184,
"rps_doc_frac_chars_dupe_9grams": 0.24858222901821136,
"rps_doc_frac_chars_top_2gram": 0.06186629831790924,
"rps_doc_frac_chars_top_3gram": 0.04940710961818695,
"rps_doc_frac_chars_top_4gram": 0.01718508079648018,
"rps_doc_books_importance": -1188.9051513671875,
"rps_doc_books_importance_length_correction": -1188.9051513671875,
"rps_doc_openwebtext_importance": -626.2802124023438,
"rps_doc_openwebtext_importance_length_correction": -626.2802124023438,
"rps_doc_wikipedia_importance": -555.0552368164062,
"rps_doc_wikipedia_importance_length_correction": -555.0552368164062
},
"fasttext": {
"dclm": 0.23804432153701782,
"english": 0.9307125806808472,
"fineweb_edu_approx": 2.9878501892089844,
"eai_general_math": 0.07668793201446533,
"eai_open_web_math": 0.252011775970459,
"eai_web_code": 0.0038746600039303303
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.85",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.8",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-3,505,115,065,970,726,400 | Nearsightedness
The Enclave Corrective LensesNearsightedness (myopia) is a common vision condition in which you can see objects near to you more clearly, than objects far away.
The degree of your nearsightedness determines your ability to focus on distant objects. People with severe nearsightedness can see clearly only objects just a few inches away, while those with mild nearsightedness may clearly see objects several yards away.
Nearsightedness may develop gradually or rapidly, often worsening during childhood and adolescence. Nearsightedness tends to run in families.
A comprehensive eye exam can confirm nearsightedness. You can easily correct the condition with eyeglasses or contact lenses. | {
"url": "https://www.eyedoctor-collegestation.com/nearsightedness-wolf-pen-creek.html",
"source_domain": "www.eyedoctor-collegestation.com",
"snapshot_id": "crawl=CC-MAIN-2018-47",
"warc_metadata": {
"Content-Length": "21983",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ZXWGR6I4TNSX4GPTIEQIKYORPMD2ZWBM",
"WARC-Concurrent-To": "<urn:uuid:390aaf3a-43c9-4032-9f37-53824856c792>",
"WARC-Date": "2018-11-20T12:20:50",
"WARC-IP-Address": "104.130.169.208",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:P3GKW2AV6KG2BPHL4IPGGZF64DLE4IRB",
"WARC-Record-ID": "<urn:uuid:a9985cae-4c5a-4388-9122-b484e2007788>",
"WARC-Target-URI": "https://www.eyedoctor-collegestation.com/nearsightedness-wolf-pen-creek.html",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:e257d98b-e5fa-4191-b23e-f403027c945d>"
},
"warc_info": "isPartOf: CC-MAIN-2018-47\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November 2018\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-164-6-12.ec2.internal\r\nsoftware: Apache Nutch 1.15 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 0.11-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
16,
17,
178,
179,
437,
438,
580,
581
],
"line_end_idx": [
16,
17,
178,
179,
437,
438,
580,
581,
706
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 706,
"ccnet_original_nlines": 8,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.44247788190841675,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.008849560283124447,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.10619468986988068,
"rps_doc_frac_unique_words": 0.6633663177490234,
"rps_doc_mean_word_length": 5.841584205627441,
"rps_doc_num_sentences": 7,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.015992641448975,
"rps_doc_word_count": 101,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.020338980481028557,
"rps_doc_frac_chars_top_3gram": 0,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -51.09040069580078,
"rps_doc_books_importance_length_correction": -51.940792083740234,
"rps_doc_openwebtext_importance": -30.1143741607666,
"rps_doc_openwebtext_importance_length_correction": -30.964765548706055,
"rps_doc_wikipedia_importance": -24.10942840576172,
"rps_doc_wikipedia_importance_length_correction": -24.959819793701172
},
"fasttext": {
"dclm": 0.06666553020477295,
"english": 0.9304099678993225,
"fineweb_edu_approx": 3.0393731594085693,
"eai_general_math": 0.8331885933876038,
"eai_open_web_math": 0.6065784692764282,
"eai_web_code": 0.09341598302125931
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.72",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "1",
"label": "Remember"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "17",
"label": "Product Page"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "1",
"label": "No Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
-4,069,349,866,775,296,000 | Open Access
Open Peer Review
This article has Open Peer Review reports available.
How does Open Peer Review work?
Intraoperative angiography should be standard in cerebral aneurysm surgery
BMC Surgery20099:7
DOI: 10.1186/1471-2482-9-7
Received: 10 March 2009
Accepted: 30 April 2009
Published: 30 April 2009
Abstract
Intraoperative angiography (IOA) has proven to be a safe and effective adjunct to surgical repair of cerebral aneurysms. Substantial practice variation exists regarding use of this modality in different centers, including use of IOA routinely, selectively, or rarely. In this editorial, we discuss our experience and review the existing literature to develop an argument for routine use of IOA during cerebral aneurysm surgery.
Editorial
Intraoperative angiography (IOA) has been considered since the 1960s for use during surgical repair of cerebral aneurysms. The potential to confirm complete aneurysm occlusion and patency of the parent vasculature intraoperatively are the key clinical uses that underlie IOA. However, no consensus exists regarding routine use of IOA in cerebral aneurysm surgery. Different institutional paradigms include use of IOA rarely or never, selectively based on aneurysm complexity, or routinely in all aneurysm cases.
The fundamental value of IOA during aneurysm repair is to confirm complete occlusion of the aneurysm, and to demonstrate patency of surrounding vasculature (Figure 1, 2 and 3). As many as 5% – 7.3% of surgically treated aneurysms are unexpectedly incompletely occluded, leading to additional treatment or to ongoing risk of rupture.[1, 2] Without IOA, the surgeon's only means to confirm complete aneurysm occlusion is to puncture the aneurysm dome – an incompletely occluded aneurysm will hemorrhage from the puncture site, which although not usually problematic is certainly not an optimal means to discover incomplete aneurysm occlusion. Parent vessel occlusion during surgical clipping of a cerebral aneurysm occurs in approximately 3 – 9% of cases.[1, 35] Although rare, parent vessel occlusion can lead to permanent neurological deficit or death. Furthermore, only a small window of time exists in which to recognize parent vessel occlusion and restore flow before irreversible ischemia of brain parenchyma will occur, such that postoperative investigations demonstrating parent vessel occlusion do not generally lead to successful intervention. Because IOA can demonstrate both incomplete aneurysm occlusion and parent vessel occlusion in a facile and timely manner, and lead to corrective intervention during the initial craniotomy, IOA has significant potential to improve surgical outcomes.
Figure 1
Anteroposterior (a) and lateral (b) views of CT angiogram. These images demonstrate large middle cerebral artery aneurysm and giant anterior communicating artery aneurysm.
Figure 2
Intraoperative angiogram demonstrating occlusion of middle cerebral artery aneurysm with patency of middle cerebral branches. The anterior communicating artery aneurysm is also occluded, but there is no filling of the anterior cerebral artery, suggesting parent vessel occlusion by the clip.
Figure 3
Intraoperative angiogram after clip revision. Flow in the parent vessel has been restored, but the aneurysm now fills.
Intraoperative angiography is both effective and accurate. In a single-center study of 517 aneurysms that underwent IOA during cerebral aneurysm surgery, a 12.4% revision of clip placement due to abnormalities found on IOA was reported.[3] The largest percentage of parent vessel occlusions were related to aneurysms of the proximal internal carotid artery. Aneurysms greater than 15 mm were independent predictors for the need for clip revision. The same study looked at the accuracy of IOA: the accuracy rate of IOA in detecting abnormalities as compared to postoperative angiography was 95%.[3]
While surgical repair of large and/or complex aneurysms carries a higher likelihood of findings on IOA leading to clip revision, even experienced surgeons cannot adequately predict the need for IOA on a selective basis. In a study of 200 patients treated at an experienced center, all of whom underwent IOA, 20% were predicted by the surgeon to need IOA, while 80% were predicted to not need IOA. The prediction was based on location, size, and unique features.[6] Of the 159 cases not predicted to need IOA, 7 (4.4%) needed clip revision due to aneurysm remnants, parent vessel occlusions, and undiagnosed aneurysms. Even in the most experienced hands, the potential for abnormal findings on IOA cannot be predicted with enough accuracy to justify selective use.
The potential value of IOA must be weighed against the morbidity and practical challenges of the procedure. Complications of IOA include stroke, dissection, emboli, arterial dissection, and hematoma. Complication rates have been reported in the range of 0.4% to 2.6%, and in our experience the risk of IOA was 3%. [25] While this represents increased morbidity compared to conventional cerebral angiography, these complication rates compare favorably to the rate of complications of surgical aneurysm repair which may be amenable to correction with IOA.
The biggest practical challenge of performing IOA routinely is having a skilled practitioner available to perform the procedure. This is particularly the case for night and weekend surgery. In our experience with implementing IOA routinely at two institutions, lack of radiology support led to inability to perform IOA in 35% of cases. [4] For this reason, implementation of a program of routine IOA requires a small number of "champions" that are committed to performing the procedure irrespective of schedule. The speed with which the IOA can be obtained is also a critical practical consideration, since in the event of parent vessel occlusion rapid restoration of flow is required to prevent stroke. We generally place a sheath in the femoral artery in the angiography suite before the operation, to facilitate rapid vascular catheterization and angiography intraoperatively. The responsiveness and coordination of the radiology team is also critical in the timeliness of results. This coordination is facilitated by performing IOA routinely, to build the experience and refine the systems. Other causes for not obtaining IOA in our experience included lack of radiolucent head holders, positioning of the patient in the lateral position, trapping or wrapping of the aneurysm, and individual patient contraindications to angiography. [4]
It is our opinion that IOA should be performed routinely on all patients undergoing cerebral aneurysm surgery. Morbidity due to incomplete aneurysm occlusion and/or parent vessel occlusion is not infrequent and is clinically important, and both complications may be avoided in certain cases by IOA. The limited morbidity of IOA is greatly outweighed by these potential benefits. Performing IOA in selective cases will not maximize the potential value since the need for IOA cannot be completely predicted.[5] Even the simplest aneurysm repair in the most experienced hands can have complications potentially amenable to discovery by IOA with consequent correctional intervention. Finally, optimization of reliability, speed, and efficacy of IOA can only be achieved within an institution when its use is routine.
Declarations
Authors’ Affiliations
(1)
Texas A&M Health Science Center College of Medicine
References
1. Kivisaari RP, Porras M, Ohman J, Siironen J, Ishii K, Hernesniemi J: Routine cerebral angiography after surgery for saccular aneurysms: is it worth it?. Neurosurgery. 2004, 55 (5): 1015-1024. 10.1227/01.NEU.0000141043.07303.60.View ArticlePubMedGoogle Scholar
2. Hauck EF, Wohlfeld B, Welch BG, White JA, Samson D: Clipping of very large or giant unruptured intracranial aneurysms in the anterior circulation: an outcome study. J Neurosurg. 2008, 109 (6): 1012-1018. 10.3171/JNS.2008.109.12.1012.View ArticlePubMedGoogle Scholar
3. Tang G, Cawley CM, Dion JE, Barrow DL: Intraoperative angiography during aneurysm surgery: a prospective evaluation of efficacy. J Neurosurg. 2002, 96 (6): 993-999.View ArticlePubMedGoogle Scholar
4. Chiang VL, Gailloud P, Murphy KJ, Rigamonti D, Tamargo RJ: Routine intraoperative angiography during aneurysm surgery. J Neurosurg. 2002, 96 (6): 988-992.View ArticlePubMedGoogle Scholar
5. Alikhani PLS, Friedman JA: Implementing Intraoperative Angiography for Aneurysm Surgery – Lessons Learned and Practical Considerations. Congress of Neurological Surgeons (CNS). San Diego, CA. 2007Google Scholar
6. Klopfenstein JD, Spetzler RF, Kim LJ, Feiz-Erfan I, Han PP, Zabramski JM, Porter RW, Albuquerque FC, McDougall CG, Fiorella DJ: Comparison of routine and selective use of intraoperative angiography during aneurysm surgery: a prospective assessment. J Neurosurg. 2004, 100 (2): 230-235.View ArticlePubMedGoogle Scholar
7. Pre-publication history
1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/9/7/prepub
Copyright
© Friedman and Kumar; licensee BioMed Central Ltd. 2009
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Advertisement | {
"url": "http://bmcsurg.biomedcentral.com/articles/10.1186/1471-2482-9-7",
"source_domain": "bmcsurg.biomedcentral.com",
"snapshot_id": "crawl=CC-MAIN-2017-22",
"warc_metadata": {
"Content-Length": "76527",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ISD74L2T3VBIGCISPR45SQOIB7MK7HAH",
"WARC-Concurrent-To": "<urn:uuid:c0a899ab-709e-475a-94be-d4eada709892>",
"WARC-Date": "2017-05-26T15:35:15",
"WARC-IP-Address": "151.101.32.95",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:5J3MBT647P54P7TCQNQPS65SAJA4YNBE",
"WARC-Record-ID": "<urn:uuid:dcd97ad1-c65d-44f8-b290-a04731bfeaa5>",
"WARC-Target-URI": "http://bmcsurg.biomedcentral.com/articles/10.1186/1471-2482-9-7",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:4f6e1e77-e80e-40e8-83f9-744f77f79ba4>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-185-224-210.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2017-22\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for May 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
12,
29,
30,
83,
84,
116,
117,
192,
193,
212,
213,
240,
241,
265,
266,
290,
291,
316,
317,
326,
327,
755,
756,
766,
767,
1279,
1280,
2681,
2690,
2691,
2863,
2864,
2873,
2874,
3166,
3167,
3176,
3177,
3296,
3297,
3895,
3896,
4660,
4661,
5215,
5216,
6558,
6559,
7372,
7373,
7386,
7387,
7409,
7410,
7414,
7466,
7467,
7478,
7479,
7744,
8015,
8217,
8409,
8625,
8948,
8977,
8978,
9099,
9100,
9110,
9111,
9167,
9168,
9504,
9505
],
"line_end_idx": [
12,
29,
30,
83,
84,
116,
117,
192,
193,
212,
213,
240,
241,
265,
266,
290,
291,
316,
317,
326,
327,
755,
756,
766,
767,
1279,
1280,
2681,
2690,
2691,
2863,
2864,
2873,
2874,
3166,
3167,
3176,
3177,
3296,
3297,
3895,
3896,
4660,
4661,
5215,
5216,
6558,
6559,
7372,
7373,
7386,
7387,
7409,
7410,
7414,
7466,
7467,
7478,
7479,
7744,
8015,
8217,
8409,
8625,
8948,
8977,
8978,
9099,
9100,
9110,
9111,
9167,
9168,
9504,
9505,
9518
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 9518,
"ccnet_original_nlines": 75,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.27580174803733826,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.04956268146634102,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.23032070696353912,
"rps_doc_frac_unique_words": 0.410518616437912,
"rps_doc_mean_word_length": 5.692476272583008,
"rps_doc_num_sentences": 103,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.600581169128418,
"rps_doc_word_count": 1369,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.05697420984506607,
"rps_doc_frac_chars_dupe_6grams": 0.014885149896144867,
"rps_doc_frac_chars_dupe_7grams": 0.014885149896144867,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.007699219975620508,
"rps_doc_frac_chars_top_3gram": 0.02155780978500843,
"rps_doc_frac_chars_top_4gram": 0.015013470314443111,
"rps_doc_books_importance": -808.832763671875,
"rps_doc_books_importance_length_correction": -808.832763671875,
"rps_doc_openwebtext_importance": -399.0039367675781,
"rps_doc_openwebtext_importance_length_correction": -399.0039367675781,
"rps_doc_wikipedia_importance": -296.4654235839844,
"rps_doc_wikipedia_importance_length_correction": -296.4654235839844
},
"fasttext": {
"dclm": 0.030307110399007797,
"english": 0.8966389894485474,
"fineweb_edu_approx": 1.993649959564209,
"eai_general_math": 0.08568614721298218,
"eai_open_web_math": 0.18817663192749023,
"eai_web_code": 0.004723310004919767
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.0222",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.022",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "4",
"label": "Missing Images or Figures"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "4",
"label": "Advanced Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "5",
"label": "Exceptionally Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-2,108,461,725,096,046,000 | Peroxides and Macrophages in the Toxicity of Fine Particulate Matter in Rats
Dr. Laskin and her colleagues at the Environmental and Occupational Health Sciences Institute at Rutgers University tested the hypothesis that oxidants in ambient air, such as hydrogen peroxide, may be transported by fine particulate matter into the lungs and thus contribute to lung tissue injury. The investigators used ammonium sulfate particles because of their prevalence in the ambient air of the eastern United States and their reportedly low toxicity in animals and humans. Rats inhaled ammonium sulfate, hydrogen peroxide, or combinations thereof, for 2 hours on a single occasion to assess lung tissue injury and presence of inflammatory markers in the lung. They also assessed activation of alveolar macrophages, which are involved in the first line of defense against foreign materials that enter the lung. Exposures with 18O-labeled hydrogen peroxide were conducted to measure deposition in the lung. Additional experiments assessed lung injury and inflammation after rats inhaled organic peroxide, and investigated hydrogen peroxide formation in an indoor environment. | {
"url": "https://www.healtheffects.org/publication/peroxides-and-macrophages-toxicity-fine-particulate-matter-rats",
"source_domain": "www.healtheffects.org",
"snapshot_id": "crawl=CC-MAIN-2021-31",
"warc_metadata": {
"Content-Length": "70512",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:2QHFZHDOFKD25VTJONP7LUZXCJWXSKOI",
"WARC-Concurrent-To": "<urn:uuid:0b25569f-719f-459a-9a5d-01963ca2dc94>",
"WARC-Date": "2021-07-23T21:43:38",
"WARC-IP-Address": "23.185.0.3",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:H73RGHCTENXJIDVQTYTLDSSKUT3HAJSD",
"WARC-Record-ID": "<urn:uuid:7359c26c-f004-47b3-9610-bffe733fd237>",
"WARC-Target-URI": "https://www.healtheffects.org/publication/peroxides-and-macrophages-toxicity-fine-particulate-matter-rats",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:37689417-e9b8-4af1-b3cc-11b2392a12ed>"
},
"warc_info": "isPartOf: CC-MAIN-2021-31\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for July/August 2021\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-171.ec2.internal\r\nsoftware: Apache Nutch 1.18 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.2-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
77,
78
],
"line_end_idx": [
77,
78,
1160
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1160,
"ccnet_original_nlines": 2,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3529411852359772,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.005347589962184429,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.08556149899959564,
"rps_doc_frac_unique_words": 0.6257309913635254,
"rps_doc_mean_word_length": 5.695906639099121,
"rps_doc_num_sentences": 7,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.371474742889404,
"rps_doc_word_count": 171,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.025667350739240646,
"rps_doc_frac_chars_top_3gram": 0.04312115162611008,
"rps_doc_frac_chars_top_4gram": 0,
"rps_doc_books_importance": -89.57923126220703,
"rps_doc_books_importance_length_correction": -89.57923126220703,
"rps_doc_openwebtext_importance": -64.5418472290039,
"rps_doc_openwebtext_importance_length_correction": -63.018226623535156,
"rps_doc_wikipedia_importance": -37.58662796020508,
"rps_doc_wikipedia_importance_length_correction": -37.58662796020508
},
"fasttext": {
"dclm": 0.02534407004714012,
"english": 0.9401460289955139,
"fineweb_edu_approx": 3.0498900413513184,
"eai_general_math": 0.3631005883216858,
"eai_open_web_math": 0.1775904893875122,
"eai_web_code": 0.0027105200570076704
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "614.4",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Public health"
}
},
"secondary": {
"code": "615.5",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "4",
"label": "Analyze"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "4",
"label": "Graduate/Expert Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
6,675,073,458,209,914,000 | 2 Benefits Individuals Do Not Really Understand In Connection With LASIK Eye Surgery
The eye can be analyzed with relative ease regarding both its function and its structure. A practical evaluation consists of the capability to relocate the orbit and the reaction of the pupil to light and accommodation.
The function of the eye may be checked in several ways. The patient may be asked to determine illuminated letter or items of differing sizes on what is referred to as the Snellen chart.
Conversely, the examination of the structural part of the eye may be made in several methods. Tension within the eyeball is measured by a "tonometer." In certain diseases, especially in glaucoma, the tension in the eyeball is increased significantly.
It ought to be well remembered that a client with an eye issue might have other issues. Frequently other physical conditions are primary and affect the eye as a effect. The appearance of the eye can inform the doctor and the patient to problems in some disturbances of other parts of the body even before other signs present themselves.
Consequently, one's reliance on sight is stressed when one deals with a temporary or possible long-term loss of this crucial sense. When corrective steps are sought, specific forms of vision correction such as contact lenses or spectacles are recommended.
On the other hand, some individuals are bothered with that they have actually some framed lenses or contact lenses in front of their eyes.
For this reason, advanced surgical operations were developed to encourage decreased utilization of contact lenses or glasses. Among which is the now popular LASIK eye surgery.
Basically, LASIK eye surgery is the short term for "Laser-Assisted In Situ Keratomileusis." Like its concrete equivalent, LASIK eye surgical treatment is another form of vision correction. The only difference is that with this kind of surgical treatment, one's vision is remedied completely.
With LASIK eye surgery, the refractive errors in the cornea are completely changed. This can be done utilizing an "excimer laser."
The primary function of this surgery is to create a threadlike, rounded "flap" in the cornea using a blade known as "microkeratome." In a series of unfolding and laser processing, the cornea is finally reformed, permitting much better the eye to direct more light into the retina.
Appeal vs. Disadvantages
In the middle of the growing appeal of LASIK eye surgical treatment, there are still disadvantages that people must know. Most likely, the primary reason this kind of eye surgical treatment has become well accepted is since the majority of its cases had been effective.
In spite of its success, there are still some disadvantages. Here is the list:
1. It is an operation used to the most sensitive part of the eye
Due to the fact that LASIK eye surgery includes the operation of the retina, which is one of the most sensitive portions of the eye, many people say that the operation can be very dangerous.
To puts it simply, a easy mistake might view it now almost trigger an individual's lifetime loss of sight. It is important to consider lots of factors prior to choosing whether LASIK eye surgery is the best restorative measure one has to go through.
2. It is not a perfect procedure
LASIK eye surgical treatment might fix your vision however it does not always mean that it can provide you a twenty-twenty. Even if statistical reports show that 70% of the patients might have 20/20 vision, this does not always mean they have ideal vision also.
Offered all these things, it can be deduced that, in spite of the popularity of the operation, LASIK might not always be the ideal eye surgery the way many people view it
On the other hand, the assessment of the structural part of the eye might be made in a number of methods. It must be well remembered that a patient with an eye problem may have other issues. Frequently other physical conditions are primary and affect the eye as a consequence. The look of the eye can signal the physician and the patient to troubles in some disruptions of other parts of the body even before other symptoms provide themselves.
Like its concrete counterpart, LASIK eye surgical treatment is another kind of vision correction.
Leave a Reply
Your email address will not be published. Required fields are marked * | {
"url": "http://jeffreynkyk936.shotblogs.com/2-benefits-individuals-do-not-really-understand-in-connection-with-lasik-eye-surgery-5216104",
"source_domain": "jeffreynkyk936.shotblogs.com",
"snapshot_id": "crawl=CC-MAIN-2018-17",
"warc_metadata": {
"Content-Length": "16308",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:FJR7QV2G2KCQA55RSIXE3YXOKFZQV2KU",
"WARC-Concurrent-To": "<urn:uuid:0645db16-9393-42ed-adf1-25aa6ddfcd87>",
"WARC-Date": "2018-04-22T19:39:37",
"WARC-IP-Address": "23.95.122.145",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:CORXICECJFLW57H2VPQX5QWM7XE3NE43",
"WARC-Record-ID": "<urn:uuid:49c53a28-5248-4b6d-b9b2-2a009ddda285>",
"WARC-Target-URI": "http://jeffreynkyk936.shotblogs.com/2-benefits-individuals-do-not-really-understand-in-connection-with-lasik-eye-surgery-5216104",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:0c9eb72a-21b6-4a23-b1fd-b530c7ee5ec8>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-228-166-67.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2018-17\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for April 2018\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
85,
86,
306,
307,
493,
494,
745,
746,
1083,
1084,
1340,
1341,
1480,
1481,
1657,
1658,
1950,
1951,
2082,
2083,
2364,
2365,
2390,
2391,
2661,
2662,
2741,
2742,
2807,
2808,
2999,
3000,
3250,
3251,
3284,
3285,
3547,
3548,
3719,
3720,
3721,
4165,
4166,
4264,
4265,
4279,
4280
],
"line_end_idx": [
85,
86,
306,
307,
493,
494,
745,
746,
1083,
1084,
1340,
1341,
1480,
1481,
1657,
1658,
1950,
1951,
2082,
2083,
2364,
2365,
2390,
2391,
2661,
2662,
2741,
2742,
2807,
2808,
2999,
3000,
3250,
3251,
3284,
3285,
3547,
3548,
3719,
3720,
3721,
4165,
4166,
4264,
4265,
4279,
4280,
4350
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4350,
"ccnet_original_nlines": 47,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4515337347984314,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.014723929576575756,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.10674846917390823,
"rps_doc_frac_unique_words": 0.4222833514213562,
"rps_doc_mean_word_length": 4.83356237411499,
"rps_doc_num_sentences": 40,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.020096778869629,
"rps_doc_word_count": 727,
"rps_doc_frac_chars_dupe_10grams": 0.04325554892420769,
"rps_doc_frac_chars_dupe_5grams": 0.13944223523139954,
"rps_doc_frac_chars_dupe_6grams": 0.09846328943967819,
"rps_doc_frac_chars_dupe_7grams": 0.07911211997270584,
"rps_doc_frac_chars_dupe_8grams": 0.06374502182006836,
"rps_doc_frac_chars_dupe_9grams": 0.06374502182006836,
"rps_doc_frac_chars_top_2gram": 0.02703472040593624,
"rps_doc_frac_chars_top_3gram": 0.015936249867081642,
"rps_doc_frac_chars_top_4gram": 0.028457600623369217,
"rps_doc_books_importance": -333.01434326171875,
"rps_doc_books_importance_length_correction": -333.01434326171875,
"rps_doc_openwebtext_importance": -173.17530822753906,
"rps_doc_openwebtext_importance_length_correction": -173.17530822753906,
"rps_doc_wikipedia_importance": -104.02357482910156,
"rps_doc_wikipedia_importance_length_correction": -104.02357482910156
},
"fasttext": {
"dclm": 0.06775254011154175,
"english": 0.96128910779953,
"fineweb_edu_approx": 2.8345468044281006,
"eai_general_math": 0.01573132909834385,
"eai_open_web_math": 0.31950002908706665,
"eai_web_code": 0.00035595998633652925
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.722",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "5",
"label": "Evaluate"
},
"secondary": {
"code": "2",
"label": "Understand"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "12",
"label": "Listicle"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
-6,478,629,264,619,248,000 | Difference Between Plantar Fasciitis and Achilles Tendonitis
Plantar Fasciitis and Achilles Tendonitis are two of the most common causes of pain in the foot and lower leg. Both conditions involve inflammation of the soft tissues of the foot, but they are distinct …
Plantar Fasciitis and Achilles Tendonitis are two of the most common causes of pain in the foot and lower leg. Both conditions involve inflammation of the soft tissues of the foot, but they are distinct conditions with distinct causes and treatments. Understanding the differences between the two can help you get the right diagnosis and treatment.
Plantar Fasciitis is an inflammation of the plantar fascia, a thick band of tissue that connects the heel bone to the toes and provides support for the arch of the foot. The condition is most common in people who are active, especially if they engage in activities that involve a lot of running or jumping. It is also more common in people who wear shoes that do not provide adequate support and in those who have high arches or flat feet. Symptoms include sharp pain near the heel that is worse in the morning, pain in the arch of the foot, and difficulty walking.
Achilles Tendonitis is an inflammation of the Achilles tendon, the thick cord of tissue that connects the calf muscles to the heel bone. The condition is commonly seen in athletes, particularly runners, who put a lot of pressure on their Achilles tendon when they run. It is also more common in people who have tight calf muscles or flat feet. Symptoms include pain and stiffness along the back of the leg, swelling in the area, and difficulty standing on the toes.
Treatment for both conditions involves relieving the inflammation and reducing the pressure on the affected area. This can include rest, ice, compression, elevation, stretching, and physical therapy. In some cases, a doctor may prescribe anti-inflammatory medications or corticosteroid injections to help reduce the inflammation. Surgery may be recommended if the condition does not respond to other treatments.
You may also like What is the Difference Between a Mole and a Freckle
When it comes to Plantar Fasciitis and Achilles Tendonitis, the most important thing is to get an accurate diagnosis so that you can get the right treatment. Understanding the differences between the two conditions can help you make an informed decision about your treatment.
Difference in Location
Plantar fasciitis and Achilles tendonitis are both common forms of tendonitis, which is an inflammation of the tendons. However, they are both located in different areas of the body. Plantar fasciitis affects the tissue on the bottom of the foot, known as the plantar fascia. This tissue supports the arch of the foot and connects the heel bone to the toes. Achilles tendonitis affects the large tendon in the back of the ankle, called the Achilles tendon. This tendon connects the calf muscles to the heel bone and is important for movement of the foot.
Difference in Symptoms
The symptoms of plantar fasciitis and Achilles tendonitis are also different. Plantar fasciitis is typically characterized by heel pain, which is often most severe when first standing from rest in the morning. It can also cause pain when walking or standing for long periods of time, as well as swelling in the arch of the foot.
Achilles tendonitis, on the other hand, is characterized by pain in the back of the ankle. This pain is typically aggravated by activities such as running and jumping, and can also cause swelling and tenderness in the area.
Difference in Treatment
The treatment of plantar fasciitis and Achilles tendonitis also differs. Treatment for plantar fasciitis typically includes rest, stretching, and physical therapy. Over-the-counter medications may also be used for pain relief. In more severe cases, orthotics or a night splint may be used to support the arch of the foot and reduce symptoms.
You may also like Difference Between an Ulcer and Pancreatitis
Achilles tendonitis treatment often involves rest, stretching, and physical therapy as well. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used to reduce inflammation and pain. In severe cases, a course of corticosteroid injections may be used. Surgery may be necessary in extreme cases.
Leave a Comment | {
"url": "https://differencesfinder.com/difference-between-plantar-fasciitis-and-achilles-tendonitis/",
"source_domain": "differencesfinder.com",
"snapshot_id": "CC-MAIN-2024-22",
"warc_metadata": {
"Content-Length": "99794",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:UIU447UPXAYZMS37PHYHE43GR5F3U5QD",
"WARC-Concurrent-To": "<urn:uuid:e4f1bb81-a10f-4a45-9755-8b271feac8b8>",
"WARC-Date": "2024-05-21T01:10:53",
"WARC-IP-Address": "50.31.176.103",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:GABSFE5W22UO34IJTDLN5UM5WG6AO3T3",
"WARC-Record-ID": "<urn:uuid:73108e03-2bf3-499e-81a7-2a5e4a99524d>",
"WARC-Target-URI": "https://differencesfinder.com/difference-between-plantar-fasciitis-and-achilles-tendonitis/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:d0ab8e1c-67bb-438c-a320-6b749af5e47d>"
},
"warc_info": "isPartOf: CC-MAIN-2024-22\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for May 2024\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-27\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.5-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
61,
62,
267,
268,
617,
618,
1184,
1185,
1651,
1652,
2064,
2065,
2136,
2137,
2413,
2414,
2437,
2438,
2993,
2994,
3017,
3018,
3347,
3348,
3572,
3573,
3597,
3598,
3940,
3941,
4005,
4006,
4306,
4307
],
"line_end_idx": [
61,
62,
267,
268,
617,
618,
1184,
1185,
1651,
1652,
2064,
2065,
2136,
2137,
2413,
2414,
2437,
2438,
2993,
2994,
3017,
3018,
3347,
3348,
3572,
3573,
3597,
3598,
3940,
3941,
4005,
4006,
4306,
4307,
4322
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 4322,
"ccnet_original_nlines": 34,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.44458597898483276,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0.02857143059372902,
"rps_doc_frac_no_alph_words": 0.09808917343616486,
"rps_doc_frac_unique_words": 0.2950354516506195,
"rps_doc_mean_word_length": 4.99716329574585,
"rps_doc_num_sentences": 38,
"rps_doc_symbol_to_word_ratio": 0.0012738900259137154,
"rps_doc_unigram_entropy": 4.699074745178223,
"rps_doc_word_count": 705,
"rps_doc_frac_chars_dupe_10grams": 0.09423787146806717,
"rps_doc_frac_chars_dupe_5grams": 0.3187624216079712,
"rps_doc_frac_chars_dupe_6grams": 0.23616236448287964,
"rps_doc_frac_chars_dupe_7grams": 0.14646607637405396,
"rps_doc_frac_chars_dupe_8grams": 0.13057054579257965,
"rps_doc_frac_chars_dupe_9grams": 0.09423787146806717,
"rps_doc_frac_chars_top_2gram": 0.028384899720549583,
"rps_doc_frac_chars_top_3gram": 0.02299177087843418,
"rps_doc_frac_chars_top_4gram": 0.05364745855331421,
"rps_doc_books_importance": -317.7643127441406,
"rps_doc_books_importance_length_correction": -317.7643127441406,
"rps_doc_openwebtext_importance": -198.50201416015625,
"rps_doc_openwebtext_importance_length_correction": -198.50201416015625,
"rps_doc_wikipedia_importance": -152.81765747070312,
"rps_doc_wikipedia_importance_length_correction": -152.81765747070312
},
"fasttext": {
"dclm": 0.17498165369033813,
"english": 0.9412614703178406,
"fineweb_edu_approx": 3.098378896713257,
"eai_general_math": 0.015601989813148975,
"eai_open_web_math": 0.3227245807647705,
"eai_web_code": 0.0005530699854716659
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "617.72",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
},
"secondary": {
"code": "617.7",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Surgery and Dentistry"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
2,549,397,034,744,001,500 | Get your Health question answered in 3 easy steps
A Doctor will be with you shortly
Ask a Doctor Now
168 Doctors are Online
Having large tonsils and feeling something stuck around tonsils. Suggest
User rating for this question
Excellent
Answered by
ENT Specialist
Practicing since : 1998
Answered : 660 Questions
Question
I have had large tonsils for a long time, but they never hurt. My right tonsil is larger than the other. I visited the ENT last month, and told him about my condition, and after he looked at it, he did not find anything serious or any exhibition of something serious. I have no sore throat, no fever, nothing anemic. But since yesterday, especially when I don't drink much water, I feel something like a fish bone stuck in my left, right around where the tonsil is. I also had a mild wisdom tooth infection last month, but it was on my left. There is no sign of any infection in any of my wisdom teeth, and I am taking them out during my vacations in India next month. I am visiting a dentist tomorrow, and a physician as well. I am also going to the ENT for another routine check-up for my tonsils.
Posted Thu, 28 Nov 2013 in Ear, Nose and Throat Problems
Answered by Dr. Prahlad Duggal 2 hours later
Brief Answer: Hexidine mouthwash regularly Detailed Answer: Hello, just an increase in size of tonsils in not an indication for any intervention. You have had tonsils enlarged for long time but there were no associated symptoms. Just by the size, the indication for removal of tonsils is when these cause respiratory difficulty or foreign body sensation in throat. The other indications are mainly infective and any focus of infection in the vicinity (oral cavity) leads to more frequent or retained infection in the tonsillar crypts. You are having a foreign body sensation in throat, which can be because of slight increase in the size of an already big tonsil because of infection, or sometimes collection of debris in one of the tonsillar crypts. Please use regularly hexidine mouthwash and that will help in partially taking care of your tonsillar infection if any and tooth infection if any. Another thing, slight asymmetry in the size of two tonsils is normal but a significant asymmetry especially of recent onset needs a visit to ENT. My suggestion is, when you are visiting a dentist in vacations, do visit an ENT also and take opinion. Regards
Above answer was peer-reviewed by
Follow-up: Having large tonsils and feeling something stuck around tonsils. Suggest 7 hours later
Thank you for your answer! Yes, I am using saltwater rinsing and cloves multiple times a day, and I don't have hexidine yet, so I am using a crest pro-health mouthwash. Does it make a significant difference? Also, the effect that I spoke of comes and goes; it is not persistent. And also, as far as I can remember, my right tonsil has always been a little larger than the left.
Answered by Dr. Prahlad Duggal 3 hours later
Brief Answer: Does not make any difference Detailed Answer: Hi, Thanks for writing back, You can use any regular mouth wash which has got antiseptic properties and usually it does not make any difference. Just make sure that last thing you do before going to bed is use of mouth wash and the effect last for longer periods when you are asleep. As I have already stated a recent onset significant difference in tonsillar size should be evaluated. Take care.
Above answer was peer-reviewed by
Follow-up: Having large tonsils and feeling something stuck around tonsils. Suggest 2 hours later
Thank you for your reply! I visited the practitioner in my university, and told her my problem. She said she could not see any infection in my tonsils. However, she could see a whitish patch in the back of my throat towards my right, which is what is called post nasal drip. I have been given antihistamines for the weekend before my appointment with the ENT. Would that be okay?
Answered by Dr. Prahlad Duggal 8 hours later
Brief Answer: Nasal decongestants, mucolytics, steam Detailed Answer: Hi, That you are having PND on right side supports that you are having a focus of infection in the sinus and needs to be investigated for that with xray PNS and CT PNS (if need be). Please take nasal decongestants and mucolytics and this helps in clearing the sinuses along with steam inhalation. Regards
Above answer was peer-reviewed by
Follow-up: Having large tonsils and feeling something stuck around tonsils. Suggest 15 minutes later
How major would the sinus infection be, if any? I have not had a runny nose, no coughing or sneezing, and I am breathing in and out without any discomfort. I have to admit that here in Florida, there are a lot white pollen grains flying, especially in the evening, when I have my classes.
Answered by Dr. Prahlad Duggal 3 hours later
Brief Answer: without CT will be a guess work Detailed Answer: Considering your description of symptoms, the problem should be unilateral (if it is there) and a smaller one but this can be just a guess with having a look at the CT scan. Anyway most of these can be handled endoscopically and is a comfortable procedure. Only thing is that you need to follow up with the operating surgeon for some time. Also as you do not give history of typical allergic symptoms, the chances of success will be more. Regards
Above answer was peer-reviewed by
Follow-up: Having large tonsils and feeling something stuck around tonsils. Suggest 7 hours later
Yes, indeed. The practitioner said, the PND is quite superficial. However, there is no harm in going to the ENT, and I am doing so this Monday. As I speak, the fish-bone feeling has decreased quite considerably.
Answered by Dr. Prahlad Duggal 5 minutes later
Brief Answer: Go ahead with your ENT appointment Detailed Answer: Hi, please go ahead with your appointment with ENT and in case he/she finds it necessary and advises some investigations, go ahead with those. Wish you good health.
Above answer was peer-reviewed by
Follow-up: Having large tonsils and feeling something stuck around tonsils. Suggest 4 hours later
Yes definitely. The fish bone feeling has almost completely subsided as I speak. The salt water rinsing I presume has taken effect. Do you suggest anything I need to do in the meanwhile?
Answered by Dr. Prahlad Duggal 7 hours later
Brief Answer: Relax Detailed Answer: Hi dear, just relax and things will be fine. Local rinses helps in clearing the area. Regards
Above answer was peer-reviewed by
Follow-up: Having large tonsils and feeling something stuck around tonsils. Suggest 42 hours later
Thank you sir! I went to the ENT today, and he said that although my tonsils were large, they were smooth and were alright, nothing to worry about. He checked for my lymph nodes and they seemed normal. He saw to PND; however, he saw some redness in my throat and he affirmed it to be GERD causing the fish bone feeling. He said it could also be causing the weird soreness around the jaw below the ear, given that my dentist told me the other day that the wisdom teeth showed no significant sign of redness and swelling. What do you recommend as a diet? I am having some antacid prescribed by the ENT for a few days.
Answered by Dr. Prahlad Duggal 7 hours later
Brief Answer: Avoid spicy, oily food, tea, coffee, alcohol Detailed Answer: Hi, Thanks for the query. Please follow the advice of your doctor there. As far as diet is concerned, you should avoid spicy and oily things, tea coffee to the minimum and alcohol to be avoided all together. You have to avoid taking NSAID pain killers as well. Not to take very large volume of food at a given time and do not lie down immediately after taking a meal. Wish you good health.
Above answer was peer-reviewed by
Share on Facebook
Share on Twitter
Share on Google+
Question is related to
Diseases and Conditions
Medical Topics
The user accepted the expert's answer
Ask an ENT Specialist
© Ebix, Inc. All Rights Reserved.
All the information, content and live chat provided on the site is intended to be for informational purposes only, and not a substitute for professional or medical advice. You should always speak with your doctor before you follow anything that you read on this website. Any health question asked on this site will be visible to the people who browse this site. Hence, the user assumes the responsibility not to divulge any personally identifiable information in the question. Use of this site is subject to our Terms & Conditions
Already Rated.
Your rating:
Ask a Doctor | {
"url": "http://www.healthcaremagic.com/premiumquestions/Having-large-tonsils-and-feeling-something-stuck-around-tonsils-Suggest/77051",
"source_domain": "www.healthcaremagic.com",
"snapshot_id": "crawl=CC-MAIN-2016-44",
"warc_metadata": {
"Content-Length": "80649",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:A5GZYXVTER3UKD3IMKUGPZT3LB6XLHZ5",
"WARC-Concurrent-To": "<urn:uuid:956a4dc0-b58d-4675-a6fe-ebd94982b201>",
"WARC-Date": "2016-10-24T22:09:04",
"WARC-IP-Address": "207.198.118.30",
"WARC-Identified-Payload-Type": null,
"WARC-Payload-Digest": "sha1:OGPHELAKINXGS3GY57WD2LWX5RDLICCO",
"WARC-Record-ID": "<urn:uuid:ceb2ec2b-85e6-4c23-b254-a77aabbbd8f6>",
"WARC-Target-URI": "http://www.healthcaremagic.com/premiumquestions/Having-large-tonsils-and-feeling-something-stuck-around-tonsils-Suggest/77051",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:4e76b708-0141-4a1b-8438-5cb8d3aee4b3>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-171-6-4.ec2.internal\r\nsoftware: Nutch 1.6 (CC)/CC WarcExport 1.0\r\nisPartOf: CC-MAIN-2016-44\r\noperator: CommonCrawl Admin\r\ndescription: Wide crawl of the web for October 2016\r\npublisher: CommonCrawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
50,
84,
101,
124,
125,
198,
199,
229,
239,
251,
252,
267,
291,
316,
325,
1125,
1182,
1184,
1186,
1231,
2386,
2420,
2422,
2520,
2898,
2900,
2902,
2947,
3404,
3438,
3440,
3538,
3918,
3920,
3922,
3967,
4342,
4376,
4378,
4479,
4768,
4770,
4772,
4817,
5327,
5361,
5363,
5461,
5673,
5675,
5677,
5724,
5955,
5989,
5991,
6089,
6276,
6278,
6280,
6325,
6456,
6490,
6492,
6591,
7207,
7209,
7211,
7256,
7722,
7756,
7758,
7776,
7793,
7810,
7833,
7857,
7872,
7873,
7911,
7912,
7934,
7935,
7969,
8500,
8515,
8528,
8529
],
"line_end_idx": [
50,
84,
101,
124,
125,
198,
199,
229,
239,
251,
252,
267,
291,
316,
325,
1125,
1182,
1184,
1186,
1231,
2386,
2420,
2422,
2520,
2898,
2900,
2902,
2947,
3404,
3438,
3440,
3538,
3918,
3920,
3922,
3967,
4342,
4376,
4378,
4479,
4768,
4770,
4772,
4817,
5327,
5361,
5363,
5461,
5673,
5675,
5677,
5724,
5955,
5989,
5991,
6089,
6276,
6278,
6280,
6325,
6456,
6490,
6492,
6591,
7207,
7209,
7211,
7256,
7722,
7756,
7758,
7776,
7793,
7810,
7833,
7857,
7872,
7873,
7911,
7912,
7934,
7935,
7969,
8500,
8515,
8528,
8529,
8541
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 8541,
"ccnet_original_nlines": 87,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.4298297166824341,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.029947150498628616,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.13270698487758636,
"rps_doc_frac_unique_words": 0.32972240447998047,
"rps_doc_mean_word_length": 4.607989311218262,
"rps_doc_num_sentences": 88,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.5303568840026855,
"rps_doc_word_count": 1477,
"rps_doc_frac_chars_dupe_10grams": 0.13047310709953308,
"rps_doc_frac_chars_dupe_5grams": 0.18527770042419434,
"rps_doc_frac_chars_dupe_6grams": 0.14545989036560059,
"rps_doc_frac_chars_dupe_7grams": 0.13958272337913513,
"rps_doc_frac_chars_dupe_8grams": 0.13958272337913513,
"rps_doc_frac_chars_dupe_9grams": 0.13958272337913513,
"rps_doc_frac_chars_top_2gram": 0.01616220921278,
"rps_doc_frac_chars_top_3gram": 0.01851307973265648,
"rps_doc_frac_chars_top_4gram": 0.021598590537905693,
"rps_doc_books_importance": -805.7986450195312,
"rps_doc_books_importance_length_correction": -805.7986450195312,
"rps_doc_openwebtext_importance": -502.12677001953125,
"rps_doc_openwebtext_importance_length_correction": -502.12677001953125,
"rps_doc_wikipedia_importance": -401.8214416503906,
"rps_doc_wikipedia_importance_length_correction": -401.8214416503906
},
"fasttext": {
"dclm": 0.13598591089248657,
"english": 0.9691783785820007,
"fineweb_edu_approx": 1.2303084135055542,
"eai_general_math": 0.024883149191737175,
"eai_open_web_math": 0.33745187520980835,
"eai_web_code": 0.0003746699949260801
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.12",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.1",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "18",
"label": "Q&A Forum"
},
"secondary": {
"code": "21",
"label": "Customer Support"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
-8,098,880,624,138,529,000 | Abstract
Eosinophils are potent inflammatory cells involved in allergic reactions. Inhibition of apoptosis of purified eosinophils by certain cytokines has been previously shown to be an important mechanism causing tissue eosinophilia. To elucidate the role of Bcl-2 family members in the inhibition of eosinophil apoptosis, we examined the expression of the known anti-apoptotic genes Bcl-2, Bcl-xL, and A1, as well as Bax and Bcl-xS, which promote apoptosis in other systems. We show herein that freshly isolated human eosinophils express significant amounts of Bcl-xL and Bax, but only little or no Bcl-2, Bcl-xS, or A1. As assessed by reverse transcription-polymerase chain reaction, immunoblotting, flow cytometry, and immunocytochemistry, we show that spontaneous eosinophil apoptosis is associated with a decrease in Bcl-xL mRNA and protein levels. In contrast, stimulation of the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-5 (IL-5) results in maintenance or upregulation of Bcl-xL mRNA and protein levels. Moreover, Bcl-2 protein is not induced by GM-CSF or IL-5 in purified eosinophils. Bcl-2 protein is also not expressed in tissue eosinophils as assessed by immunohistochemistry using two different eosinophilic tissue models. Furthermore, Bcl-xL antisense but not scrambled phosphorothioate oligodeoxynucleotides can partially block the cytokine-mediated rescue of apoptotic death in these cells. These data suggest that Bcl-xL acts as an anti-apoptotic molecule in eosinophils.
© 1998 by The American Society of Hematology.
EOSINOPHILIC INFILTRATION into tissues is usually followed by elimination of these cells by apoptosis. Cytokine-mediated inhibition of apoptosis contributes to the accumulation of eosinophils in tissues.1 Such eosinophilia is often observed in patients with chronic allergic diseases such as bronchial asthma.2,3 In the past few years there has been some progress in defining the tyrosine kinases that are activated by the interleukin-3 (IL-3)/IL-5/granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor β-subunit. In contrast, no information is available regarding the genetic control of eosinophil apoptosis in allergic diseases.
Members of the Bcl-2 family of proteins are important regulators of apoptosis in many cellular systems.4 The first member of the family, Bcl-2, was originally cloned from the breakpoint of a t(14;18) translocation present in many human B-cell lymphomas. Increased production of Bcl-2 protein as a result of t(14;18) translocation contributes to neoplastic B-cell expansion by preventing B-cell death.4 Besides Bcl-2, there are other members of the family that inhibit apoptosis. For instance, the proteins encoded by Bcl-xL4,5 and A16 genes are also potent blockers of apoptosis. In contrast, other members of the Bcl-2 family promote cell death. For example, Bax7 and Bcl-xS5 are such pro-apoptotic proteins.
There have been some reports on the expression of Bcl-2 in eosinophils. Whereas two groups8,9 obtained evidence for Bcl-2 expression, a third group10 did not observe significant Bcl-2 levels. Therefore, the expression of Bcl-2 and other members of the Bcl-2 family in eosinophils does not appear to be clear at the moment. Moreover, all previously published work analyzed gene expression, but no functional data are currently available on Bcl-2 family members in eosinophils. To better understand the regulation of eosinophil apoptosis in chronic eosinophilic inflammation, we have investigated the expression of Bcl-2, Bcl-xL, A1, Bax, and Bcl-xS in freshly purified ex vivo eosinophils from control individuals and patients with atopic dermatitis as well as in tissue eosinophils that reflect the in vivo situation of chronic eosinophilic inflammation. Moreover, we measured the expression of these genes in eosinophils cultured in the presence or absence of GM-CSF and IL-5 in vitro. Furthermore, this study provides functional evidence for a role of Bcl-xL in the control of eosinophil apoptosis.
MATERIALS AND METHODS
Antibodies.
Anti–Bcl-2 monoclonal antibody (MoAb), control IgG1 MoAb, swine anti-rabbit fluorescein isothiocyanate (FITC)-conjugated secondary IgG antibody, and control rabbit IgG were from Dako (Zurich, Switzerland). FITC-conjugated anti–Bcl-2 MoAb was from Ancell Corp (Bayport, MN). Polyclonal rabbit antibodies against Bcl-x and Bax were purchased from Santa Cruz Biotechnology, Inc (Santa Cruz, CA). Polyclonal rabbit anti-Bcl-xS antibody was from Calbiochem-Novabiochem Corp (San Diego, CA). Goat anti-rabbit and anti-mouse horseradish peroxidase (HRP)-labeled secondary antibodies were obtained from Amersham International (Bucks, UK). FITC-conjugated control IgG1 MoAb was from Coulter (Hialeah, FL). Anti–IL-3 and anti–GM-CSF MoAbs were purchased from Genzyme (Cambridge, MA). Anti–IL-5 MoAb (5A5) was a kind gift from Dr J. Tavernier (University of Gent, Gent, Belgium). Anti-eosinophil cationic protein (ECP) MoAb (EG1) was from Pharmacia (Uppsala, Sweden). Anti-CD16 MoAb microbeads were from Miltenyi Biotec (Bergisch-Gladbach, Germany).
Eosinophil purification and cell cultures.
Eosinophils were purified from patients with atopic dermatitis and healthy normal individuals as previously described.11-14Eosinophils were cultured at 1 × 106/mL (expression experiments) or 0.5 × 106/mL (antisense experiments) for the indicated times using complete culture medium (RPMI 1640 supplemented with 10% fetal calf serum [FCS]). GM-CSF was a kind gift from Dr T. Hartung (University of Konstanz, Konstanz, Germany). IL-5 was obtained from Genzyme. The final cytokine concentrations were 25 ng/mL. Phosphorothioate oligodeoxynucleotide were synthesized by Genset S.A. (Paris, France). Sequences used were as follows: antisense Bcl-xL, 5′-TGT ATC CTT TCT GGG AAA GC-3′; and scrambled Bcl-xL, 5′-TAA GTT CCG ATG CGA CTT GT-3′. These antisense molecules were selected from a panel of different oligodeoxynucleotides as previously described.15The oligodeoxynucleotides were given to purified eosinophils that had been cultured for 20 hours in complete culture medium (at this time, the cells did not express detectable Bcl-xL protein levels), and were delivered in the form of complexes with the cationic lipid DOTAP (Boehringer Mannheim, Mannheim, Germany). Equal volumes of oligodeoxynuleotide (6 μmol/L) and DOTAP (0.2 mmol/L) were mixed and allowed to complex for 10 minutes at room temperature. The final oligodeoxynucleotide concentrations were 0.45 μmol/L. The initial phase (first 4 hours) of incubation with the oligodeoxynucleotides was performed in medium without serum to increase the uptake of these molecules by the eosinophils. Cells were then cultured again in complete culture medium in the presence or absence of GM-CSF or IL-5 for another 24 hours (apoptosis assay) or 36 hours (cell death assay). Therefore, cell viability was determined after the eosinophils had been in culture for a total of 60 hours.
Reverse transcription-polymerase chain reaction (RT-PCR).
mRNA expression of Bcl-2 family members was studied using Southern blot analysis linked to RT-PCR.1,11,12 Primers for Bcl-2 (5′-ACA ACA TCG CCC TGT GGA TGA C-3′ and 5′-ATA GCT GAT TCG ACG TTT TGC C-3′), Bcl-x (5′-GGA ATT CTT GGA CAA TGG ACT GGT TGA-3′ and 5′-CCC AAG CTT GTA GAG TGG ATG GTC AGT G-3′), Bax (5′-GGA ATT CTG ACG GCA ACT TCA ACT GGG-3′ and 5′-GGA ATT CTT CCA GAT GGT GAG CGA GG-3′), and A1 (5′-GAA GAT GAC AGA CTG TGA AT-3′ and 5′-TCA ACA GTA TTG CTT CAG GAG-3′) amplifications were synthesized (Bcl-2: HSC Biotechnology Service Centre, Toronto, Ontario, Canada; Bcl-x and Bax: R & D Systems, Abingdon, UK; A1: Microsynth, Balgach, Switzerland) according to previously published sequences.6,16 For positive controls, PCR amplifications were performed at the same time using cDNAs from HL-60 (Bcl-2, Bcl-x, Bax) and Jurkat (A1) cells. For negative controls, PCR reactions were performed without template DNA. Primers for β-actin control amplification were obtained from Clontech (Palo Alto, CA). The cDNAs used for the probes were cloned by PCR amplification of positive template DNA (cDNAs from HL-60, Jurkat cells, and neutrophils), and their specificities confirmed by sequencing.
Immunofluorescence.
Purified eosinophils (0.1 × 106) were stained with FITC-conjugated anti–Bcl-2 or control MoAb for 15 minutes at room temperature after a 45-minute permeabilization of the cell membrane with Permeafix (Ortho Diagnostic Systems, Raritan, NJ). To determine Bcl-x and Bax expression, cells were initially incubated with 10 μg/mL anti-Bcl-x, anti-Bcl-xS, anti-Bax, or control rabbit antibody for 15 minutes at room temperature, washed, and then incubated with FITC-conjugated purified swine anti-rabbit IgG antibody for 15 minutes at room temperature. Directly or indirectly stained cells were washed, and fixed in phosphate-buffered saline (PBS)-buffered 2% paraformaldehyde solution. Eosinophils were analyzed by flow cytometry in an EPICS XL (Coulter).
Immunocytochemistry.
Bcl-x, Bcl-xS, and Bax protein expression was also investigated by immunocytochemistry using a commercial kit (Histostain SP kit; Zymed Laboratories, San Francisco, CA) according to the manufacturer's instructions. Briefly, cytospins were prepared from 0.1 × 106 purified eosinophils. Slides were fixed in freshly made and filtered PBS-buffered 4% paraformaldehyde solution for 20 hours at room temperature in the dark. After washing with H2O and PBS, slides were incubated with Peroxo-Block (Zymed Laboratories) for 10 minutes to quench endogenous peroxidase activity. After blocking with nonimmune serum, 1 μg/mL primary antibody was added for 1 hour. This incubation was followed by addition of biotinylated secondary antibody and streptavidin-peroxidase conjugate. Bound peroxidase was detected by addition of substrate chromogen mixture, followed by hematoxylin counterstaining. Slides were mounted, and examined under a Zeiss Axioscope microscope (Oberkochen, Germany) at a magnification of ×1,000.
For Bcl-2 staining, the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method was used.11 Staining was performed with a commercial kit (Dako) according to the manufacturer's instructions.
Immunoprecipitation, gel electrophoresis, and immunoblotting.
Immunoprecipitation, gel electrophoresis, and immunoblotting were performed as previously described,13 using anti–Bcl-x antibody.
Immunohistochemistry.
Immunohistochemistry was performed using nasal polyp and bladder cancer tissues as previously described.1 Anti-ECP, anti–Bcl-2, anti–IL-3, anti–IL-5, or anti–GM-CSF MoAb immunostainings were performed using the APAAP method with a commercial kit (Dako) according to the manufacturer's instructions. In additional experiments, sections were stained with anti–Bcl-x and anti-Bax antibody. These immunostainings were performed using a kit for rabbit primary antibody (Zymed Laboratories). Sections were examined under a Zeiss Axioscope microscope at a magnification of ×400 or ×1,000.
Determination of eosinophil death and apoptosis.
Cell death of eosinophils was assessed by uptake of 1 μmol/L ethidium bromide and flow cytometric analysis (EPICS XL) as previously described.12-14 To determine whether eosinophil death was apoptosis, eosinophils were morphologically examined.17Cytospin preparations were made, stained with Diff-Quik (Baxter, Düdingen, Switzerland), and analyzed as well as photographed under a Zeiss Axioscope microscope at a magnification of ×1,000.
RESULTS AND DISCUSSION
Bcl-xL, but not Bcl-xS, is significantly expressed by eosinophils.
We first measured mRNA levels by RT-PCR in freshly isolated as well as cultured eosinophils in the presence or absence of the survival factors GM-CSF or IL-5. Because the PCR primers used bind to sequences shared by Bcl-xL and Bcl-xS, this technique allowed simultaneous identification of both Bcl-x mRNAs. As shown in Fig 1, freshly purified eosinophils expressed Bcl-xL but not Bcl-xS mRNA. The expression of Bcl-xL appeared to increase after GM-CSF stimulation of the eosinophils in vitro but rapidly decreased when eosinophils were cultured without cytokine support (Fig 1). To better quantify the expression of Bcl-xL mRNA in response to eosinophil hematopoietins, RT-PCR was performed using different numbers of cycles. These experiments clearly showed that Bcl-xLmRNA expression in eosinophils is downregulated in the absence and upregulated in the presence of eosinophil survival factors such as GM-CSF (Fig 2D) or IL-5 (not presented).
Fig. 1.
mRNA expression of Bcl-2 family members by purified blood eosinophils as assessed by RT-PCR using 20 cycles of amplification. Freshly isolated peripheral blood eosinophils (0) expressed significant levels of mRNA for Bcl-xL and Bax, but not for Bcl-2, Bcl-xS, and A1. When eosinophils were cultured in medium without cytokine support, the levels of Bcl-xL rapidly decreased, but were maintained or slightly increased after GM-CSF stimulation in vitro. In contrast, Bax mRNA levels remained unchanged when eosinophils were cultured in the presence or absence of GM-CSF. The same results were observed when eosinophils were cultured with IL-5 (not presented). Furthermore, Bcl-2 and A1 mRNA levels did not increase after incubation with eosinophil hematopoietins. As a control, human β-actin cDNA was amplified and PCR products were stained by ethidium bromide in an agarose gel. Positive control amplifications were performed using cDNAs from HL-60 (Bcl-x, Bax, Bcl-2) and Jurkat (A1) cells. All data are representative of eight independent experiments.
Fig. 1.
mRNA expression of Bcl-2 family members by purified blood eosinophils as assessed by RT-PCR using 20 cycles of amplification. Freshly isolated peripheral blood eosinophils (0) expressed significant levels of mRNA for Bcl-xL and Bax, but not for Bcl-2, Bcl-xS, and A1. When eosinophils were cultured in medium without cytokine support, the levels of Bcl-xL rapidly decreased, but were maintained or slightly increased after GM-CSF stimulation in vitro. In contrast, Bax mRNA levels remained unchanged when eosinophils were cultured in the presence or absence of GM-CSF. The same results were observed when eosinophils were cultured with IL-5 (not presented). Furthermore, Bcl-2 and A1 mRNA levels did not increase after incubation with eosinophil hematopoietins. As a control, human β-actin cDNA was amplified and PCR products were stained by ethidium bromide in an agarose gel. Positive control amplifications were performed using cDNAs from HL-60 (Bcl-x, Bax, Bcl-2) and Jurkat (A1) cells. All data are representative of eight independent experiments.
Fig. 2.
Bcl-xL, but not Bcl-xS, protein is significantly expressed by purified blood eosinophils. (A) Immunocytochemistry. Bcl-x (the antibody used reacts with both Bcl-xL and Bcl-xS proteins) proteins were expressed in freshly isolated peripheral blood eosinophils (0), and levels rapidly decreased under conditions of cytokine withdrawal in vitro, but were maintained in the presence GM-CSF. (B) Flow cytometry. The Bcl-x protein expression observed in freshly isolated peripheral blood eosinophils (0) was undetectable in the absence of eosinophil hematopoietins and appeared to be increased by cytokine exposure in cultured eosinophils after 20 hours. (C) Immunoprecipitation and immunoblot. Bcl-xL (arrow), but not Bcl-xS(arrowhead), protein expression was observed in freshly isolated peripheral blood eosinophils (0). Bcl-xL protein expression was increased after GM-CSF stimulation but decreased after cytokine withdrawal in vitro. (Right) The positions of molecular size standards. (D) Semiquantitative RT-PCR. Bcl-xL protein expression correlates with the expression of Bcl-xL mRNA. Cytokine withdrawal in vitro decreased Bcl-xL mRNA in eosinophils, whereas stimulation with GM-CSF or IL-5 (not presented) increased Bcl-xL mRNA expression. (Top) Numbers of PCR cycles. (E and F) Immunocytochemistry and flow cytometry. No detectable Bcl-xS (the antibody used reacts specifically with Bcl-xS) protein expression was observed in freshly isolated peripheral blood eosinophils (0). (A, B, E, and F) are representative of eight independent experiments, (C and D) of three independent experiments.
Fig. 2.
Bcl-xL, but not Bcl-xS, protein is significantly expressed by purified blood eosinophils. (A) Immunocytochemistry. Bcl-x (the antibody used reacts with both Bcl-xL and Bcl-xS proteins) proteins were expressed in freshly isolated peripheral blood eosinophils (0), and levels rapidly decreased under conditions of cytokine withdrawal in vitro, but were maintained in the presence GM-CSF. (B) Flow cytometry. The Bcl-x protein expression observed in freshly isolated peripheral blood eosinophils (0) was undetectable in the absence of eosinophil hematopoietins and appeared to be increased by cytokine exposure in cultured eosinophils after 20 hours. (C) Immunoprecipitation and immunoblot. Bcl-xL (arrow), but not Bcl-xS(arrowhead), protein expression was observed in freshly isolated peripheral blood eosinophils (0). Bcl-xL protein expression was increased after GM-CSF stimulation but decreased after cytokine withdrawal in vitro. (Right) The positions of molecular size standards. (D) Semiquantitative RT-PCR. Bcl-xL protein expression correlates with the expression of Bcl-xL mRNA. Cytokine withdrawal in vitro decreased Bcl-xL mRNA in eosinophils, whereas stimulation with GM-CSF or IL-5 (not presented) increased Bcl-xL mRNA expression. (Top) Numbers of PCR cycles. (E and F) Immunocytochemistry and flow cytometry. No detectable Bcl-xS (the antibody used reacts specifically with Bcl-xS) protein expression was observed in freshly isolated peripheral blood eosinophils (0). (A, B, E, and F) are representative of eight independent experiments, (C and D) of three independent experiments.
To determine whether the expression of Bcl-xL and Bcl-xS mRNAs correlates with the expression of their proteins, we performed immunocytochemistry, flow cytometry, and immunoblotting following immunoprecipitation using anti–Bcl-x (reacts with both Bcl-xL and Bcl-xS proteins) and specific anti–Bcl-xS antibodies. As shown in Fig 2A and B, and Fig 3A, freshly purified blood and tissue eosinophils expressed Bcl-x protein. Moreover, levels of Bcl-x protein were maintained or increased in GM-CSF–stimulated eosinophils. In contrast, levels of Bcl-x protein decreased under conditions of cytokine withdrawal in vitro (Fig 2A through C). Immunoblotting studies after anti–Bcl-x immunoprecipitation showed that the Bcl-x expression observed by immunocytochemistry and flow cytometry was totally caused by Bcl-xL expression, because no protein from the Bcl-xS splice form was detected (Fig 2C). In agreement with these data and recently published work,10Bcl-xS expression was also not seen using a specific anti–Bcl-xS antibody as assessed by immunocytochemistry (Fig 2E) and flow cytometry (Fig 2F). Together, these results suggest that expression of Bcl-xL transcripts correlates with the patterns of Bcl-xL protein expression in both freshly isolated or in vitro cultured eosinophils. Moreover, Bcl-x function does not appear to be regulated at the level of splicing in eosinophils.
Fig. 3.
Bcl-x and Bax, but not Bcl-2, proteins are significantly expressed by eosinophils in eosinophilic tissues. (A) Immunohistochemical staining with the indicated antibody using nasal polyp tissues. Bcl-x and Bax, but not Bcl-2, proteins were detectable in tissue eosinophils. In the Bcl-2 panel, some representative eosinophils are marked with arrows. The Bcl-2+ control was bone marrow tissue from a patient with a B-cell lymphoma. Moreover, IL-5 protein was highly expressed in nasal polyp tissues. (B) Staining of tissue infiltrated by bladder cancer cells as well as eosinophils. Again, eosinophils expressed no detectable Bcl-2 protein (see cells marked with an arrow in the third panel), although high levels of the eosinophil hematopoietins were present in this tissue.
Fig. 3.
Bcl-x and Bax, but not Bcl-2, proteins are significantly expressed by eosinophils in eosinophilic tissues. (A) Immunohistochemical staining with the indicated antibody using nasal polyp tissues. Bcl-x and Bax, but not Bcl-2, proteins were detectable in tissue eosinophils. In the Bcl-2 panel, some representative eosinophils are marked with arrows. The Bcl-2+ control was bone marrow tissue from a patient with a B-cell lymphoma. Moreover, IL-5 protein was highly expressed in nasal polyp tissues. (B) Staining of tissue infiltrated by bladder cancer cells as well as eosinophils. Again, eosinophils expressed no detectable Bcl-2 protein (see cells marked with an arrow in the third panel), although high levels of the eosinophil hematopoietins were present in this tissue.
Bax is expressed at high levels by eosinophils.
As shown in Fig 1, Bax mRNA was highly expressed in freshly isolated eosinophils. In addition, Bax mRNA levels remained unchanged when eosinophils were cultured in the presence or absence of GM-CSF (Fig 1) or IL-5 (not presented).
To determine Bax protein expression, an anti–Bax antibody was used. This antibody was able to stain tissue and purified blood eosinophils (Fig 3A, and Fig 4A and B). Moreover, we had no evidence for a change in Bax protein expression after in vitro cell cultures of eosinophils in the presence or absence of cytokines with anti-apoptotic properties (Fig 4A and B).
Fig. 4.
Bax protein is expressed by purified blood eosinophils. Bax protein levels remained unchanged when eosinophils were cultured in the presence or absence of eosinophil hematopoietins, as seen by immunocytochemistry (A) and flow cytometry (B). Each figure is representative of eight independent experiments.
Fig. 4.
Bax protein is expressed by purified blood eosinophils. Bax protein levels remained unchanged when eosinophils were cultured in the presence or absence of eosinophil hematopoietins, as seen by immunocytochemistry (A) and flow cytometry (B). Each figure is representative of eight independent experiments.
Bcl-2 and A1 are expressed at very low levels by eosinophils.
We again used RT-PCR to determine Bcl-2 and A1 mRNA levels. As shown in Fig 1, freshly isolated as well as cultured eosinophils in the presence or absence of GM-CSF from normal control individuals and allergic patients do not express Bcl-2 and A1 mRNA. Note that positive signals for Bcl-2 and A1 were only obtained when RT-PCR with a higher number of cycles (>25) was performed.
To determine whether eosinophils express Bcl-2 protein under conditions where they are exposed to eosinophil hematopoietins, we investigated tissues with significant eosinophilic infiltration using immunohistochemistry. We have previously shown that delayed eosinophil apoptosis occurs in nasal polyp tissues.1 Although high levels of IL-5 were present in these tissues, Bcl-2 expression was not observed in eosinophils (Fig 3A). Moreover, we had the chance to investigate eosinophil-infiltrated tissue from a patient with bladder cancer. Immunohistochemical examination of this tissue showed that the eosinophil hematopoietins IL-3, IL-5, and GM-CSF were highly expressed, especially by the cancer cells (Fig 3B). Again, the eosinophils under these pathologic conditions did not appear to express significant amounts of Bcl-2 protein (Fig. 3B). Furthermore, we used immunocytochemistry and flow cytometric analysis to measure Bcl-2 protein levels in purified blood eosinophils. We did not observe immunoreactive Bcl-2 in resting or GM-CSF–stimulated eosinophils (not presented). Together, these results show that Bcl-2 and A1 are either not present or are present at very low levels in human eosinophils.
Role for Bcl-xL in the regulation of eosinophil apoptosis by cytokines.
Bcl-xL is an anti-apoptotic protein that regulates apoptosis in many cellular systems,4,5 perhaps by regulating the electrical and osmotic homeostasis of mitochondria.17 Although the expression of Bcl-xL in mature eosinophils might be little compared with umbilical cord blood–derived eosinophils as assessed by immunoblotting,10 our in vivo and in vitro expression studies suggested that Bcl-xL might be a good candidate involved in the anti-apoptotic pathway mediated by cytokines in eosinophils. To test this hypothesis, we determined the effect of decreasing the levels of Bcl-xL expression. Eosinophils that had been cultured for 20 hours did not express detectable levels of Bcl-xL protein (Fig 2B). Exposure of these eosinophils to an optimal dose of phosphorothioate-derivatized Bcl-xLantisense oligodeoxynucleotides for another 28 hours clearly inhibited GM-CSF– or IL-5–mediated upregulation of Bcl-xL protein levels, whereas scrambled control oligodeoxynucleotides had no effect (Fig 5A).
Fig. 5.
Bcl-xL antisense but not scrambled oligodeoxynucleotides partially inhibit cytokine-mediated rescue of spontaneous eosinophil apoptosis. (A) Eosinophils lost the expression of Bcl-xL protein after in vitro culture for 24 hours (see Fig 2B). In these cells, IL-5–induced Bcl-xL expression within 24 hours (total cell culture time: 48 hours). Whereas scrambled Bcl-xL oligodeoxynucleotides (sc Bcl-xL) had no effect on IL-5–mediated upregulation of Bcl-xL protein levels, no significant induction of Bcl-xL protein expression was observed in eosinophils treated with Bcl-xLantisense molecules (as Bcl-xL). The same data were observed using GM-CSF to upregulate Bcl-xL protein expression (not presented). This figure is representative of five independent experiments. (B) Bcl-xL antisense but not scrambled oligodeoxynucleotides partially inhibited the effects of GM-CSF and IL-5 on eosinophil viability (*; P < .001). In addition, no significant effects of the oligodeoxynucleotides on spontaneous eosinophil death were observed (not presented). Means ± SEM of six independent experiments are presented. (C) Bcl-xL antisense and scrambled oligodeoxynucleotides-treated eosinophils were cultured in the presence of IL-5 as described in Materials and Methods for a total of 48 hours. Cells were stained with Giemsa-May-Grünwald (Diff-Quik). Apoptotic eosinophils are characterized by reduced cell volume as well as nuclear condensation. Some cells demonstrate secondary necrosis (lower panel, the two cells in the right margin; these cells show complete nuclear fragmentation). In these experiments, we did not observe any cell death that was the result of primary necrosis. The Bcl-xL antisense-treated cell populations demonstrated much more apoptosis. Data are representative of three independent experiments.
Fig. 5.
Bcl-xL antisense but not scrambled oligodeoxynucleotides partially inhibit cytokine-mediated rescue of spontaneous eosinophil apoptosis. (A) Eosinophils lost the expression of Bcl-xL protein after in vitro culture for 24 hours (see Fig 2B). In these cells, IL-5–induced Bcl-xL expression within 24 hours (total cell culture time: 48 hours). Whereas scrambled Bcl-xL oligodeoxynucleotides (sc Bcl-xL) had no effect on IL-5–mediated upregulation of Bcl-xL protein levels, no significant induction of Bcl-xL protein expression was observed in eosinophils treated with Bcl-xLantisense molecules (as Bcl-xL). The same data were observed using GM-CSF to upregulate Bcl-xL protein expression (not presented). This figure is representative of five independent experiments. (B) Bcl-xL antisense but not scrambled oligodeoxynucleotides partially inhibited the effects of GM-CSF and IL-5 on eosinophil viability (*; P < .001). In addition, no significant effects of the oligodeoxynucleotides on spontaneous eosinophil death were observed (not presented). Means ± SEM of six independent experiments are presented. (C) Bcl-xL antisense and scrambled oligodeoxynucleotides-treated eosinophils were cultured in the presence of IL-5 as described in Materials and Methods for a total of 48 hours. Cells were stained with Giemsa-May-Grünwald (Diff-Quik). Apoptotic eosinophils are characterized by reduced cell volume as well as nuclear condensation. Some cells demonstrate secondary necrosis (lower panel, the two cells in the right margin; these cells show complete nuclear fragmentation). In these experiments, we did not observe any cell death that was the result of primary necrosis. The Bcl-xL antisense-treated cell populations demonstrated much more apoptosis. Data are representative of three independent experiments.
The ability of antisense oligodeoxynucleotides to specifically inhibit the upregulation of Bcl-xL protein allowed exploration of its role in the prevention of apoptosis by eosinophil hematopoietins in this cellular system. Apoptosis assays were performed after a total cell culture time of 48 hours and cell death assays after 60 hours. No significant effects of the oligodeoxynucleotides on the viability of eosinophils in the absence of IL-5 or GM-CSF were observed (not presented). In contrast, antisense but not scrambled Bcl-xLoligodeoxynucleotides consistantly inhibited by approximately 34% the ability of IL-5 or GM-CSF to prevent eosinophil death (Fig 5B). The effect of the antisense molecules was highly significant (t-test, P < .001). We also investigated whether the observed cell death was apoptosis. Using analysis of the eosinophil morphology,18 we observed much more pycnosis of the nucleus and cell shrinkage in cells that had been treated with antisense Bcl-xL oligodeoxynucleotides (Fig 5C). Quantitative analysis (counting of 300 cells) showed similar results as observed in the cell death experiments: The antisense molecules reduced the anti-apoptotic effect of IL-5 in average by 33% (not presented). Furthermore, no differences were observed between eosinophils from normal control individuals and allergic patients.
These data suggest that Bcl-xL is functionally active within the intracellular anti-apoptotic pathway mediated by cytokines such as IL-5 or GM-CSF in eosinophils. However, the inhibitory effect of Bcl-xL antisense oligodeoxynucleotides on GM-CSF– or IL-5–mediated delay of eosinophil apoptosis was only partial. This could be due in part to the fact that, although the antisense molecules significantly blocked Bcl-xL protein synthesis, some Bcl-xL expression was still induced by IL-5. It is possible that these relatively little Bcl-xL levels were enough to promote GM-CSF or IL-5 responses in the majority of the eosinophils. Another explanation for the incomplete block of cytokine-mediated inhibition of eosinophil apoptosis by Bcl-xL antisense oligodeoxynucleotides would be the involvement of other, as yet unidentified, gene products. Therefore, further definition of the genetic control of eosinophil apoptosis is required.
ACKNOWLEDGMENT
We thank T. Hartung (University of Konstanz, Konstanz, Germany) for GM-CSF, J. Tavernier (University of Gent, Gent, Belgium) for anti–IL-5 MoAb, A. Schapowal (Clinic for Allergy and Dermatology Davos, Davos, Switzerland) for nasal polyp tissues, and St. Gratzl (Kantonsspital Chur, Chur, Switzerland) for the cancer tissue.
Supported by grants from the Swiss National Science Foundation (32-49210.96) and the OPO-Foundation, Zurich, Switzerland (both to H.-U.S.).
Address reprint requests to Hans-Uwe Simon, MD, Swiss Institute of Allergy and Asthma Research, University of Zurich, Obere Strasse 22, CH-7270 Davos, Switzerland; e-mail: hus@siaf.unizh.ch.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
REFERENCES
REFERENCES
1
Simon
HU
Yousefi
S
Schranz
C
Schapowal
A
Bachert
C
Blaser
K
Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia.
J Immunol
158
1997
3902
2
Bousquet
J
Chanez
P
Lacoste
JY
Barnéon
G
Ghavanian
N
Enander
I
Venge
P
Ahlstedt
S
Simony-Lafontaine
J
Godard
P
Michel
FB
Eosinophilic inflammation in asthma.
N Engl J Med
323
1990
1033
3
Simon
HU
Blaser
K
Inhibition of programmed eosinophil death: A key pathogenic event for eosinophilia?
Immunol Today
16
1995
53
4
Yang
E
Korsmeyer
SJ
Molecular thanatopsis: A discourse on the BCL2 family and cell death.
Blood
88
1996
386
5
Boise
LH
Gonzalez-Garcia
M
Postema
CE
Ding
L
Lindsten
T
Turka
LA
Mao
X
Nunez
G
Thompson
CB
bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death.
Cell
74
1993
597
6
Karsan
A
Yee
E
Kaushansky
K
Harlan
JM
Cloning of a human Bcl-2 homologue: Inflammatory cytokines induce human A1 in cultured endothelial cells.
Blood
87
1996
3089
7
Oltvai
ZN
Milliman
CL
Korsmeyer
SJ
Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.
Cell
74
1993
609
8
Ochiai
K
Kagami
M
Matsumura
R
Tomioka
H
IL-5 but not interferon-gamma (IFN-γ) inhibits eosinophil apoptosis by up-regulation of bcl-2 expression.
Clin Exp Immunol
107
1997
198
9
(suppl 1)
Saita
N
Yamanaka
T
Kohrogi
H
Matsumoto
M
Suga
M
Ando
M
Hirashima
M
Expression of apoptosis-related antigen on eosinophils in chronic eosinophilic pneumonia.
Int Arch Allergy Immunol
114
1997
64
10
Druilhe
A
Arock
M
Le Goff
L
Pretolani
M
Human eosinophils express Bcl-2 family proteins: Modulation of Mcl-1 expression by IFN-γ.
Am J Respir Cell Mol Biol
18
1998
315
11
Yousefi
S
Hemmann
S
Weber
M
Hölzer
C
Hartung
K
Blaser
K
Simon
HU
IL-8 is expressed by human peripheral blood eosinophils. Evidence for increased secretion in asthma.
J Immunol
154
1995
5481
12
Simon
HU
Yousefi
S
Dommann-Scherrer
CC
Zimmermann
DR
Bauer
S
Barandun
J
Blaser
K
Expansion of cytokine-producing CD4−CD8− T cells associated with abnormal Fas expression and hypereosinophilia.
J Exp Med
183
1996
1071
13
Yousefi
S
Hoessli
DC
Blaser
K
Mills
GB
Simon
HU
Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils.
J Exp Med
183
1996
1407
14
Hebestreit
H
Yousefi
S
Balatti
I
Weber
M
Crameri
R
Simon
D
Hartung
K
Schapowal
A
Blaser
K
Simon
HU
Expression and function of the Fas receptor on human blood and tissue eosinophils.
Eur J Immunol
26
1996
1775
15
Ziegler
A
Luedke
GH
Fabbro
D
Altmann
KH
Stahel
RA
Zangemeister-Wittke
U
Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the bcl-2 coding sequence.
J Natl Cancer Inst
89
1997
1027
16
Akbar
AN
Borthwick
NJ
Wickremasinghe
RG
Panayiotidis
P
Pilling
D
Bofill
M
Krajewski
S
Reed
JC
Salmon
M
Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: Selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bxl-xS) gene expression.
Eur J Immunol
26
1996
294
17
Vander Heiden
MG
Chandel
NS
Williamson
EK
Schumacker
PT
Thompson
CB
Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria.
Cell
91
1997
627
18
Simon
HU
Novel therapeutic strategies via the apoptosis pathways to resolve chronic eosinophilic inflammation.
Cell Death Diff
3
1996
349 | {
"url": "https://ashpublications.org/blood/article/92/3/778/175287/Role-for-Bcl-xL-in-Delayed-Eosinophil-Apoptosis",
"source_domain": "ashpublications.org",
"snapshot_id": "crawl=CC-MAIN-2019-47",
"warc_metadata": {
"Content-Length": "206678",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:6JCYRH3U7EVZGWBK5XQOPTSJZAOU4NCV",
"WARC-Concurrent-To": "<urn:uuid:221b004a-2009-4e1a-8c37-09be56069115>",
"WARC-Date": "2019-11-16T20:53:37",
"WARC-IP-Address": "209.135.210.73",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:2OMVSSXKBATXSXR3WPPGYQWBXEBJGTJR",
"WARC-Record-ID": "<urn:uuid:9272c2d0-4b76-404c-8791-66225bfba8f4>",
"WARC-Target-URI": "https://ashpublications.org/blood/article/92/3/778/175287/Role-for-Bcl-xL-in-Delayed-Eosinophil-Apoptosis",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:8e48e562-b0b6-4e9d-b981-f1cc1f49a719>"
},
"warc_info": "isPartOf: CC-MAIN-2019-47\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-116.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
9,
10,
1533,
1534,
1580,
1581,
2225,
2226,
2936,
2937,
4038,
4039,
4061,
4062,
4074,
4075,
5114,
5115,
5158,
5159,
6990,
6991,
7049,
7050,
8246,
8247,
8267,
8268,
9019,
9020,
9041,
9042,
10047,
10048,
10244,
10245,
10307,
10308,
10438,
10439,
10461,
10462,
11044,
11045,
11094,
11095,
11532,
11533,
11556,
11557,
11624,
11625,
12570,
12571,
12579,
12580,
13633,
13634,
13642,
13643,
14696,
14697,
14705,
14706,
16300,
16301,
16309,
16310,
17904,
17905,
19285,
19286,
19294,
19295,
20069,
20070,
20078,
20079,
20853,
20854,
20902,
20903,
21134,
21135,
21500,
21501,
21509,
21510,
21815,
21816,
21824,
21825,
22130,
22131,
22193,
22194,
22574,
22575,
23781,
23782,
23854,
23855,
24855,
24856,
24864,
24865,
26675,
26676,
26684,
26685,
28495,
28496,
29838,
29839,
30772,
30773,
30788,
30789,
31113,
31114,
31254,
31255,
31446,
31447,
31664,
31665,
31676,
31677,
31688,
31690,
31696,
31699,
31707,
31709,
31717,
31719,
31729,
31731,
31739,
31741,
31748,
31750,
31847,
31857,
31861,
31866,
31871,
31873,
31882,
31884,
31891,
31893,
31901,
31904,
31913,
31915,
31925,
31927,
31935,
31937,
31943,
31945,
31954,
31956,
31974,
31976,
31983,
31985,
31992,
31995,
32032,
32045,
32049,
32054,
32059,
32061,
32067,
32070,
32077,
32079,
32163,
32177,
32180,
32185,
32188,
32190,
32195,
32197,
32207,
32210,
32280,
32286,
32289,
32294,
32298,
32300,
32306,
32309,
32325,
32327,
32335,
32338,
32343,
32345,
32354,
32356,
32362,
32365,
32369,
32371,
32377,
32379,
32388,
32391,
32483,
32488,
32491,
32496,
32500,
32502,
32509,
32511,
32515,
32517,
32528,
32530,
32537,
32540,
32646,
32652,
32655,
32660,
32665,
32667,
32674,
32677,
32686,
32689,
32699,
32702,
32803,
32808,
32811,
32816,
32820,
32822,
32829,
32831,
32838,
32840,
32850,
32852,
32860,
32862,
32968,
32985,
32989,
32994,
32998,
33000,
33010,
33016,
33018,
33027,
33029,
33037,
33039,
33049,
33051,
33056,
33058,
33063,
33065,
33075,
33077,
33167,
33192,
33196,
33201,
33204,
33207,
33215,
33217,
33223,
33225,
33233,
33235,
33245,
33247,
33337,
33363,
33366,
33371,
33375,
33378,
33386,
33388,
33396,
33398,
33404,
33406,
33414,
33416,
33424,
33426,
33433,
33435,
33441,
33444,
33545,
33555,
33559,
33564,
33569,
33572,
33578,
33581,
33589,
33591,
33608,
33611,
33622,
33625,
33631,
33633,
33642,
33644,
33651,
33653,
33765,
33775,
33779,
33784,
33789,
33792,
33800,
33802,
33810,
33813,
33820,
33822,
33828,
33831,
33837,
33840,
33951,
33961,
33965,
33970,
33975,
33978,
33989,
33991,
33999,
34001,
34009,
34011,
34017,
34019,
34027,
34029,
34035,
34037,
34045,
34047,
34057,
34059,
34066,
34068,
34074,
34077,
34160,
34174,
34177,
34182,
34187,
34190,
34198,
34200,
34207,
34210,
34217,
34219,
34227,
34230,
34237,
34240,
34260,
34262,
34391,
34410,
34413,
34418,
34423,
34426,
34432,
34435,
34445,
34448,
34463,
34466,
34479,
34481,
34489,
34491,
34498,
34500,
34510,
34512,
34517,
34520,
34527,
34529,
34771,
34785,
34788,
34793,
34797,
34800,
34814,
34817,
34825,
34828,
34839,
34842,
34853,
34856,
34865,
34868,
34948,
34953,
34956,
34961,
34965,
34968,
34974,
34977,
35079,
35095,
35097,
35102
],
"line_end_idx": [
9,
10,
1533,
1534,
1580,
1581,
2225,
2226,
2936,
2937,
4038,
4039,
4061,
4062,
4074,
4075,
5114,
5115,
5158,
5159,
6990,
6991,
7049,
7050,
8246,
8247,
8267,
8268,
9019,
9020,
9041,
9042,
10047,
10048,
10244,
10245,
10307,
10308,
10438,
10439,
10461,
10462,
11044,
11045,
11094,
11095,
11532,
11533,
11556,
11557,
11624,
11625,
12570,
12571,
12579,
12580,
13633,
13634,
13642,
13643,
14696,
14697,
14705,
14706,
16300,
16301,
16309,
16310,
17904,
17905,
19285,
19286,
19294,
19295,
20069,
20070,
20078,
20079,
20853,
20854,
20902,
20903,
21134,
21135,
21500,
21501,
21509,
21510,
21815,
21816,
21824,
21825,
22130,
22131,
22193,
22194,
22574,
22575,
23781,
23782,
23854,
23855,
24855,
24856,
24864,
24865,
26675,
26676,
26684,
26685,
28495,
28496,
29838,
29839,
30772,
30773,
30788,
30789,
31113,
31114,
31254,
31255,
31446,
31447,
31664,
31665,
31676,
31677,
31688,
31690,
31696,
31699,
31707,
31709,
31717,
31719,
31729,
31731,
31739,
31741,
31748,
31750,
31847,
31857,
31861,
31866,
31871,
31873,
31882,
31884,
31891,
31893,
31901,
31904,
31913,
31915,
31925,
31927,
31935,
31937,
31943,
31945,
31954,
31956,
31974,
31976,
31983,
31985,
31992,
31995,
32032,
32045,
32049,
32054,
32059,
32061,
32067,
32070,
32077,
32079,
32163,
32177,
32180,
32185,
32188,
32190,
32195,
32197,
32207,
32210,
32280,
32286,
32289,
32294,
32298,
32300,
32306,
32309,
32325,
32327,
32335,
32338,
32343,
32345,
32354,
32356,
32362,
32365,
32369,
32371,
32377,
32379,
32388,
32391,
32483,
32488,
32491,
32496,
32500,
32502,
32509,
32511,
32515,
32517,
32528,
32530,
32537,
32540,
32646,
32652,
32655,
32660,
32665,
32667,
32674,
32677,
32686,
32689,
32699,
32702,
32803,
32808,
32811,
32816,
32820,
32822,
32829,
32831,
32838,
32840,
32850,
32852,
32860,
32862,
32968,
32985,
32989,
32994,
32998,
33000,
33010,
33016,
33018,
33027,
33029,
33037,
33039,
33049,
33051,
33056,
33058,
33063,
33065,
33075,
33077,
33167,
33192,
33196,
33201,
33204,
33207,
33215,
33217,
33223,
33225,
33233,
33235,
33245,
33247,
33337,
33363,
33366,
33371,
33375,
33378,
33386,
33388,
33396,
33398,
33404,
33406,
33414,
33416,
33424,
33426,
33433,
33435,
33441,
33444,
33545,
33555,
33559,
33564,
33569,
33572,
33578,
33581,
33589,
33591,
33608,
33611,
33622,
33625,
33631,
33633,
33642,
33644,
33651,
33653,
33765,
33775,
33779,
33784,
33789,
33792,
33800,
33802,
33810,
33813,
33820,
33822,
33828,
33831,
33837,
33840,
33951,
33961,
33965,
33970,
33975,
33978,
33989,
33991,
33999,
34001,
34009,
34011,
34017,
34019,
34027,
34029,
34035,
34037,
34045,
34047,
34057,
34059,
34066,
34068,
34074,
34077,
34160,
34174,
34177,
34182,
34187,
34190,
34198,
34200,
34207,
34210,
34217,
34219,
34227,
34230,
34237,
34240,
34260,
34262,
34391,
34410,
34413,
34418,
34423,
34426,
34432,
34435,
34445,
34448,
34463,
34466,
34479,
34481,
34489,
34491,
34498,
34500,
34510,
34512,
34517,
34520,
34527,
34529,
34771,
34785,
34788,
34793,
34797,
34800,
34814,
34817,
34825,
34828,
34839,
34842,
34853,
34856,
34865,
34868,
34948,
34953,
34956,
34961,
34965,
34968,
34974,
34977,
35079,
35095,
35097,
35102,
35105
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 35105,
"ccnet_original_nlines": 441,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.24026067554950714,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.07414916902780533,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.24503983557224274,
"rps_doc_frac_unique_words": 0.23236925899982452,
"rps_doc_mean_word_length": 5.664619445800781,
"rps_doc_num_sentences": 320,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.9525604248046875,
"rps_doc_word_count": 5048,
"rps_doc_frac_chars_dupe_10grams": 0.3293582797050476,
"rps_doc_frac_chars_dupe_5grams": 0.3944046199321747,
"rps_doc_frac_chars_dupe_6grams": 0.36765170097351074,
"rps_doc_frac_chars_dupe_7grams": 0.35537680983543396,
"rps_doc_frac_chars_dupe_8grams": 0.3385906517505646,
"rps_doc_frac_chars_dupe_9grams": 0.3327155113220215,
"rps_doc_frac_chars_top_2gram": 0.006119950208812952,
"rps_doc_frac_chars_top_3gram": 0.006819370202720165,
"rps_doc_frac_chars_top_4gram": 0.005245670210570097,
"rps_doc_books_importance": -2931.80419921875,
"rps_doc_books_importance_length_correction": -2931.80419921875,
"rps_doc_openwebtext_importance": -1426.727294921875,
"rps_doc_openwebtext_importance_length_correction": -1426.727294921875,
"rps_doc_wikipedia_importance": -1087.4627685546875,
"rps_doc_wikipedia_importance_length_correction": -1087.4627685546875
},
"fasttext": {
"dclm": 0.028958739712834358,
"english": 0.9285949468612671,
"fineweb_edu_approx": 1.962406873703003,
"eai_general_math": 0.48016107082366943,
"eai_open_web_math": 0.35174888372421265,
"eai_web_code": 0.009823859669268131
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.07922",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.079",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "4",
"label": "Analyze"
},
"secondary": {
"code": "5",
"label": "Evaluate"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "8",
"label": "Documentation"
}
},
"reasoning_depth": {
"primary": {
"code": "4",
"label": "Advanced Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "3",
"label": "Mostly Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | 1a01aa77535b9ecfb87b9fc36adbcd2f |
2,744,955,016,205,145,600 | In this specific article : Sex after and during Pregnancy
In this specific article : Sex after and during Pregnancy
Expecting mothers and their lovers usually wonder if it is safe to own sex during maternity. Can it lead to miscarriage? Can it damage the developing fetus? Is there intercourse jobs in order to prevent? Here is the given information you have been to locate.
Is Intercourse Secure During Pregnancy?
Intercourse is a normal, normal element of pregnancy — if you are having a standard pregnancy. Penetration and intercourses movement won’t damage the infant, that is protected by the stomach while the uterus muscular walls. Your child can also be cushioned because of the sacs that are amniotic.
The contractions of orgasm are not just like work contractions. Nevertheless, as being a safety that is general, some health practitioners advise avoiding intercourse when you look at the last days of being pregnant, believing that hormones in semen called prostaglandins can stimulate contractions. One exclusion may be for ladies that are overdue and wish to cause work. Some health practitioners think that prostaglandins in semen actually induce work in a full-term or past-due maternity, because the gel utilized to “ripen” the cervix and cause work also incorporates prostaglandins. Read more »
Titan Poker | {
"url": "http://www.onlinepokern.com/poker/category/top-free-online-dating-sites-2/",
"source_domain": "www.onlinepokern.com",
"snapshot_id": "crawl=CC-MAIN-2019-47",
"warc_metadata": {
"Content-Length": "63731",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:BD3QTV7CYEXQOETFZW2HEVR5FEYMRQES",
"WARC-Concurrent-To": "<urn:uuid:6b0c55c1-3814-439e-99b4-89d6b79c41b7>",
"WARC-Date": "2019-11-21T23:48:23",
"WARC-IP-Address": "77.104.155.236",
"WARC-Identified-Payload-Type": "application/xhtml+xml",
"WARC-Payload-Digest": "sha1:2KYBTPEIGNITANTDW7QM5I7X3F3XGLAY",
"WARC-Record-ID": "<urn:uuid:d31711f2-d1e4-4c9b-9446-ba7a9e9ee188>",
"WARC-Target-URI": "http://www.onlinepokern.com/poker/category/top-free-online-dating-sites-2/",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:1a3e6d2d-25ac-4e0b-8401-6dc3e5d0b231>"
},
"warc_info": "isPartOf: CC-MAIN-2019-47\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for November 2019\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-133.ec2.internal\r\nsoftware: Apache Nutch 1.16 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.1-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: http://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
58,
59,
117,
118,
377,
378,
418,
419,
715,
716,
1317,
1318
],
"line_end_idx": [
58,
59,
117,
118,
377,
378,
418,
419,
715,
716,
1317,
1318,
1329
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 1329,
"ccnet_original_nlines": 12,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 10,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.43096235394477844,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1171548068523407,
"rps_doc_frac_unique_words": 0.5857142806053162,
"rps_doc_mean_word_length": 5.185714244842529,
"rps_doc_num_sentences": 14,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.553968906402588,
"rps_doc_word_count": 210,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0.08631771802902222,
"rps_doc_frac_chars_dupe_6grams": 0.08631771802902222,
"rps_doc_frac_chars_dupe_7grams": 0.08631771802902222,
"rps_doc_frac_chars_dupe_8grams": 0.08631771802902222,
"rps_doc_frac_chars_dupe_9grams": 0.08631771802902222,
"rps_doc_frac_chars_top_2gram": 0.04132230952382088,
"rps_doc_frac_chars_top_3gram": 0.025711659342050552,
"rps_doc_frac_chars_top_4gram": 0.03856749087572098,
"rps_doc_books_importance": -115.79017639160156,
"rps_doc_books_importance_length_correction": -115.79017639160156,
"rps_doc_openwebtext_importance": -61.81529998779297,
"rps_doc_openwebtext_importance_length_correction": -61.81529998779297,
"rps_doc_wikipedia_importance": -36.61582565307617,
"rps_doc_wikipedia_importance_length_correction": -36.61485290527344
},
"fasttext": {
"dclm": 0.42795705795288086,
"english": 0.9361070394515991,
"fineweb_edu_approx": 2.2199957370758057,
"eai_general_math": 0.022735709324479103,
"eai_open_web_math": 0.3461034893989563,
"eai_web_code": 0.0010957099730148911
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "618.122",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Women — Health and hygiene, Children — Health and hygiene, Gynecology, and Pediatrics"
}
},
"secondary": {
"code": "618.12",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Women — Health and hygiene, Children — Health and hygiene, Gynecology, and Pediatrics"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "1",
"label": "Truncated Snippets"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "9",
"label": "FAQ"
}
},
"reasoning_depth": {
"primary": {
"code": "2",
"label": "Basic Reasoning"
},
"secondary": {
"code": "3",
"label": "Intermediate Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "1",
"label": "General Audience"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | 6e3c8d3593f3f69280bb5502b214ab8e |
2,830,068,885,619,165,000 | Skip to content
How To Optimize Your Post-Meal Walk So It Helps Regulate Blood Sugar
Gretchen Lidicker, M.S.
Author:
February 8, 2023
Gretchen Lidicker, M.S.
mbg Health Contributor
By Gretchen Lidicker, M.S.
mbg Health Contributor
Gretchen Lidicker earned her master’s degree in physiology with a focus on alternative medicine from Georgetown University. She is the author of “CBD Oil Everyday Secrets” and “Magnesium Everyday Secrets.”
Photo by BONNINSTUDIO / Stocksy
February 8, 2023
Our editors have independently chosen the products listed on this page. If you purchase something mentioned in this article, we may earn a small commission.
Taking a walk after eating is something many of us do out of sheer instinct or habit. We feel a little too full, want to stretch our legs, or find we can avoid a post-meal energy slump if we get some steps in.
But in recent years, science has uncovered some legitimate health benefits to walking after eating, especially when it comes to staving off a blood sugar spike and crash following a high-carb or sugar-filled meal.
Advertisement
This ad is displayed using third party content and we do not control its accessibility features.
But we have so many questions: How long do we have to walk to get the benefits? How fast? And how soon after we eat? We sat down with L.J. Amaral M.S., RDN, CSO, a registered dietitian, researcher, and expert in metabolic therapy, to get all those questions answered.
First, some background on blood sugar.
About 1 in 10 adults1 in the United States has diabetes, and an additional 96 million—1 in 3 adults1 in the U.S.—have prediabetes. Unhealthy blood sugar levels are connected to diseases like Alzheimer's, obesity2, anxiety disorders, chronic fatigue3, and infertility in both men and women. And blood sugar isn't just about diabetes; it's about overall health and wellness.
Knowing all that, it's clear why more and more people are monitoring their blood sugar levels throughout the day and testing interventions to keep them healthy. Continuous glucose monitors (small devices that use a sensor placed right under the skin to measure blood sugar and send that information to your phone or another device) have soared in popularity among people who do not have diabetes but want to understand how their diet, lifestyle, stress, and activities like a post-meal walk affect their blood sugar.
Most of the advice related to blood sugar focuses on diet. Often, it has to do with what you should not eat to avoid spikes: soda, fruit juice, refined carbs, pasta, crackers, cookies, etc. This might be one reason that the post-meal walk is so appealing. It's a healthy habit that you can add to your routine, instead of yet another unhealthy thing to avoid. And even more importantly, it's a way to minimize the damage when you do eat blood-sugar-spiking foods, which we all will at some point.
Advertisement
This ad is displayed using third party content and we do not control its accessibility features.
How can a post-meal walk help stabilize blood sugar?
Walking after eating seems to help blood sugar in a number of different ways. After we eat there is an abundance of glucose in our bloodstream, Amaral explains.
"When you are walking and active after a meal, the demand for energy [which glucose provides] goes toward your many organs and tissues, but especially the muscles," she says. And because the demand for glucose4 in your muscles is higher when you walk than when you sit, glucose uptake is higher when you are moving. Any type of physical exercise5 will increase your muscle glucose uptake, but walking tends to be the easiest to do right after a meal when blood sugar tends to be the most elevated.
According to Amaral, a similar process happens in your heart and other key organs. "Energy or sugar will be required for your heart to pump blood around your body/tissues more efficiently, creating more of a shunt for glucose to go toward the heart instead of staying in the bloodstream if you were to be sedentary," she says.
According to Amaral, this can help control a blood sugar spike and reduce one's risk of insulin resistance. "The demand [for glucose] is also rapid, so instead of requiring insulin for glucose to enter the cell (think of insulin as the key to unlock the cell to let glucose in to provide energy), no insulin is required."
And again, it's not just walking that has blood-sugar-balancing benefits. "Any light-moderate exercise could work! Swimming is great for those with gait instability, yoga, biking, tai chi, gardening, Pilates, and moderate housework," Amaral adds.
Ways to optimize your walk.
So, how quickly after eating should you walk to maximize the benefits? Amaral recommends getting moving within 30 minutes of wrapping up your meal. However, she adds, a 2016 review of 39 studies suggests that exercising anywhere between 30 minutes and 120 minutes after eating is ideal—with positive health effects present even six hours post-meal.
When it comes to intensity, the study showed that light-intensity walking can support blood sugar health, but Amaral recommends trying to reach a moderate aerobic pace through brisk walking. "Moderate-intensity exercise is considered effective when you can hold a conversation but cannot sing," she explains.
And as for how long you should stay moving, one meta-analysis published last year in the journal Sports Medicine6 found that walking for as little as two to five minutes is enough to positively affect blood sugar levels.
Beyond helping with blood sugar, research shows that breaking up long periods of sitting can also reduce blood pressure. Walking has also been associated with increased longevity overall—with one study finding that 10 minutes of brisk walking per day can make your telomeres (important markers of cellular aging) look up to 16 years younger7.
Advertisement
This ad is displayed using third party content and we do not control its accessibility features.
What are the limitations of walking for blood sugar balance?
Naturally, any cookie, bread, or soda lover in the room is going to be wondering: Does this mean I can eat whatever I want, as long as I walk after? Does walking actually reduce all the negative effects of sugar, or just some? Essentially: Are there limits?
According to Amaral: "Walking is quite effective for lowering blood sugar with a normal intake of macronutrients, but the breadth of its blood-sugar-lowering benefits is all dependent on the load, or amount of sugar, taken in, and other nutrients consumed at the same time."
As she explains it, if you're getting a massive influx of sugar—for example, you drink a Coca-Cola on an empty stomach, which delivers 30 grams of sugar straight to your bloodstream—a post-meal walk isn't going to be as effective. If you sipped the soda with a source of protein, healthy fat, or fiber, though, you'll experience less of a spike. "The fibers help to blunt the response of glucose by taking longer to cleave, digest and absorb," Amaral says. Looking to pair your treats wisely? Here are a few foods that are high in fiber and the best fiber supplements for blood sugar balance.
Of course, even the best post-meal walk won't totally erase the negative consequences of high sugar intake. "It will not completely negate the adverse effects of eating sugars and processed foods, though, especially as they can still activate pro-inflammatory pathways," Amaral says.
She also points out that everyone has a slightly different metabolic response to food. (She's had patients follow the exact same diet and still have massive variations in their blood sugars.) One study suggests that factors like gut microbiome composition and individualized labs could determine how you respond to exercise after a meal.
In the future, we might be able to use AI to predict bio-individual glucose responses. For now, though, we can study how our bodies respond to different foods by noticing how we feel after meals or watching out for these signs of a blood sugar spike. Continuous glucose monitors can also provide more granular data on blood sugar fluctuations and how they change with exercise.
The takeaway.
A post-meal walk is a pretty powerful tool for better blood sugar health, especially after a meal that is likely to spike blood sugar. To get the most benefit, wait 30 minutes, walk at a light-to-moderate pace, and focus on getting more healthy fats, protein, and fiber into every meal.
Advertisement
This ad is displayed using third party content and we do not control its accessibility features.
Gretchen Lidicker, M.S.
Gretchen Lidicker, M.S.
mbg Health Contributor
Gretchen Lidicker is an mbg health contributor, content strategist, and the author of CBD Oil Everyday Secrets: A Lifestyle Guide to Hemp-Derived Health and Wellness and Magnesium Everyday Secrets: A Lifestyle Guide to Epsom Salts, Magnesium Oil, and Nature's Relaxation Mineral. She holds a B.S. in biology and earned her master’s degree in physiology with a concentration in complementary and alternative medicine from Georgetown University. | {
"url": "https://www.mindbodygreen.com/articles/walking-for-blood-sugar-management",
"source_domain": "www.mindbodygreen.com",
"snapshot_id": "CC-MAIN-2023-14",
"warc_metadata": {
"Content-Length": "122049",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:UNU2PZA5KIAYOYN4CGVL54UUY4FPXS7K",
"WARC-Concurrent-To": "<urn:uuid:e15ef1a2-fad0-4f15-892d-ace8b4ef56e8>",
"WARC-Date": "2023-03-31T10:35:52",
"WARC-IP-Address": "18.160.46.64",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:GLHYP36C7N73OIC4VZRF4I6X3JBW2AC4",
"WARC-Record-ID": "<urn:uuid:bb6ea0bf-050c-41c6-9913-649a8a20f6a4>",
"WARC-Target-URI": "https://www.mindbodygreen.com/articles/walking-for-blood-sugar-management",
"WARC-Truncated": null,
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:cf6e9ac4-2fc9-403e-b94c-d78568722a3f>"
},
"warc_info": "isPartOf: CC-MAIN-2023-14\r\npublisher: Common Crawl\r\ndescription: Wide crawl of the web for March/April 2023\r\noperator: Common Crawl Admin (info@commoncrawl.org)\r\nhostname: ip-10-67-67-81\r\nsoftware: Apache Nutch 1.19 (modified, https://github.com/commoncrawl/nutch/)\r\nrobots: checked via crawler-commons 1.4-SNAPSHOT (https://github.com/crawler-commons/crawler-commons)\r\nformat: WARC File Format 1.1\r\nconformsTo: https://iipc.github.io/warc-specifications/specifications/warc-format/warc-1.1/"
} | {
"line_start_idx": [
0,
16,
17,
86,
87,
111,
119,
136,
160,
183,
210,
233,
439,
471,
488,
645,
646,
856,
857,
1071,
1072,
1086,
1183,
1184,
1453,
1454,
1493,
1494,
1868,
1869,
2387,
2388,
2886,
2887,
2901,
2998,
2999,
3052,
3053,
3214,
3215,
3713,
3714,
4043,
4044,
4366,
4367,
4614,
4615,
4643,
4644,
4993,
4994,
5303,
5304,
5525,
5526,
5869,
5870,
5884,
5981,
5982,
6043,
6044,
6302,
6303,
6578,
6579,
7172,
7173,
7457,
7458,
7796,
7797,
8175,
8176,
8190,
8191,
8478,
8479,
8493,
8590,
8614,
8638,
8661,
8662
],
"line_end_idx": [
16,
17,
86,
87,
111,
119,
136,
160,
183,
210,
233,
439,
471,
488,
645,
646,
856,
857,
1071,
1072,
1086,
1183,
1184,
1453,
1454,
1493,
1494,
1868,
1869,
2387,
2388,
2886,
2887,
2901,
2998,
2999,
3052,
3053,
3214,
3215,
3713,
3714,
4043,
4044,
4366,
4367,
4614,
4615,
4643,
4644,
4993,
4994,
5303,
5304,
5525,
5526,
5869,
5870,
5884,
5981,
5982,
6043,
6044,
6302,
6303,
6578,
6579,
7172,
7173,
7457,
7458,
7796,
7797,
8175,
8176,
8190,
8191,
8478,
8479,
8493,
8590,
8614,
8638,
8661,
8662,
9105
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 9105,
"ccnet_original_nlines": 85,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.3935057818889618,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.016510730609297752,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.1579526662826538,
"rps_doc_frac_unique_words": 0.39086633920669556,
"rps_doc_mean_word_length": 4.906648635864258,
"rps_doc_num_sentences": 89,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 5.671636581420898,
"rps_doc_word_count": 1489,
"rps_doc_frac_chars_dupe_10grams": 0.052012041211128235,
"rps_doc_frac_chars_dupe_5grams": 0.10867779701948166,
"rps_doc_frac_chars_dupe_6grams": 0.09170544892549515,
"rps_doc_frac_chars_dupe_7grams": 0.07774432003498077,
"rps_doc_frac_chars_dupe_8grams": 0.07774432003498077,
"rps_doc_frac_chars_dupe_9grams": 0.052012041211128235,
"rps_doc_frac_chars_top_2gram": 0.03148097172379494,
"rps_doc_frac_chars_top_3gram": 0.012318640016019344,
"rps_doc_frac_chars_top_4gram": 0.011497399769723415,
"rps_doc_books_importance": -899.8904418945312,
"rps_doc_books_importance_length_correction": -899.8904418945312,
"rps_doc_openwebtext_importance": -532.2569580078125,
"rps_doc_openwebtext_importance_length_correction": -532.2569580078125,
"rps_doc_wikipedia_importance": -346.38946533203125,
"rps_doc_wikipedia_importance_length_correction": -346.38946533203125
},
"fasttext": {
"dclm": 0.20626622438430786,
"english": 0.9430748224258423,
"fineweb_edu_approx": 2.0667054653167725,
"eai_general_math": 0.017377730458974838,
"eai_open_web_math": 0.22934192419052124,
"eai_web_code": 0.0028451099060475826
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "613.71",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
},
"secondary": {
"code": "613.704",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Health and Hygiene"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"document_type_v2": {
"primary": {
"code": "10",
"label": "Knowledge Article"
},
"secondary": {
"code": "16",
"label": "Personal Blog"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "2",
"label": "High School Level"
},
"secondary": {
"code": "1",
"label": "General Audience"
}
}
} | 9222580d47c553ea90dc0f5e416f8f3a |
2,128,341,518,705,252,000 | This site uses cookies. If you continue browsing without changing your cookie settings, it is our understanding that you are consenting to their installation Ok | Click here to learn more.
CRIS Research Foundation to beat cancer.
NK Cell Therapy project in children with cancer
Name of the Project NK (Natural Killer) Cell Therapy in Children with Cancer
Principal Researcher: Dr Antonio Pérez Martínez
Centres: Niño Jesús Children’s Hospital, CNIO (Spanish National Cancer Research Centre), La Paz University Hospital in Madrid, St. Jude Children’s Hospital, Memphis, EEUU.
Timeline: 2011 to 2018
Donations received: € 320,000
Background
Tumour cells appear when normal cells, after accumulating alterations every time they multiply, manage to evade the body’s control mechanisms, which control when, how and where cells must multiply. It is not easy for the immune system to distinguish between healthy and tumour cells, as they are very similar. This is why, on many occasions, tumour cells are not detected by the immune system.
The goal of this Investigation is to help the cells in the immune system to identify and destroy tumour cells.
Project Description
NK (Natural Killer) cells are very efficient in destroying damaged, altered or tumour cells. These cells patrol the body, eliminating any cell that may involve a danger.
In the clinical trials led by Antonio Pérez, NK cells are being extracted from suitable donors, activated to make them more efficient and multiplied in order to inject large quantities of these cells in children suffering from cancer (such as in Project Lydia LINK). The safety of this therapy has been demonstrated in multiple clinical trials. Currently, the effectiveness of the therapy is being optimised, as there is still a lot of room for improvement, and one of the objectives of this group is to improve effectiveness.
Antonio Pérez’s laboratory is working to introduce in Natural Killer cells certain molecules that allow them to be more effective in recognising the cells to be eliminated. They are also working to introduce these molecules in another type of cell that is very efficient in destroying tumour cells, called memory T cells. This type of groundbreaking approximation is called CAR (Chimeric Antigen Receptor) and has a direct application in clinical trials.
TERAPIA NK lab
Achievements in the past year
Work on this front has resulted in a series of very relevant publications, as the CAR therapeutic strategy is currently one of the most promising. An article relating to CAR and memory cells is currently pending an evaluation at a high-impact scientific magazine.
The group headed by Antonio Pérez has recently been submitted to external evaluation and has been promoted to the category of a Consolidated group, reflecting the group’s promising track record and the results of their research. Read more
| {
"url": "http://criscancer.org/en/research-projects/cris-funding-projects/nk-cell-therapy-project-for-children-with-cancer/",
"source_domain": "criscancer.org",
"snapshot_id": "crawl=CC-MAIN-2017-39",
"warc_metadata": {
"Content-Length": "118178",
"Content-Type": "application/http; msgtype=response",
"WARC-Block-Digest": "sha1:ACJVGGDKG5ZPBHAYRIEIK533YG3GPTNG",
"WARC-Concurrent-To": "<urn:uuid:375341d5-92ea-4e8a-98a6-8718d7e6ffc0>",
"WARC-Date": "2017-09-22T11:34:48",
"WARC-IP-Address": "52.212.188.0",
"WARC-Identified-Payload-Type": "text/html",
"WARC-Payload-Digest": "sha1:3FSX6KDF5SAQ5WQTSGDIMBCML2CYSPGS",
"WARC-Record-ID": "<urn:uuid:889532f4-232d-46db-8eb0-f5c256955e26>",
"WARC-Target-URI": "http://criscancer.org/en/research-projects/cris-funding-projects/nk-cell-therapy-project-for-children-with-cancer/",
"WARC-Truncated": "length",
"WARC-Type": "response",
"WARC-Warcinfo-ID": "<urn:uuid:5271cdbe-b3fa-4265-a36b-d5b0b6ff7b56>"
},
"warc_info": "robots: classic\r\nhostname: ip-10-182-87-105.ec2.internal\r\nsoftware: Nutch 1.6 (CC)\r\nisPartOf: CC-MAIN-2017-39\r\noperator: Common Crawl Admin\r\ndescription: Wide crawl of the web for September 2017\r\npublisher: Common Crawl\r\nformat: WARC File Format 1.0\r\nconformsTo: http://bibnum.bnf.fr/WARC/WARC_ISO_28500_version1_latestdraft.pdf"
} | {
"line_start_idx": [
0,
189,
230,
231,
279,
280,
357,
358,
406,
407,
579,
580,
603,
604,
634,
635,
637,
638,
640,
641,
652,
653,
1047,
1048,
1159,
1160,
1162,
1163,
1183,
1184,
1354,
1355,
1882,
1883,
2338,
2339,
2341,
2342,
2357,
2358,
2360,
2361,
2391,
2392,
2656,
2657,
2896,
2897
],
"line_end_idx": [
189,
230,
231,
279,
280,
357,
358,
406,
407,
579,
580,
603,
604,
634,
635,
637,
638,
640,
641,
652,
653,
1047,
1048,
1159,
1160,
1162,
1163,
1183,
1184,
1354,
1355,
1882,
1883,
2338,
2339,
2341,
2342,
2357,
2358,
2360,
2361,
2391,
2392,
2656,
2657,
2896,
2897,
2898
]
} | {
"red_pajama_v2": {
"ccnet_original_length": 2898,
"ccnet_original_nlines": 47,
"rps_doc_curly_bracket": 0,
"rps_doc_ldnoobw_words": 0,
"rps_doc_lorem_ipsum": 0,
"rps_doc_stop_word_fraction": 0.37142857909202576,
"rps_doc_ut1_blacklist": 0,
"rps_doc_frac_all_caps_words": 0.0266666691750288,
"rps_doc_frac_lines_end_with_ellipsis": 0,
"rps_doc_frac_no_alph_words": 0.12952381372451782,
"rps_doc_frac_unique_words": 0.514285683631897,
"rps_doc_mean_word_length": 5.175824165344238,
"rps_doc_num_sentences": 21,
"rps_doc_symbol_to_word_ratio": 0,
"rps_doc_unigram_entropy": 4.999500274658203,
"rps_doc_word_count": 455,
"rps_doc_frac_chars_dupe_10grams": 0,
"rps_doc_frac_chars_dupe_5grams": 0,
"rps_doc_frac_chars_dupe_6grams": 0,
"rps_doc_frac_chars_dupe_7grams": 0,
"rps_doc_frac_chars_dupe_8grams": 0,
"rps_doc_frac_chars_dupe_9grams": 0,
"rps_doc_frac_chars_top_2gram": 0.02802547998726368,
"rps_doc_frac_chars_top_3gram": 0.019108280539512634,
"rps_doc_frac_chars_top_4gram": 0.01698514074087143,
"rps_doc_books_importance": -215.46958923339844,
"rps_doc_books_importance_length_correction": -215.46958923339844,
"rps_doc_openwebtext_importance": -127.47486877441406,
"rps_doc_openwebtext_importance_length_correction": -127.47486877441406,
"rps_doc_wikipedia_importance": -74.35694122314453,
"rps_doc_wikipedia_importance_length_correction": -74.35694122314453
},
"fasttext": {
"dclm": 0.020138440653681755,
"english": 0.9451587200164795,
"fineweb_edu_approx": 2.4400687217712402,
"eai_general_math": 0.009114859625697136,
"eai_open_web_math": 0.12421774864196777,
"eai_web_code": 0.00036395000643096864
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "616.9944072",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
},
"secondary": {
"code": "616.9944",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Pathology and Diseases"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "2",
"label": "Conceptual"
},
"secondary": {
"code": "3",
"label": "Procedural"
}
},
"document_type_v1": {
"primary": {
"code": "2",
"label": "Academic/Research"
},
"secondary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
}
},
"extraction_artifacts": {
"primary": {
"code": "3",
"label": "Irrelevant Content"
},
"secondary": {
"code": "0",
"label": "No Artifacts"
}
},
"missing_content": {
"primary": {
"code": "2",
"label": "Click Here References"
},
"secondary": {
"code": "0",
"label": "No missing content"
}
},
"document_type_v2": {
"primary": {
"code": "3",
"label": "Academic Writing"
},
"secondary": {
"code": "13",
"label": "News (Org.)"
}
},
"reasoning_depth": {
"primary": {
"code": "3",
"label": "Intermediate Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "3",
"label": "Mostly Correct"
},
"secondary": {
"code": "4",
"label": "Highly Correct"
}
},
"education_level": {
"primary": {
"code": "3",
"label": "Undergraduate Level"
},
"secondary": {
"code": "2",
"label": "High School Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.