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Diseases and Conditions
Frozen shoulder
Definition
Frozen shoulder, also known as adhesive capsulitis, is a condition characterized by stiffness and pain in your shoulder joint. Signs and symptoms typically begin gradually, worsen over time and then resolve, usually within one to three years.
Your risk of developing frozen shoulder increases if you're recovering from a medical condition or procedure that prevents you from moving your arm — such as a stroke or a mastectomy.
Treatment for frozen shoulder involves range-of-motion exercises and, sometimes, corticosteroids and numbing medications injected into the joint capsule. In a small percentage of cases, arthroscopic surgery may be indicated to loosen the joint capsule so that it can move more freely.
It's unusual for frozen shoulder to recur in the same shoulder, but some people can develop it in the opposite shoulder. | {
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-7,700,226,005,920,106,000 | Top
10
Doctor insights on: Can You See Yeast On Colonoscopy
Share
1
1
Extreme itch after all food no rash.Colonoscopy endoscopy thryoid blood(full) abdominal CT contrast brain MRI urine 4 yeast clean hysterectmy 6yr ago?
Extreme itch after all food no rash.Colonoscopy endoscopy thryoid blood(full) abdominal CT contrast brain MRI urine 4 yeast clean hysterectmy 6yr ago?
Perhaps food allergy: To find out which food is causing the itch, you will probably need an allergist. You can try an elimination diet, food skin tests or blood tests for food to narrow down what you are eating that you are allergic to. If it happens after every meal, it is likely to be a staple food like wheat, milk or egg, so you are being exposed every time you eat. Quantities that seem small are huge to your cells. ...Read more
See 1 more doctor answer
Dr. Charles Cattano
1,988 doctors shared insights
Colonoscopy (Definition)
Colonoscopy is the procedure of using a long flexible camera to visualize the entire colon from the inside with the option to take pictures, video, perform biopsies, remove polyps, etc. Generally people are sedated and do ...Read more
2
2
Can they find candida on colonoscopy?
Can they find candida on colonoscopy?
Yes and no: Candida is rare in the colon. If there, the test could find it. It is usually a vaginal problem, and occasionally an esophogeal issue. ...Read more
3
3
Suffering w/ GERD 6 months & diagnosed w/candida 3 yrs ago after colonoscopy which was never treated. Can there be a link?
Unlikely: Gerd and esophageal candida are usually unrelated. Gerd means that acid is escaping the stomach and leaks up into the esophagus. Stomach acid generally kills the yeast in the esophagus that causes candida. If you have been taking antibiotics, steroids (prednisone), or other immunosuppressants, then this is likely the cause of the esophageal candida. ...Read more
4
4
Could chronic IBS, occasional achy joints/face rash be result of candida? Low (1.5) neutrophils, other white cells normal. Colonoscopy norm, no fever.
No: Listen, man. If you buy into this "candida" cult, you will never, ever feel well again. They'll persuade you that you have an incurable illness that needs constant, intensive, varying management, and will get you focused on it to the detriment of the things you need to do to enjoy life. This level of neuts isn't dangerous and is probably just you. Manage your IBS and get on with your life. ...Read more
5
5
What kind of dr do u see colonoscopy?
What kind of dr do u see colonoscopy?
GI doctor: Colonoscopy is a procedure typically performed by a gastroenterologist for the screening and detection of colorectal cancer and precancerous lesions, usually after age 50. ...Read more
See 2 more doctor answers
6
6
Do colonoscopies see the duodenum?
Do colonoscopies see the duodenum?
No: Colonoscopy gets to the proximal start of the colon. The duodenum is the beginning of the small intestine into which the stomach empties. To see the duodenum, a telescopic tube is inserted through the mouth and past the stomach. ...Read more
7
7
How soon after my colonoscopy (fro possible blockage) should my GI that did the procedure see me?
No way to know: There is no set time for follow up after a colonoscopy. It depends on why the procedure was done and what was found at the time. If you have any doubts you should just call your gastroenterologist. ...Read more
8
8
Saw GI for positive iFOB test who scheduled upperGI/colonoscopy. Given that I'm young, I don't see why this is necessary unless things worsen?
You should proceed: if this is your doctor's recommendation. Likelihood of finding a pathological condition that requires treatment is low b/c of your age, but it is not zero. ...Read more
9
9
Fissure&hemerhoid pain much worse after colonoscopy, can the scope going in make these conditions worse? Dr cant see me until august to give results
Painful condition: The colonoscopy should not cause a measurable worsening of your condition, but the procedure may cause temporary irritation and a transient increase in pain. The underlying problem may be getting worse, though, so if the worsening persists, tell your doctor or seek additional care. ...Read more
10
10
Can you see taenia solium through colonoscopy?
Rarely probably: Taenia solium is a tape worm humans get from eating poorly cooked pork. The primary site is the small intestine but they can grow to 6 or 7 feet in length so i would assume they often extend into the colon and could be seen on colonoscopy. I have never seen one on colonoscopy. ...Read more
See 1 more doctor answer
Yeast (Definition)
Any of various unicellular fungi of the genus saccharomyces, especially s. Cerevisiae, reproducing by budding and from ascospores and capable ...Read more
Candida (Definition)
Is a type of fungus which normally lives in small amounts on mucus membranes. An overgrowth of candida in the mouth produces a condition called 'thrush'. This is often triggered ...Read more | {
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-9,175,208,014,160,029,000 | Vitamin D, Not Just Another Vitamin
Ahhh, the “Sunshine Vitamin”, the “Feel Good Vitamin”, the “Essential Vitamin!” Yes, Vitamin D is all of those and more!
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“Feel Good” because Vitamin D is said to have a great influence on our brain and helping us just plain feel good! Scientists are still trying to figure out exactly how that connection works but they have seen how it can help those with depression and seasonal affective disorder. I personally notice the difference in my mood and energy levels when I am exposed to that glorious fire ball! Maybe also because our winters are so long and we anticipate the sunshiny, warm days that much more.
“Essential” for the development of bones and teeth basically by helping us absorb and use calcium and phosphorous.
I had always been told that we get enough Vitamin D from our food so I had no need to worry. But actually there are very few foods that have therapeutic levels of naturally occurring vitamin D, and even fortified foods do not contain enough vitamin D to support our needs. (No, not even in milk! You would have to drink like 100 glasses a day!) Vitamin D can refer to different forms of this vitamin. Two forms are important in humans: vitamin D2, which is made by plants, and vitamin D3, which is made by human skin when exposed to sunlight.
I was reading a naturopathic article that suggests adequate amounts of vitamin D can significantly reduce the threats of diseases. Such as a wide range of cancers (breast, ovarian, colon, lymphoma, kidney, endometrial), type 1 diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, depression, high blood pressure, seasonal affective disorder, and heart attacks. So why are we not being told this? Prevention is key!
As important as this is, most of us are deficient and don’t even know it. Researchers estimate that more than 50 percent of the general population is at risk of vitamin D deficiency. Personally, I think that estimate is modest and would guess that almost all Canadians are deficient! Because there are few obvious symptoms before things are problematic, it might be a good idea to get a vitamin D serum test done to see what your levels are and how well you are absorbing it. Also important to know, if you have any gastrointestinal issues (like celiac, chrohn’s, or irritable bowel) you will probably have difficulty absorbing Vitamin D. As it is a fat-soluble vitamin and those mentioned can’t absorb fat. This one I learnt after a visit to my naturopath! Unfortunately, Manitoba health does not cover this test anymore so you will have to pay to have it done.
Symptoms of vitamin D deficiency range but one that doctors routinely will check for with babies is a sweaty head. Apparently a classic symptom! Other symptoms range from chronic fatigue, to achy bones, to more serious issues like immune deficiency.
Vitamin D is available in capsule form but I personally like the Vitamin D oral spray that Innotech Nutrition offers. Offering 1000 IU’s in each spray with no sugar, salt, wheat, yeast, milk derivatives, artificial preservatives, artificial flavors or colours. The spray form is not only convenient (and tastes good) but it is also more readily absorbed by the body. How much you take really depends on how much you are needing/absorbing.
Vitamin D Fast Facts:
• SPF 15 sunscreen blocks production of vitamin D by 99%
• A UV index greater than 4 is necessary to make vitamin D
• A light skinned person in a bathing suit makes up to 15,000 IU vitamin D in 15-20 minutes in July at midday
• Darker skin requires up to 7x more sunlight exposure to make the same amount as lighter skin
• You can get vitamin D from reflected light while sitting in the shade but not through a glass window
• Rickets and osteomalacia are classic vitamin D deficiency diseases. *Rickets is a softening or weakening of the bones. *In adults, vitamin D deficiency can lead to osteomalacia, which causes weak bones and muscles.
Interested in knowing about the discovery of Vitamin D? Read on here: The Contribution of Adolf Windaus
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-5,545,524,177,305,012,000 | Skip to Content
Durabac Forte (acetaminophen / caffeine / magnesium salicylate / phenyltoloxamine) and Alcohol / Food Interactions
There are 6 alcohol/food/lifestyle interactions with Durabac Forte (acetaminophen / caffeine / magnesium salicylate / phenyltoloxamine) which include:
Minor
Nicotine ↔ caffeine
Minor Drug Interaction
Consumer information for this minor interaction is not currently available. Some minor drug interactions may not be clinically relevant in all patients. Minor drug interactions do not usually cause harm or require a change in therapy. However, your healthcare provider can determine if adjustments to your medications are needed.
For clinical details see professional interaction data.
Moderate
phenyltoloxamine ↔ food
Moderate Food Interaction
Consumer information for this interaction is not currently available.
GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.
References
1. Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7
2. Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990):
3. "Product Information. Fycompa (perampanel)." Eisai Inc, Teaneck, NJ.
4. "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc, Rockville, MD.
View all 4 references
Minor
caffeine ↔ food
Minor Food Interaction
Consumer information for this minor interaction is not currently available. Some minor drug interactions may not be clinically relevant in all patients. Minor drug interactions do not usually cause harm or require a change in therapy. However, your healthcare provider can determine if adjustments to your medications are needed.
For clinical details see professional interaction data.
Major
High Blood Pressure (Hypertension)
Severe Potential Hazard, Moderate plausibility
CNS stimulants - cardiac disease
The use of CNS stimulants is contraindicated in patients with significant cardiovascular impairment such as uncompensated heart failure, severe coronary disease, severe hypertension (including that associated with hyperthyroidism or pheochromocytoma), cardiac structural abnormalities, serious arrhythmias, etc. Sudden death has been reported in adults and children taking CNS stimulant treatment. Additionally, stroke, myocardial infarction, chest pain, syncope, arrhythmias and other symptoms have been reported in adults under treatment. A careful assessment of the cardiovascular status should be done in patients being considered for treatment. This includes family history, physical exam and further cardiac evaluation (EKG and echocardiogram). Patients who develop symptoms should have a detailed cardiac evaluation and if needed, treatment should be suspended.
References
1. "Product Information. Dopram (doxapram)." West-Ward Pharmaceutical Corporation, Eatontown, NJ.
Major
High Blood Pressure (Hypertension)
Severe Potential Hazard, Moderate plausibility
CNS stimulants - hypertension
CNS stimulant medications have shown to increase blood pressure and their use is contraindicated in patients with severe hypertension. Caution should be used when administering to patients with preexisting high blood pressure and other cardiovascular conditions. All patients under treatment should be regularly monitored for changes in blood pressure and heart rate.
References
1. "Product Information. Dopram (doxapram)." West-Ward Pharmaceutical Corporation, Eatontown, NJ.
Moderate
High Blood Pressure (Hypertension)
Moderate Potential Hazard, Moderate plausibility
caffeine - cardiotoxicity
Like other methylxanthines, caffeine at high dosages may be associated with positive inotropic and chronotropic effects on the heart. Caffeine may also produce an increase in systemic vascular resistance, resulting in elevation of blood pressure. Therapy with products containing caffeine should be administered cautiously in patients with severe cardiac disease, hypertension, hyperthyroidism, or acute myocardial injury. Some clinicians recommend avoiding caffeine in patients with symptomatic cardiac arrhythmias and/or palpitations and during the first several days to weeks after an acute myocardial infarction.
References
1. "Multum Information Services, Inc. Expert Review Panel"
Durabac Forte (acetaminophen / caffeine / magnesium salicylate / phenyltoloxamine) drug Interactions
There are 1112 drug interactions with Durabac Forte (acetaminophen / caffeine / magnesium salicylate / phenyltoloxamine)
Durabac Forte (acetaminophen / caffeine / magnesium salicylate / phenyltoloxamine) disease Interactions
There are 25 disease interactions with Durabac Forte (acetaminophen / caffeine / magnesium salicylate / phenyltoloxamine) which include:
Drug Interaction Classification
The classifications below are a general guideline only. It is difficult to determine the relevance of a particular drug interaction to any individual given the large number of variables.
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 information available.
Do not stop taking any medications without consulting your healthcare provider.
Disclaimer: Every effort has been made to ensure that the information provided by Multum is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. Multum's information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill, knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective, or appropriate for any given patient. Multum Information Services, Inc. does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. Copyright 2000-2018 Multum Information Services, Inc. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.
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How To Lose Weight Fast - Just Got Easier - Weight Loss
Sect. Big Breakfast Lose Weight J7j and How To Lose Weight Fast
- Some Really Interesting Info On Calories In Food.
You came to this article with Big Breakfast Lose Weight j7j and how to lose weight fast in mind. This is the knowledge that you need to make second nature, for losing weight. The data on the nutrition label on the foods that you buy is quite important to you. A picture is worth a thousand words. Lets see an example.
Green beans are quite popular, and so are lima beans. But they have vastly different calorie content. If you compare 1 cup of each, cooked, you might be quite shocked to know that green beans only possesses 38 calories while lima beans boast 260 calories.
Ponder this for while before you move on. Both are vegetables. Both have nutrition. Limas are 7 times more calories. You could gain a couple or 3 pounds a month by eating limas every day.
How about another example. Slice an apple. Eat it. Get 60 calories. Or, go grab a slice of apple pie and get 400 calories.
- Losing Weight, Hormones And Muscles.
Now we will delve into the ways to burn fat. If you have revved up the metabolism, then it will be looking for calories to burn. Your fat can supply these. Muscles are your friends. They are like the fat burning furnace. When they are active, the metabolism get going and you are using up fat and accomplishing Big Breakfast Lose Weight j7j and how to lose weight fast . Getting active is fun. Sitting around is no fun, its just lazy. When you think of all the friends that you have, put muscles high on the list. They want to work. Muscles are for working because they like working. Getting active with your muscles will have a nice side advantage of feeling more energetic. Nice to hear new, useful information Yes?
Your body puts hormones into the blood that are connected with burning fat. What stimulates the body to release these hormones into the blood stream? It is your diet. Yes, certain items in your diet will do this.
It's a proportions act. Keep the percentage of carbohydrates medium or less than medium. Keep the percentage high for proteins.
- Negative Calorie Truth.
You truly must use negative calories all the time. Its like achieving Big Breakfast Lose Weight j7j and how to lose weight fast for free. Put this into practice today. Do not delay.
You may not have thought of it, but eating burns calories, while you eat. There is a certain amount of calories required to eat and digest any food. Now think about this. What if you eat a food that has fewer calories than it requires to digest it? In our efforts to achieve Big Breakfast Lose Weight j7j and how to lose weight fast , this must be in our arsenal.
Calories that are in the fat can be used for this. Not what you expected, but happy to hear? Reflect on this. You got to lose weight, and all that you did was munch on some food.
Just eating the wrong snacks can cause you to put on fat. So you know what is coming next. Replace your snacks that will make you gain weight with negative calorie foods that will make you lose weight. Negative calorie foods. Do not leave home without them. Literally.
Apples and oranges are one of the most popular negative calorie foods.
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Women’s Health: Getting the Nutritional Support You Need
Getting all of the nutritional support you need to perform at your best can be hard and over time your nutritional status can suffer. So what are some of the main nutrients and herbs that can support your health from the inside out and help you perform at your best?
• B Group Vitamins help metabolise carbohydrates, proteins and fats from the foods you eat, providing you with the energy you need to get through the day. B group vitamins also support a healthy nervous system through their role in the production of hormones and neurotransmitters. As your body cannot store B vitamins, daily consumption is required.
• Iron is required for cellular energy production as it facilitates oxygen transport from the lungs to the rest of the body via haemoglobin, the primary iron- containing protein found in red blood cells. Myoglobin, also an iron-containing protein, transports oxygen in our muscle cells and supports the supply of oxygen to equal the demand of working muscles. Menstruation, pregnancy, absorption issues and inadequate dietary intake can all affect your levels of iron.
• Vitamin D aids the absorption of calcium, which helps build healthy bones and teeth. Vitamin D also helps maintain healthy mood, a healthy immune system and supports normal sugar metabolism.
• Iodine is needed for the synthesis of thyroid hormones and is essential for the normal functioning of the thyroid gland. The thyroid gland is a butterfly shaped gland that sits underneath your voice box and regulates body temperature, basal metabolic rate, cellular metabolism and growth and development.
• Chromium is essential for sugar metabolism. It can be needed in greater demand for those people who do a lot of physical activity or those who eat a diet high in refined sugars.
• Silica is important for the strong, healthy development and functioning of connective tissue, particularly the skin and is abundant in bones, hair, skin and nails.
• Antioxidant nutrients vitamins C, E and B2, selenium, zinc, citrus bioflavonoids and the herbs Grape seed, St Mary’s thistle and Ginkgo all contain antioxidant properties that decrease the risk of cell damage caused by free radicals. Grape seed in particular contains oligomeric procyanidins (OPCs), potent antioxidants that can assist in maintaining a healthy cardiovascular system.
Ensure your body has the right nutrients it needs to live life to the fullest. So if you need some help maintaining or improving your general wellbeing, when will you put looking after your health on top of your ‘to do’ list?
Subscribe to our newsletter
Keep up with the latest health news, recipes, new products and exclusive product sales from Herbs of Gold. | {
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-897,854,572,669,593,000 | Data Availability StatementAll data generated or analyzed during the current study are included in this published article
Data Availability StatementAll data generated or analyzed during the current study are included in this published article. in NSCLC and mesothelioma, second-generation CAR-T cells were constructed targeting mesothelin (MSLN), that is loaded in mesothelioma and NSCLC but is under expressed in normal tissues. The second-generation style incorporated co-stimulatory Compact disc28 and 4-1BB signaling domains to improve Alimemazine hemitartrate the proliferation. Following a successful evaluation of CAR-T cells by movement cytometry, cytotoxicity tests had been performed utilizing the LDH package to verify the eliminating aftereffect of CAR-T cells on focus on cells. In Alimemazine hemitartrate any other case, the eliminating tumor activity of MSLN CAR-T cells was confirmed by creating a mouse model using tumor-derived cells from individuals to inoculate the mice. Once the effector-to-target percentage can be 0.5:1, CAR-T MSLN cells exhibited higher capability to get rid of tumor cells than T cells significantly. In tests, mice whose tail vein was injected with CAR-T MSLN cells proven considerably slower tumor development. Without constant administration, both organizations became synchronized in development of tumor size steadily, which suggests how the persistence of CAR-T cells can be an essential concern in preclinical research. persistence (13C15). However, on focus on, off tumor toxicity can be a major problem in CAR-T therapy, where the antigen can be expressed in regular tissues (16). Consequently, creating CAR-T cells that Alimemazine hemitartrate focus on tumor cells with negligible off-tumor toxicity can be of important importance. Mesothelin (MSLN) can be an immunogenic glycoprotein that’s loaded in ovarian malignancies, NSCLC and mesotheliomas (17). Because of its low manifestation in regular mesothelial cells, MSLN can be an ideal applicant for targeted immunotherapy in mesotheliomas (18). In today’s research, second-generation CAR-T cells focusing on MSLN, the scFvs, that have affinities to intracellular site of co-stimulatory element Compact disc28, 4-1BB and Compact disc3, had been constructed. Both in and tests, this process was proven to exert powerful results on tumor clearance. In the mobile level, the CAR-T cells made of healthy individuals appeared to have significantly more potent impact than those produced from individuals, indicating the benefit of allogenic CAR-T therapy. The considerably elevated focusing on of CAR-T cells may be accomplished having a 0.5:1 effector to focus on (E:T) ratio, as well as the antitumor aftereffect of CAR-T cells increase with increases from the E:T ratio rapidly. When it reached 40:1, 78% cells had been damaged. Within an mouse model, the difference in development price of tumor size was significant at day time 5, and both combined groups became synchronized in growth of tumor size. These findings claim that CAR-T cells focusing on MSLN could inhibit tumor development both and tumor cell lysis was performed with Wilcoxon matched up pairs authorized rank test, as well as the test was examined with independent test t-test. P 0.05 was considered to indicate a significant difference statistically. Results Successful structure of pCAR-MSLN recombinant lentiviral appearance vector Second era CAR molecules had been designed for today’s research. The lentiviral vector pCAR-MSLN integrated with anti-MSLN CAR includes co-stimulator also, Compact disc28 and 4-1BB. The vectors had been excised by tests. Once the E:T proportion reached 0.5:1, the antitumor aftereffect of CAR-T cells was significantly greater than control T cells (P 0.05; Fig. 2C and D), as indicated by LDH assay of tumor cells. The CAR-T cells made of the healthful donor and sufferers exhibited a lot more powerful antitumor effects weighed against their particular T cells (all P 0.05; Fig. 2C and D). To verify that CAR-T cells could exert exactly the same effect on other styles of cells, recombinant CHO-K1-MSLN overexpressing MSLN was utilized as a focus on of CAR-T cells made of healthy individual. Relative to HeLa cells, the elevated targeting of CAR-T cells was achieved with 0 significantly.5:1 E:T ratio, as well as the antitumor aftereffect of CAR-T cells increased rapidly with increases from the E:T ratio (P=0.04). Rabbit polyclonal to PIWIL2 When this Alimemazine hemitartrate reached 40:1, 78% cells had been lysed (Fig. 2E). The in vivo Alimemazine hemitartrate antitumor aftereffect of CAR-T cells Using the effective E:T proportion obtained from tests, NPG mice had been utilized to validate antitumor activity. All tumors grew pursuing tail vein shot, whereas those infused with CAR-T cells grew slower. The difference in development price of tumor size was significant at PG-D31 (P=0.03), whereas subsequently, both groupings gradually synchronized in tumor development price without continuous shot (Fig. 3). This result shows that a sophisticated technique that enhances the result of CAR-T cells must regularly suppress the tumor. Open up in another window Body 3. (A) Tumor level of tumor-bearing NPG mice infused with CAR-T MSLN cells. (B) Tumor quantity modification of tumor-bearing NPG mice infused with CAR-T MSLN cells. *P 0.05, **P 0.01 vs. Control T. CAR, chimeric antigen receptor; MSLN, mesothelin. Dialogue The.
Supplementary MaterialsDisclaimer: Helping information has been peer\reviewed however, not copyedited
Supplementary MaterialsDisclaimer: Helping information has been peer\reviewed however, not copyedited. acceptance of the School of Strathclyde Regional Ethical Review -panel [Timetable 1 procedure; Pets (Scientific Techniques) Action 1986, UK], under UK OFFICE AT HOME WP1066 regulations. All tests utilized either common carotid arteries or second\purchase mesenteric arteries (as defined) extracted from man SpragueCDawley rats (10C12?weeks aged; 250C350?g), killed by either (we) an overdose of CO2 or (ii) an overdose of pentobarbital sodium (200?mg?kg?1, i.p.; Euthatal or Pentoject; Merial Animal Wellness Ltd, Woking, UK) as defined. Stream\mediated nitric oxide creation Nitric oxide creation was evaluated in the endothelium of carotid artery arrangements, using a adjustment of an operation for visualization of endothelial Ca2+ signalling (Wilson is normally volumetric flow price (cm3?s?1) and may be the liquid viscosity (0.0089?dyne cm?2 for drinking water). The endothelium was imaged using an inverted epi\fluorescence microscope (TE2000U; Nikon, Tokyo, Japan). DAF\FM was thrilled with 488?nm wide\field epifluorescence illumination supplied by a monochromator (Photon Technology International/Horiba UK, Ltd, Stanmore, Fluorescence and UK) emission was imaged in 10?Hz utilizing a 40 goal zoom lens (numerical aperture 1.3), a 0.7 coupling zoom lens WP1066 and a back again\lighted electron\multiplying charge\coupled gadget (EMCCD) camera (Cascade 512B; Photometrics, Tucson, AZ, USA) (1 binning). DAF\FM fluorescence strength measurements, averaged over the field\of\watch, are portrayed as baseline\corrected fluorescence strength (is normally DAF\FM fluorescence at period and was attained by convolving carotid artery and second\purchase mesenteric artery arrangements. The endothelium of arrangements were incubated using a launching solution filled with the fluorescent Ca2+ signal, Cal\520 acetoxymethyl ester (Cal\520/AM) (5?m), 0.02% Pluronic F\127 and 0.35% DMSO in PSS for 30?min in 37?C. Cal\520/AM was utilized throughout as the signal is reported to own highest indication\to\noise ratio of the very most typically obtainable Ca2+ dyes (Lock arteries was initially packed with Cal\520/AM (5?m), seeing that described above, and incubated with another launching alternative containing a membrane permeant caged IP3, caged IP3 4,5\dimethoxy\2\nitrobenzyl (10?m), 0.02% Pluronic F\127 and 0.35% DMSO in PSS for 30?min in 37?C. Photolysis of caged IP3 was attained using a regularity tripled neodymium: yttrium aluminium garnet (Nd:Yag; wavelength 355?nm) laser beam (Rapp Optoelektronic, Hamburg, Germany) attached right to the TE2000U microscope program (McCarron and and and cushioning) with a user\defined variety of pixels in the planes, and a mean spatial picture of every event is established by averaging each pixel strength within enough time window. These pictures are normalized to the best pixel worth after that, and a 2\D elliptical Gaussian function is normally suited to this indicate spatial picture. The Gaussian appropriate function reviews the and centroid positions, and regular deviations, and angle from the lengthy axis from the causing elliptical function. Ca2+ event traces are extracted in the padding?=?40?pixels (23?um), group radius?=?15?pixels (8.5?um) that occurred within a 20?pixel (11.5?um) radius were grouped and regarded as due to the same site. The email address details are provided as peak event amplitude (carotid artery arrangements, where ACh had free of charge usage of the endothelium, than for pressurized carotid artery arrangements, where ACh needed to traverse the vascular wall structure (Wilson arteries extracted from different pets (natural replicates). The mean??SEM is reported for the biological replicates. In IL-20R1 some full cases, the total variety of cells that averaged measurements had been made is normally reported as specialized replicates. From tests performed in Great\K+ PSS Aside, the Ca2+ replies from the same specific cells were matched. In those tests using Great\K+ PSS, arteries contracted and significantly, although there is some overlap in the cells imaged, pairing specific cells had not been feasible. Unless indicated usually, all values had been normalized to regulate responses. Responses had been analysed statistically using one\method ANOVA with Dunnet’s check, as suitable. All statistical analyses had been performed using Prism, edition 6.0 (GraphPad Software program, La Jolla, CA, USA). and planning) packed with the fluorescent sign, DAF\FM. Shape?2 (dark line) displays a representative track of DAF\FM fluorescence WP1066 strength from an test where the endothelium was stimulated by liquid movement (1.5?ml?min?1). Because nitric oxide binds to DAF\FM, assessed fluorescence intensities represent the full total build up of nitric oxide..
Supplementary Components1
Supplementary Components1. augments PD-1?/? T cell proliferation and worsens GVHD. These results indicate that B7H1/CD80 connection augments Tcon cell proliferation, IL-2 production, and manifestation of PD-1, which leads to improved apoptosis mediated from the B7H1/PD1 pathway. Additionally, by interesting both PD-1 and CD80, B7H1-Ig can be a powerful restorative reagent for down-regulating the T cell immune response. BrdU-labeling and Annexin V staining. Since T cell proliferation during the 1st 3 days after HCT was fragile and it became very strong by 6 days after HCT, as previously reported (41, 42), we labeled T cells with BrdU for 72 hours for the 1st 3 days and only for 3 hours on day time 6. We found that CD4+ Tcon cell yield in the spleen of B7H1?/? recipients Rabbit Polyclonal to PTGIS was significantly lower 3 days after HCT as compared with WT recipients (P 0.05, Fig. 1C). The reduced Tcon yield in the spleen of B7H1?/? recipients was associated with significantly reduced proliferation of Tcon cells (P 0.05, Fig. 1D, top row), although apoptosis of Tcon was related (Fig.1D, reduce row). Nevertheless, by 6 times after HCT, the CD4+ Tcon cell yield was increased in the spleen and liver of B7H1 significantly?/? recipients, in comparison with WT recipients (P 0.05, Fig.1E & G). The elevated Tcon produce in B7H1?/? recipients was connected with significant reduced amount of Tcon apoptosis, as judged by reduced percentage of Annexin V+ Tcon cells in both spleen and liver organ of B7H1?/? recipients in comparison with WT recipients (P 0.001, Fig.1F & H ). The Tcon proliferation in the B7H1?/? recipients Avermectin B1a was lower still, as judged by significant loss of BrdU+ Tcon cells in the liver organ and spleen of B7H1?/? recipients, in comparison with WT recipients (P 0.01, Fig.1F & H). These outcomes indicate that insufficient host tissue appearance of B7H1 (including hematopoietic cells and non-hematopoietic cells) network marketing leads to decrease in proliferation and apoptosis of alloreactive Compact disc4+ Tcon cells. The decrease in apoptosis of turned on T cells seems to outweigh the decrease in T cell proliferation, as having less host-tissue appearance of B7H1 eventually results Avermectin B1a within an accumulation of donor Tcon cells Avermectin B1a in both spleen and liver organ and exacerbation of GVHD. It really is appealing that reduced amount of donor Tcon cell proliferation is normally associated with reduced amount of apoptosis in the lack of host-tissue appearance of B7H1. Insufficient host tissue appearance of B7H1 decreases proliferation without impact on apoptosis of PD-1?/? alloreactive donor Compact disc4+ Tcon cells, leading to reduction of extension of Tcon cells and ameliorating GVHD Because the connections of B7H1 with PD-1 generally suppresses T cell routine progression of turned on T cells (19), the above mentioned observation of reduced amount of T cell proliferation in B7H1?/? hosts probably resulted in the disruption of B7H1/Compact disc80 connections. Thus, we further tested the function of B7H1/Compact disc80 interaction over the apoptosis and proliferation of Tcon cells by transplanting PD-1?/? Tcon cells into B7H1 and WT?/? recipients. First, we discovered that donor PD-1?/? Compact disc4+ Tcon cells had been much more powerful than WT Compact disc4+ Tcon cells in inducing severe GVHD. While recipients that received Compact disc25?CD8? -SPL cells (2.5 106) from PD-1?/? C57BL/6 donors all.
Supplementary MaterialsSupplementary Information 41467_2020_16997_MOESM1_ESM
Supplementary MaterialsSupplementary Information 41467_2020_16997_MOESM1_ESM. genome cancer and instability. locus on chromosome XV17. Significantly, this system actions frequencies of noncrossover (NCO) and CO in DSB restoration, and in addition distinguishes between brief and long-tract GC (Fig.?1a; Supplementary Fig.?1). Upon I-gene and segregation: white (and deletion was proven to boost DSB-induced chromosome reduction occasions inside a different hereditary program, because of abortive BIR occasions14 possibly. To verify if the alteration from the HR restoration might be due to early chromosome segregation in deletion seriously affected BIR, from the cell-cycle stage irrespective, confirming our earlier observation how the BIR defect of will be faulty in BIR for yet another reason than lacking signalling to Pif1. Open up in another windowpane Fig. 2 Rad9 promotes DSB repair through BIR.a Scheme of the genetic system to test BIR in JRL092 background. b Southern blot of deletion increased the amount of resected DNA far from the DSB, the levels of the ssDNA generated very close to the break site in wild-type and deletion impaired the D-loop extension, measured through a PCR-based assay more severely than in the BIR assay, similar to deletion Mavatrep (Fig.?5h). This result suggests that a decreased interaction between Sgs1 and Rad51 might reduce strand rejection and D-loop reversion, favouring BIR in deletion somewhat decreased DSB resection acceleration alone so when coupled with deletion in the JKM139 history (Supplementary Fig.?2a-c), the and increase COs with this background23 greatly,25. First, we discovered that the deletion triggered a mild reduced amount of the wild-type and and rescued the CO occasions from the deletion was proven to trigger BIR defects connected with improved chromosome loss occasions, that have been rescued by keeping the cells clogged in Mavatrep G2/M with nocodazole14 partly,15. Nevertheless, in the diploid assay we didn’t observe higher chromosome reduction in the and rescued the BIR and CO deficiencies of deletion also limitations sister chromatid Rabbit Polyclonal to NMS exchanges and promotes Rad1/XPF-dependent translocations, most likely through SSA12,13. Consistent with our model, removing in deletion decreases the restoration occasions that trigger extended lack of heterozygosity (LOH), an activity associated with tumour advancement. How Rad9/53BP1 finely music this complex rules to protect genome stability can be a challenge for future years. Methods Candida strains, development and press circumstances All of the strains listed in Supplementary Desk?5 are derivative of JKM179, JRL092, tGI354 and W303. To create strains standard hereditary procedures were adopted51. Label and Deletions fusions were generated from the one-step PCR program. The probe; the % of BIR fix has been determined using the donor band like a launching control18. For ectopic recombination using tGI354 history, genomic DNA was digested with probe. The DSB restoration has been determined by normalizing the DNA quantity utilizing a DNA probe particular for gene (unprocessed locus). Densitometric quantification from the band intensity was performed using the ImageJ software. The SEM was calculated on three or more independent experiments. ChIP Mavatrep analysis ChIP analysis was performed as described in ref. 7 with slight modifications. Briefly, cells were grown to log phase in YEP?+?raf and arrested in G2/M with 20?g/mL nocodazole wherever indicated before addition of galactose to a final concentration of 2%. Cells were sampled before addition of galactose (0?h) and at time points after DSB induction as shown in respective figures. Crosslinking was done with 1% formaldehyde for 5?min (Myc or HA tagged proteins) or for 30?min (Rad51). The reaction was stopped by adding 0.125?M Glycine for 5?min. Immunoprecipitation was performed by incubating the samples with Dynabeads Protein G (Thermo Fisher Scientific), pre-conjugated with 5?g of 9E10 anti-Myc antibody or 12CA5 anti-HA antibody or 3?g of anti-Rad51 antibody (PA5-34905, Thermo Fisher Scientific) for 2?h at 4?C. Whole chromatin extract (Input) and immunoprecipitated DNA were analysed by quantitative PCR, using a Bio-Rad CFX connect, or droplet digital PCR (ddPCR), using a Bio-Rad QX200 droplet reader. For JKM139 derivative strains, several oligonucleotides have been designed at specific distance from the DSB to measure enrichment of Rpa1-HA, Rad51, Rad52-HA, Sgs1-MYC, Mph1-MYC. In JRL092 derivative strains, enrichments of Rad51, Sgs1 and Mph1 at the donor site have been evaluated with oligonucleotides on locus on chromosome XI. For enrichment. | {
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4,729,254,155,496,107,000 | Facial surgeon london. Plastic surgeon london. Plastic surgery. Nose job. Eyelid surgery. BLEPHAROPLASTY. Lift lift. Face lift. neck lift
The Truth about Non-Surgical Rhinoplasty
May 3, 2022
Is non surgical or surgical rhinoplasty better?
Convenience and cost are probably the most important initial considerations when someone is thinking about cosmetic plastic surgery. If something can be done “non-surgically” then most assume that this is the better option. But is it really? Non-surgical options are usually promoted as been cheaper, quicker, with less down time. However, when it comes to nose reshaping this may not be entirely accurate.
Recent articles in the Guardian and the Daily Mail have discussed how a fall in surgical rhinoplasty has been driven by non-surgical alternatives. With treatments costing as low as £300, with no need to take time off work, then it is no wonder patients are choosing this as an alternative to the “traditional” rhinoplasty.
Liquid or non-surgical rhinoplasty
Liquid or non-surgical rhinoplasty is when hylarunoic acid (a naturally occurring substance in the body) is used to alter the shape of the nose. Injecting this non-permanent filler in key areas of the nose can be a powerful tool in achieving balance and harmony between the nose and the rest of the face. However, plastic surgeons are seeing more and more patients who are unsatisfied with their non-surgical rhinoplasty or would like a permanent result.
Are non-surgical nose fillers safe?
Non-surgical rhinoplasty is not without risk. If the filler is injected into a blood vessel it can lead to catastrophic consequences such has skin loss or blindness. More commonly, non-surgical rhinoplasty cannot correct breathing difficulties with the nose, or severe crookedness. It is essentially good for someone with a small bump on the bridge of their nose. It cannot correct a large or droopy tip.
Modern surgical rhinoplasty techniques
Modern surgical rhinoplasty techniques, which are encompassed by the term “preservation rhinoplasty” can achieve dramatic and permanent changes to the nose without many of the downsides people associate with surgical rhinoplasty.
Most patients who undergo preservation rhinoplasty have little or no bruising and are able to return to work after a week (depending on the type of work). Also, because vital anatomical components are preserved (such a cartilage and ligaments) less long term changes occur. This means lower chance of needing revision surgery.
It is important that patients see a surgeon or injector who is qualified, experience and has a passion for facial surgery before undergoing any form of treatment. Both non-surgical and surgical rhinoplasty have a role to play in nose reshaping. Neither is superior to the other. It all depends on the patient and what they wish to achieve.
Preservation Rhinoplasty
Links to articles
https://www.theguardian.com/fashion/2022/apr/25/a-nosedive-in-nose-jobs-why-fewer-people-are-opting-for-rhinoplasty
https://www.dailymail.co.uk/news/article-10749581/Nose-jobs-fall-fashion-patients-choosing-non-surgical-alternatives-medics-say.html
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-498,278,564,449,521,300 | HealthyLivingTrends.com
Diet
Featured Diet Article
Diet
Choices For Low Carb Diets
by HealthyLivingTrends.com
Low Carb Diets are based on the theories of controlling carbs, and choosing the right carbs in the process.
The first low carb diet is the Atkins Diet. The theory behind Atkins diet is controlling carbohydrates, or "proactive nutrition". Atkins diet promises people to lose weight, not be hungry, better heart health, and better memory. This diet is based on the idea that people who are overweight eat too many carbohydrates. Our bodies use fat and carbohydrates for energy, with carbohydrates being used first. With fewer carbohydrates our bodies will burn off stored fat allowing us to lose weight.
The Atkins diet plan sets few limits on amount of food eaten, however it restricts the kind of food allowed; example no refined sugar, milk, white rice, or white flour. The plan allows people to eat rich foods; example meat, eggs cheese etc. Individuals are eating almost pure protein and fat. Individuals can eat red meat, fish, poultry, regular cheese, cook with butter, eat mayonnaise, and olive oil.
Carbohydrates are restricted (20 grams per day minus fiber) for the first two weeks. This equals three cups of salad or two cups of salad with two thirds cup of certain cooked vegetables each day. There are no exceptions to these rules. Later carbohydrate allowance increases in the form of fiber. These are permanently gone. Individuals can add fruits, vegetables, and whole grain foods after first two weeks. Then individuals transitions from weight loss to weight maintenance as carbohydrates are increased. Exercise is emphasized in all parts.
The second low carb diet is South Beach. South Beach dieters are encouraged to choose the right carbohydrates, such as whole grains, certain fruits and vegetables, the right fats olive and canola oils, and lean protein. How the South Beach diet plan works is that dieters follow phase one for two weeks. Individuals eat normal size portions of lean meat, fish, eggs, reduced fat cheese, nonfat yogurt, nuts, and plenty of vegetables. Snacks and desert are a part of the plan. Dieters continue with phase two until they are done losing weight. This is where individuals introduce the right carbohydrates such as whole grains, and most fruits. Some indulgences are allowed. Once individuals have reached their goal weight they move on to phase three. People continue to make excellent choices to maintain their healthy lifestyle.
The South Beach diet comes from the idea that Americans are carbohydrate crazy. Phase one is designed to help people stop craving carbohydrates and carbohydrates are downplayed through the rest of the diet. Highly processed carbohydrates get digested too soon, insulin levels shoot up., and once those carbohydrates are burned up, the individual's high insulin makes them crave food, so what do Americans eat, more carbohydrates. The South Beach diet promises to make you want to eat better food.
Low carb diets are about creating goals, and following specific plans to lose weight. Then with the right balance, low carb diets help individuals to maintain that weight loss. | {
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6,671,791,557,871,696,000 | Diet for Kidney Disease ?>
Diet for Kidney Disease
Diet for Kidney Disease
There are two types of diets for kidney disease. One type of diet is specifically for people who have progressive chronic renal failure, or kidney failure, but are not on dialysis yet. Along with medicine, a low-protein diet may slow the worsening of kidney failure. The other more restrictive type of diet is for people on dialysis whose kidneys have totally failed and are no longer working at all. This is called end stage renal disease, or ESRD.
Information
The kidneys also make hormones needed by the body. These include hormones that help make bones and blood cells. The kidneys also help control blood pressure by limiting the amount of fluid and salt in the bloodstream. People with kidney disease are at risk for vitamin deficiencies. Their bodies may not be able to make certain blood cells, which can lead to anemia. Their kidneys also prevent the body from maintaining bones as usual. The extra fluid and sodium in the bloodstream that can accumulate as a result of kidney failure can lead to high blood pressure. Hormonal changes can cause cholesterol and other fats in the blood to be high. The buildup of toxic substances can make a person with kidney disease feel ill. In children, all of these conditions may prevent normal growth and development.
PRE-DIALYSIS DIET
Eating a low-protein diet before starting dialysis may help preserve kidney function. Protein restriction can delay the start of dialysis. The healthcare provider will determine whether a low-protein diet would be useful. A registered dietitian should be consulted to help plan the diet.
This diet limits the amount of protein in the diet to about 40g to 50g per day. The protein eaten should be of high quality. Lean meat, fish, poultry, and eggs are good sources of high quality protein. Other nutrients many be low in this type of diet, so a multiple vitamin including folic acid is usually recommended. It is important that people following this type of diet get adequate calories from carbohydrates and fats. This keeps the body from using protein calories for energy. Sodium, including table salt, may also be restricted. It is also important to speak to the healthcare provider before using any salt substitutes. Individuals should consult with a registered dietitian to ensure that this diet is adequate in all nutrients.
DIET FOR PEOPLE ON DIALYSIS
People who have ESRD must undergo dialysis or receive a kidney transplant. Dialysis is a process that filters the blood to remove toxic substances. There are two types of dialysis. They are hemodialysis and peritoneal dialysis. In hemodialysis, the person’s blood is filtered through an artificial kidney machine. This machine removes waste products, as well as extra fluid and salt, from the blood just as the person’s kidneys would if they were still working. In peritoneal dialysis, the blood is cleaned inside the body using the abdominal cavity. Fluid is placed into the patient’s abdominal cavity. The waste products from the blood pass into the fluid. The fluid and waste products are then drained from the abdominal cavity through a tube.
The diet for people on dialysis may limit the following nutrients:
fluid
phosphorus
potassium
protein
sodium
Protein may or may not be restricted for people with ESRD. The decision depends on remaining kidney function and other factors. A nephrologist, a physician who specialized in kidney diseases, and a registered dietitian can provide guidance on optimal protein intake.
Sodium
The amount of sodium is restricted in this diet. The following foods are usually limited:
canned foods
convenience foods
processed foods
table salt
Salt substitutes should not be used because they contain potassium. Acceptable alternatives to salt include the following:
garlic powder
herbs
onion
spices that don’t contain salt
vinegar
Fluids
Fluid restrictions vary, depending on how much liquid the person’s kidneys are able to remove. Any food that is liquid at room temperature contains water. Foods that have a high fluid content are as follows:
apples
gelatin
grapes
ice cream and sherbet
lettuce and celery
melons
oranges
soup
tomatoes
All of these foods add to a person’s fluid intake. Fluid can build up between dialysis sessions, causing swelling and weight gain. The extra fluid affects the blood pressure and can make the heart work harder. This can cause serious heart trouble.
Potassium
Potassium is a mineral that affects how steadily the heart beats. Healthy kidneys keep the right amount of potassium in the blood to keep the heart beating at a steady pace. Potassium levels can rise between dialysis sessions and affect the heartbeat. Eating too much potassium can be very dangerous to the heart. It may even cause death. Potassium is found in many foods, including dairy products, meats, and dried beans. There are certain fruits that are especially high in potassium, such as:
apricots
avocados
bananas
cantaloupes, honeydew, and other melons
dates and other dried fruits
grapefruit and grapefruit juice
kiwifruit
mangoes and papayas
nectarines and peaches
oranges and orange juice
pears
prunes and prune juice
rhubarb
Vegetables that are high in potassium include the following:
artichokes
brussels sprouts
dried beans and lentils
fresh tomatoes, tomato paste and puree, and tomato juice
lima beans and succotash
potatoes
pumpkins and squash
spinach and Swiss chard
vegetable juice
Phosphorus
The kidneys play an important role in balancing the phosphorus and calcium in the body. When a person has kidney disease, the phosphorus from food may build up in the blood. Too much phosphorus in the blood pulls calcium from the bones. Losing calcium makes the bones weak and more likely to break. Also, too much phosphorus may make the skin itch. The following foods are high in phosphorus and need to be restricted:
cola drinks
milk and cheese
nuts and peanut butter
peas
Most people on dialysis also need to take a phosphate binder to control the phosphorus in their blood between dialysis sessions. These medications act like sponges to soak up, or bind, phosphorus while it is in the stomach. Once it is bound, the phosphorus does not get into the blood. Instead, it is passed out of the body in the stool.
Diets for kidney disease must include sufficient calories to prevent weight loss and the use of protein for energy. Due to the many food restrictions, people who have kidney disease usually need supplements of vitamins, iron, and calcium.
A diet for kidney disease takes a lot of planning. It is a very personalized diet. How much each nutrient needs to be restricted varies from individual to individual. Kidney disease usually requires frequent visits to the healthcare provider. A registered dietitian can help plan individualized meals. The dietitian can also instruct the patient on his or her special diet. Frequent blood tests show which nutrients need to be limited. Any new or worsening symptoms should be reported to the healthcare provider.
Functions and Sources
How does the nutrient affect the body?
Normally, kidneys filter many substances from the blood. These substances include the following:
by-products of chemical reactions in the body
salt
waste products from the foods we eat
water
Eventually these substances are passed out of the body in the urine. When the kidneys are damaged, they cannot filter the blood. Substances can build up to harmful levels. This buildup can damage other organs of the body and cause numerous problems. Certain substances are restricted in the diet to prevent this toxic buildup.
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7,514,462,453,147,975,000 | Norovirus Treatment – Norovirus https://www.norovirus.com Norwalk Virus & Food Poisoning Wed, 17 Jul 2019 07:56:03 +0000 en hourly 1 https://wordpress.org/?v=4.5.3 Diagnosing and Treating Norovirus https://www.norovirus.com/diagnosing-and-treating-norovirus/ Tue, 24 Jun 2014 06:23:14 +0000 https://www.norovirus.com/?p=135 The Norovirus is a very contagious virus that can cause the quick onset of vomiting and diarrhea. Norovirus are a group of viruses that cause inflammation of the stomach and large intestine lining. Currently it is the most common cause of acute gastroenteritis throughout the United States. It can be transmitted by many different methods, such […]
The post Diagnosing and Treating Norovirus appeared first on Norovirus.
]]>
© Loren Kerns
© Loren Kerns
The Norovirus is a very contagious virus that can cause the quick onset of vomiting and diarrhea. Norovirus are a group of viruses that cause inflammation of the stomach and large intestine lining. Currently it is the most common cause of acute gastroenteritis throughout the United States. It can be transmitted by many different methods, such as through sharing contaminated water, food, and more. People acquire the Noroviruses when they ingest material that is contaminated with small amounts of infected feces or fluids. This can include water and food that is contaminated during the handling or processing as well. Since it can be transmitted between persons through food and drinks, it is commonly found on cruise ships, restaurants, and in other social areas.
Diagnosing Norovirus
There are many symptoms associated with Norovirus, with the hallmark symptom being frequent vomiting. Along with the vomiting there is also going to be nausea and constant diarrhea, this is why many refer to Norovirus as the “two bucket” illness. Nausea is frequently associated and most often those infected will also have stomach pain as a result of the inflammation in the intestines. Those who are infected with Noroviruses will be sick for 24 to 48 hours. The majority of those who catch the virus will be able to make a full recovery. Other symptoms for Norovirus include headache, chills, muscle aches, fatigue, and possibly a fever. The most important symptoms to consider are the diarrhea and vomiting which can easily deplete your body of needed fluid and leave you dehydrated. Children and the elderly are most susceptible to being left dehydrated as a result of prolonged symptoms of vomiting and diarrhea. Because of the loss of fluid, thirst will also be another symptom and sign of being infected with the virus.
Treating Those With Norovirus
The illness usually resolves itself, many people are over their sickness after they are infected with Norovirus within just a few days. However, the illness can easily make it an uncomfortable few days for you. There are a few things that you can do in order to help your body recover and return to optimal health. Because of the frequent loss of fluid due to the diarrhea and vomiting, it is important to remember to stay hydrated and to drink lots of healthy fluids for the body. Those fluids which contain sugar and electrolytes are going to be more beneficial for the body. It is also important to clean your hands whenever you come into contact with any new objects or individuals. Even after your symptoms go away you can still be contagious for a few days afterwards and can easily spread it to another. The most important aspect to remember is that you need to keep your body efficiently hydrated. It can last for several days at the most so make sure that you also remember to get plenty of sleep so that your body can properly recover and initiate its own self-healing system.
The post Diagnosing and Treating Norovirus appeared first on Norovirus.
]]> | {
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-8,682,855,485,965,040,000 | @article {Mahallawi862, author = {Mahallawi, Waleed H. and Kurdi, Mohiadeen M. and Ibrahim, Nadir A.}, title = {Serostatus of IgG antibody against mumps virus in adult population of Al Madinah Al Munawarah, Saudi Arabia}, volume = {42}, number = {8}, pages = {862--868}, year = {2021}, doi = {10.15537/smj.2021.42.8.20210228}, publisher = {Saudi Medical Journal}, abstract = {Objectives: To determine the frequency and distribution of mumps-specific IgG antibodies among the healthy adult Saudi population in Al Madinah Al Munawarah, Saudi Arabia, where mandatory vaccination against measles-mumps-rubella (MMR) has been implemented for 30 years.Methods: Qualitative and quantitative indirect enzyme-linked immunosorbent assay was performed to determine the mumps IgG antibody levels in sera collected from 429 individuals, including 224 men and 205 women. Participants were stratified into 3 age groups according to vaccination history (\<20, 21-30, and \>31 years).Results: The overall seroprevalence of mumps antibodies in our population was 79.0\%. The highest proportion of individuals with IgG antibody seropositivity, at 87.8\% (95\% confidence interval (95\% CI): 84.7\%-90.8\%), was observed among the \<20 years age group, who received 2 doses of vaccine. No significant relationships were observed between mumps seropositivity and age group or gender. The multivariable analysis identified the male gender and the age group \>31 years as factors associated with an increased likelihood of seronegativity. Al Madinah Al Munawarah has achieved increased anti-mumps antibody seroprevalence since the implementation of the 2-dose MMR vaccination schedule.Conclusions: Based on our study findings, we recommend that serological screening be performed to assess the need for mumps vaccination among adults at high risk for exposure and transmission.}, issn = {0379-5284}, URL = {https://smj.org.sa/content/42/8/862}, eprint = {https://smj.org.sa/content/42/8/862.full.pdf}, journal = {Saudi Medical Journal} } | {
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9,171,928,708,982,962,000 | Gluten Intolerance versus Allergies – which one do you suffer from?
villiThe problem of gluten intolerance is quite common among the population and you too may be a victim to it. Gluten is a protein most commonly found in wheat. This is the component of the wheat which makes the dough rise and the bread chewy. There are various grades of gluten intolerance. You may be able to eat little quantities without any trouble or you may develop serious problems by eating gluten. You need to understand whether you have gluten intolerance or gluten allergy. Understanding this distinction can help you work out the best diet for your health.
What is gluten allergy?
An allergy is a reaction to a food where the body offers an immunological response. If you have gluten allergy, chemical changes will occur in your body in response to ingestion of gluten. They may also be triggered by using cosmetics containing gluten.
Here are some important facts that you should know about gluten allergy:
• When you ingest any food containing gluten and you have gluten allergy, your body will begin to release antibodies. This is a common occurrence in case of any food allergies including gluten.
• When you ingest gluten for the first time, your body releases immunoglobulin E or IgE. These antibodies circulate in your body and attach themselves to mast cells located in nose, skin, throat, abdomen etc. When you ingest gluten after this, the mast cells release histamines. These cause allergic reactions in those parts of the body.
• The common symptoms of gluten allergy are rashes, hives, eczema, swelling of tissues, trouble in breathing etc. In extreme cases, gluten allergies can lead to drop in the blood pressure and even death. However, these allergic reactions can occur in response to many other factors. So, you need to be sure that you are actually allergic to gluten.
What is gluten intolerance?
Intolerance to any food is that where your stomach suffers if you eat that food. In most cases, you can tolerate a small amount of the food. Gluten intolerance is thus a condition where you cannot eat foods containing gluten.
Here are the major facts regarding gluten intolerance:
• Gluten intolerance is not an uncommon condition. In this situation, you will not be able to eat foods containing gluten, though you may be able to tolerate small amounts now and then.
• If you have gluten intolerance and eat gluten, this will trigger an immunological response in your body. Your body mistakes gluten for a harmful substance. So, it releases chemicals to fight this enemy.
• These chemicals attack the villi in your small intestine. Looking like finger like projections, the villi play an important part in the digestion of food. They are rich in blood vessels which absorb the nutrients of the foods being processed by the small intestine.
• When the chemicals attack the villi, they are gradually destroyed. The finger like shape becomes flat and rounded, thereby decreasing the surface area. This inhibits the process of digestion and absorption of essential nutrients.
• So, if you suffer from gluten intolerance, you will have digestive troubles and other symptoms like gas, bloating, vomiting, diarrhea and abdominal cramp.
Understanding gluten intolerance and allergies
Here are some points of distinctions to help you differentiate between gluten intolerance and allergy:
• Gluten allergy is like any other food allergy. You react to the taste or even touch of the substance. Your body releases histamines leading to extreme symptoms like breathing trouble, change in blood pressure, swollen tongue etc.
• However, gluten intolerance is unlike food intolerance. In case you are intolerant of a food, your body does not have any chemical reaction; you simply cannot digest it. So, you will not have any trouble touching or smelling it.
• But in case of gluten intolerance, the body does have a chemical and immunological reaction.
• Your blood releases certain substances which attack the villi of your smaller intestine. In extreme cases this can lead to a number of complications including cancer.
• If you are gluten intolerant, you may be able to eat a little bit gluten, but it is better not to take the risk. Even the little amount will add up over time and may cause serious complications.
• It is not possible for you to find out if you have gluten intolerance or allergy. It is up to your doctor to do that. Certain blood tests and skin prick tests are necessary. Your doctor may even put you on an elimination diet to determine what allergies are suffering for. Here, you start with only a few food and then add one item at a time to determine which ones are triggering the allergic reactions.
Whether you have an allergy or intolerance, if you have any problem, you should completely eliminate gluten from your diet because in long term it can lead to severe complications.
2 thoughts on “Gluten Intolerance versus Allergies – which one do you suffer from?”
1. Shots might seem like an unusual way to treat allergies, but they’re effective at decreasing sensitivity to triggers. The substances in the shots are chosen according to the allergens identified from a person’s medical history and by the allergist during the initial testing. The U.S. Food and Drug Administration (FDA) oversees the standards used in preparing the materials for allergy shots given in the United States.
2. A gluten-free diet might also exclude oats. Medical practitioners are divided on whether oats are acceptable to celiac disease sufferers or whether they become cross-contaminated in milling facilities by other grains.`*^-
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-3,835,977,968,454,722,600 | Macular Degeneration
Progressive damage to the macula, the area near the centre of the light-sensitive retina that is responsible for detailed vision
• Increasingly common with age, especially over the age of 70
• More common in females
• Sometimes runs in families
• Smoking and excessive exposure to sunlight are risk factors
Gradual deterioration of the macula, the most sensitive region of the light-sensitive retina at the back of the eye, is known as macular degeneration. The condition leads to progressive loss of central and detailed vision. Affected people become unable to read or to recognize faces. However, the edges of their vision (peripheral vision) remain clear. Usually both eyes are affected.
Macular degeneration is more common in females and sometimes runs in families. The condition usually develops after the age of 70, although there are some rare forms that affect younger people. The risk of developing macular degeneration is increased by excessive exposure to sunlight and smoking.
What are the types?
There are two main forms, but their causes are unknown. In dry macular degeneration, light-sensitive cells in the macula and cells in the supporting layer underneath die. In wet macular degeneration, fragile new blood vessels grow beneath the macula. As the blood vessels leak fluid or bleed, the light-sensitive cells in the macula are damaged.
What are the symptoms?
Macular degeneration causes progressive visual loss over several months. Symptoms may include:
• Difficulty in reading, watching television, and recognizing faces.
• Distortion of vision so that objects appear larger or smaller than normal, or straight lines appear wavy.
Wet macular degeneration occasionally causes sudden loss of central vision due to rupture of an abnormal blood vessel. The damaged macula becomes scarred, causing permanent visual impairment. Anybody who develops symptoms should consult their doctor promptly, particularly if they experience a sudden distortion of vision.
What might be done?
Diagnosis is made by vision tests and by ophthalmoscopy of the retina. If there is a possibility of wet macular degeneration, then fluorescein angiography may be carried out to check for abnormal blood vessels.
Dry macular degeneration cannot be treated but there is limited evidence that large amounts of vitamins A, C, E, and the minerals zinc and copper may help to slow the progression of the disease. Smokers should also stop smoking.
The early stages of wet macular degeneration may be treated by injections of drugs called anti-vascular endothelial growth factor agents (anti-VEGF agents), which inhibit the growth of new blood vessels under the macula. The injections are given into the eye and are repeated monthly for up to 18 months. Alternatively, the condition may be treated by photo-dynamic therapy. In this technique, a light-sensitive dye is injected into an arm vein and passes through the bloodstream to the eye. In the eye, the dye is activated by a laser and destroys abnormal blood vessels. This procedure may need to be repeated regularly. These treatments can be effective at preventing deterioration of vision, but any vision that has been lost cannot usually be restored.
If sight becomes severely affected, aids such as magnifying glasses may help with tasks such as reading.
From the 2010 revision of the Complete Home Medical Guide © Dorling Kindersley Limited.
The subjects, conditions and treatments covered in this encyclopaedia are for information only and may not be covered by your insurance product should you make a claim.
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• Question and Answer
• Open Access
Q&A: Promise and pitfalls of genome-wide association studies
BMC Biology20108:41
https://doi.org/10.1186/1741-7007-8-41
• Received: 8 April 2010
• Accepted: 12 April 2010
• Published:
Keywords
• Linkage Disequilibrium
• Duchenne Muscular Dystrophy
• Multifactorial Disease
• Causative Locus
• Causative Allele
Why do we need genome-wide association studies?
To answer that, we first need to look at the kinds of genetic changes that have previously been studied by medical geneticists. These have usually been 'single-gene disorders', which result from mutations in single genes, where an individual with a mutant allele of the gene (in the homozygous state for a recessive disorder) has the disease with a hundred percent probability. Thus, an individual homozygous for the sickle-cell allele of the beta-globin gene will always have sickle-cell anemia (Figure 1). When all individuals with the disease genotype have the disease, we describe such a mutation as one hundred percent penetrant. When the penetrance is less, there are individuals who have the predisposing genotype, but do not have the disease. This is because other genes play a role in the determination of the disease, or because of the effects of the environment. This makes the mapping of the gene causing the disease using pedigree information (as illustrated in Figure 1) more difficult.
Figure 1
Figure 1
Pedigrees. Here a square represents a male, and a circle a female. (a) For a dominant disorder, such as Huntington's disease, represented by the allele symbol H, an individual need only inherit the mutant allele from one parent (that is, be heterozygous) to be affected. In such cases, affected individuals almost always are in fact heterozygous for the mutant allele, and they transmit it, and the disease, to half the offspring. (b) For a recessive disorder, in this case sickle cell anemia, shown by the βS allele symbol, the disease is seen only in individuals homozygous for the allele (that is, who have inherited the allele from both parents); they are typically the offspring of two heterozygotes (carriers of the disease).
Where the penetrance is very low, it is virtually impossible to map genes using pedigrees, and here we enter the world of multifactorial disorders, where the presence or absence of the disease is influenced by many genetic differences and also by the environment. The role of genes in determining whether individuals have the disease can still be important, and this is measured by the 'heritability' of the disease, which is the proportion of the determination of the disease that is caused by genetic rather than environmental differences. Heritability for such disorders is measured through the correlations between relatives, most powerfully using monozygotic (identical) and dizygotic twins. Single-gene disorders tend to be rare, whereas many important multifactorial diseases, including, for example, hypertension, diabetes and schizophrenia, have much higher frequencies in the population, but still have high heritabilities. The goal of genome-wide association studies (GWAS) is to understand common multifactorial diseases and the genes that predispose us to them.
Do common multifactorial diseases result from the combined effects of common alleles of predisposing genes?
That is indeed thought to be likely, and is the basis for the so-called 'common disease-common variant model' for multifactorial diseases. The suggestion is that, since the disease is common, its presence may arise from a set of predisposing alleles at multiple loci, each of which is itself common in the population.
If an allele predisposes us to a disease, how does it become common? Why has selection not operated to eliminate it?
For single-gene disorders, we think of the frequency as typically depending on a 'mutation-selection balance'. Mutations at the disease locus arise all the time, and (in homozygotes for recessive mutations, or heterozygotes for dominant mutations) cause disease. The disease lowers an individual's ability to survive and breed (Darwinian fitness), and mutations are eliminated from the population by selection. Eventually, the population reaches an equilibrium frequency of the disease, where the rate of loss of the disease alleles by selection is exactly balanced by the rate of gain of disease alleles by mutation. It follows that diseases with high mutation rates (such as Duchenne muscular dystrophy) are more common than diseases with lower mutation rates. Also, a disease that has a small effect on Darwinian fitness, such as one that has its effects after reproduction, will have a higher equilibrium frequency than a disease with a lethal effect in childhood. As I have said, single-gene disorders are rare: the mutation rate is relatively low, and selective pressure against them relatively strong.
Multifactorial diseases, by contrast, can be common, for a number of reasons. First, it is important to remember that an allele that predisposes to a multifactorial disease is only affected by selection to the extent that the frequency of the disease is higher in individuals with that allele than in individuals lacking it, and if it has only a small effect on the probability of the disease, the selection against it is correspondingly reduced. There is also a difference in the relevant time scale for multifactorial against single-gene disorders, which are typically caused by relatively recent mutations. A common allele predisposing us to a multifactorial disease could have arisen tens or hundreds of thousands of years ago, and may have become common in an environment that is very different from that in which we now live. Perhaps the selection operating at that time, particularly on diseases of old age, was very different from that prevailing now. There can also be gene-environment interactions, where an allele might produce a disease only in people living in a modern environment. There is also the possibility that the allele that predisposes to a disease may have other, beneficial effects. (Such an allele is described as 'pleiotropic'.) The overall effect of the allele on fitness might then be very slight or could indeed be positive. Finally, the process of random genetic drift can raise the frequencies of alleles that predispose to disease, and this could have been common during the rapid increases in population size of modern humans as they spread from their origins in Africa during the last 150,000 years.
How exactly can genome-wide association studies (GWAS) make it possible to identify the predisposing genes in multifactorial diseases?
This approach is driven by the new technologies that allow tens or hundreds of thousands of polymorphisms, usually single-nucleotide polymorphisms (SNPs), to be assessed simultaneously. This technique is applied to a set of cases (individuals with the disease) and a set of matched controls, and differences in the frequencies of SNPs between the two groups are assessed in order to identify SNPs that may be associated with the disease. With so many SNPs being tested, the situation is a bit tricky statistically as there is a danger of false positive associations - that is, associations that occur purely by chance and not because the SNP is linked to the disease. So, generally, the significance is adjusted on the basis of getting a 'false discovery rate' of 5% - that is, of all the SNPs called as being associated with the disease, it is expected that only 5% will be truly unassociated SNPs showing an association by chance in the samples.
Wait! - What is a polymorphism? Is it a kind of mutation?
This is a question with a slightly complex answer. Population geneticists have long used the term for genetic variation where, at a particular genetic locus, or, ultimately, base pair, there are two or more genetic variants where the commonest has a frequency below around 95%. In other words, it is a situation where there is not a single normal (wild-type) allele with one or more rare variants - in which case the rare variant base pairs would be called mutations. What makes the answer slightly complex is that there has recently and occasionally been a subtle change in the use of the term. Thus, if, at a given base pair, 90% of alleles have a T and 10% have an A, we say that there is a SNP - a single nucleotide polymorphism - at that base. However, occasionally, some describe this in an asymmetrical way - in which the A is said to be a polymorphism and the T is not.
So the idea is that the SNPs identify predisposing alleles and thus the biological basis of the disease?
Ultimately, yes. But there are also practical benefits just to having a way of identifying individuals at risk without knowing the mechanism. For many multifactorial diseases, treatments and tests are available that are offered on the basis of calculated risk. Thus, a diagnostic test might be carried out on an individual whose lifestyle, age, family history and other factors added up to a 22% risk of a condition, but such a test might not be offered to someone with an 18% risk. The additional information about risk that is supplied by genotype can allow a more precise targeting of tests to those individuals who are truly most at risk.
One hope is that there could be different treatments for a given disease, designed for those with differing underlying genetic causative factors. Thus, if one patient with a multifactorial disease has predisposing alleles A, C and E, while another patient with the same disease has predisposing alleles B, D and F, then it could be that the best drug treatments for these two patients are different even though their symptoms are not, because of the different etiologies of their diseases. This is what is known as personalized medicine.
But, more fundamentally, the identification of causative loci in GWAS can indeed give insight into the biology of the disease. An allelic difference detected in GWAS might only have a weak effect on the probability of getting the disease. But the modest effect seen may be slight not because the gene involved is unimportant in the pathway that leads to the disease, but because the alleles involved might both be functional alleles showing only subtle, quantitative differences in their action. The importance for treatment of the identification, through a disease association, of a gene or a pathway might well outstrip the importance of the effect of allelic differences at that gene on disease risk.
So are you implying that the SNPs associated with disease are directly causing defects in predisposing genes?
No. The simplest way in which a genetic variant, such as a SNP, can be associated with an increased risk of disease is indeed if such a variant directly causes the elevated risk. But it is much more likely, in any given case, that the SNP being investigated is associated with other genetic differences which, in fact, determine the risk. In population genetics terms, we say that the marker investigated (in this case the SNP) is in linkage disequilibrium with the genes causing the disease. Unfortunately, because of the ways that linkage disequilibrium can arise, this does not always help us to find the culprit gene.
So how does such linkage disequilibrium arise?
There are many ways in which this can happen. One simple way is through population substructure. Thus, if a population consisted of a mixture of individuals with African and European ancestry, for example, and the disease was commoner among those with European ancestry, then, if one took a random sample of cases and a random sample of controls, the cases would be enriched for people with European ancestry, and all the SNPs that showed differences in frequency between Europeans and Africans would also differ between cases and controls, even though almost all would be unlinked to any genes actually causing the disease.
So does that mean that if you are looking at GWAS across populations, you are likely to be led astray by genetic differences between the different populations?
This is a danger, but it can be prevented, in principle, by matching the ancestry of cases and controls. Thus, each time you include an affected individual (a 'case') who has a particular ancestry, you add a control with a similar ancestry. This means that the cases and controls will come from the same mix of ethnic groups, and differences in the frequency of the disease between groups will not create false positives. Even when you do this, however, it is possible you may be led astray by cryptic population stratification.
What is cryptic population stratification?
While it could be straightforward to ensure equal numbers of individuals with European versus African ancestry in the cases and controls, there will be subpopulations within these populations, which will be harder to match. Any SNP that shows a very great frequency variation between populations is at risk of being flagged up as being associated with a disease if the populations themselves show differing frequencies of the disease.
How else can linkage disequilibrium be generated?
Other ways in which linkage disequilibrium can arise involve physical linkage, where the marker is found at a chromosomal locus that is near the genetic difference actually causing the disease. This is the kind of linkage disequilibrium that GWAS is searching for. While linkage disequilibrium is not the same as physical linkage, variants that are linked in the sense of being close together on the chromosome are much more likely to be associated than are physically unlinked variants, because a chromosomal recombination event would be required to separate them, and this does not happen very often, especially if the SNP and the disease gene are very close to one another. New mutations can remain associated with physically linked variants for hundreds of generations.
So, if there is a strong association in a well matched sample between a SNP and the disease, the best guess is that there is a causative allele tightly linked physically to (and in linkage disequilibrium with) the SNP. The effect of the causative locus on the probability of getting the disease can be approximately estimated though the odds ratio associated with the SNP.
What is an odds ratio?
The odds ratio is simply the probability of having the disease given one genotype at a SNP (or other genetic variant) divided by the probability of having the disease given another genotype at the SNP. In a statistical sense, it is a measure of the effect size, rather than a significance value. So, as sample sizes go up, the odds ratios should become more accurate, and the evidence that odds ratios differ from one (with an odds ratio of one implying no genetic effect) should become more statistically significant. As very large numbers of cases and controls are now included in genome-wide association studies, more and more loci are found to show associations, and loci with low effect sizes (under 1.5) start to be detected with statistical confidence. Thus, for example, more than 30 loci have been identified as being associated with risk of Crohn's disease.
What is meant by the 'missing heritability' people seem to be talking about?
This is the mystery at the heart of results from genome-wide association studies. Each of the SNP loci showing a disease association has a frequency in the population and a genetic effect (measured by the odds ratio). From the frequency of the marker and the effect size it is possible to calculate the contribution that this locus would make to the total genetic determination (the heritability) of the disease. One can then sum the effects of all the loci discovered, to assess their combined genetic influence. But, almost always, this genetic influence is much less than the influence measured by the heritability. The 32 loci shown to affect Crohn's disease risk collectively explain only 20% of the heritability for the disease, for example. There must be some genetic explanation of the missing 80% of the heritability that is not being detected by the GWAS approach.
Where might the missing heritability be?
The GWAS methodology is designed to detect the effects of causative genetic loci where the rarer allele still has a reasonable frequency in the population (greater than 5%). If there are genetic loci influencing the trait where the rare allele has a frequency under 5%, or even under 1%, the GWAS technique is unlikely to be able to detect these loci. One idea about the cause of the missing heritability is that this is supplied by mutant alleles at very many loci, the majority of which are very rare. In a sense, we are back in the world of single-gene disorders, at least to the extent that the individual predisposing loci have rare variants, created by fairly recent mutations and on the way to elimination by selection. It should be said that another possibility is that there are many other loci with common causative alleles, but alleles with low odds ratios (that is, small effects), which will only be detected in even larger samples of cases and controls, and it is these that supply the missing heritability. There will also be an underestimation of the genetic effect of the known loci since they are represented by their surrogate linked SNPs, and the true effects of the causative alleles themselves could be greater.
So is this what is meant by genetic heterogeneity?
Yes, exactly. In general terms, genetic heterogeneity in disease causation means that the disease may be caused by different genes in different individuals. In the case discussed above, if there are very many loci that have rare alleles that are causing the disease, there will be very great differences between the genotypes of affected individuals, and it will be hard to detect the individual causative loci.
But if the variants causing the disease are rare, why are the diseases common?
As I say above, fitness-lowering mutations at a locus in mutation-selection balance should not be common, because selection is quantitatively stronger than mutation. However, disease mutations are commoner in loci such as the dystrophin locus, which is very large and has a correspondingly high mutation rate, which explains the comparatively high incidence of Duchenne muscular dystrophy. There is only one gene that can mutate to alleles that cause Duchenne muscular dystrophy, but it may be that, for common multifactorial disorders, there are very many loci that can mutate to alleles that contribute to producing the disease symptoms. So the total mutation rate for some conditions, such as schizophrenia, may be high because so many loci can mutate to predisposing alleles. In effect, it is a question of target size.
What are the achievements of GWAS so far?
There are cases of important causative variants being identified by GWAS. The GWAS approach is hypothesis-free, in that it looks at very many SNPs simultaneously rather than focusing on loci whose biology suggests that a causal relationship to the disease is likely. The result of this is that, since each SNP tested constitutes a separate hypothesis test, very significant associations are needed in order to rule out false positives. Thus, sample sizes have to be large in order to find variants with low odds ratios. However, in a study of age-related macular degeneration, a sample of only 96 cases and 50 controls identified an important causative variant in the complement factor H gene. Two of the three most significant associations came from SNPs in an intron of this locus and they were themselves significantly associated with a tyrosine-histidine substitution encoded in exon 9 of the gene, which was inferred to be the causative SNP. The finding of the causative SNP in such small samples was due to the intronic SNPs initially identified having high odds ratios - 7.4 in one case when homozygotes for a C base at the SNP were compared with other genotypes. The odds ratios were indeed so high that these intronic SNPs explained around half the total population risk. This case is unusual, in that a SNP with a massive effect on the odds ratio nevertheless showed a high population frequency for the disease-predisposing base. It could be that part of the cause is that the age of onset of the disease is one that would very rarely be attained by our ancestors, and the selection on the condition was probably minimal at the time when allelic frequencies were being determined.
Where can I find out more?
See reference list: [14].
Declarations
Authors’ Affiliations
(1)
School of Biology, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
References
1. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, NIDDK IBD Genetics Consortium, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, et al: Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008, 40: 955-962. 10.1038/ng.175.PubMed CentralView ArticlePubMedGoogle Scholar
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Copyright
© Brookfield; licensee BioMed Central Ltd. 2010
This article is published under license to BioMed Central Ltd.
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5,091,949,370,232,305,000 | language disorders and pragmatics
Receptive – Expressive Language Disorder
Does your child have trouble expressing himself with language? Or does he have trouble understanding language? These two language disorders can both appear in the same person, or a child may have only an expressive language disorder. (A language disorder is not the same as a speech disorder – children with language disorders can often produce speech sounds and intelligible speech, though they are often seen together in children.)
We begin developing language as soon as we are born. But sometimes children have difficulty understanding what people are saying to them. Perhaps a child is affected by a brain injury, perhaps other developmental problems, or by autism spectrum disorder, hearing loss, or learning difficulties. However, most often parents never find out the underlying reason their child does not understand what he hears or why he does not express himself as well as other children his age.
A child with a language disorder may have just a few of the following symptoms, or many of them. Symptoms can range from mild to severe.
Children with a receptive language disorder have trouble understanding language. They may have:
• A hard time understanding what other people have said
• A hard time understanding what gestures mean
• A hard time answering questions
• A hard time taking turns in a conversation
• Problems following directions that are spoken to them
• Problems organizing their thoughts
• Problems understanding the meanings of the words or concepts used by others
• Problems understanding meaning when words are imbedded into sentences
• Problems understanding complex sentences
Children with an expressive language disorder have problems using language to express their thoughts or needs. These children may:
• Have a hard time putting words together into sentences, or their sentences may be simple and short with the words in the wrong order
• Have difficulty finding the right words when talking, and often use placeholder words such as “um”
• Have a hard time asking questions
• Have a hard time learning songs and rhymes
• Have a vocabulary below the level of other children the same age
• Leave words out of sentences when talking
• Use certain phrases over and over, and repeat (echo) parts or all of questions
• Use tenses (past, present, future) improperly
How can I help my child with a language disorder?
A speech-language pathologist can work with your child to build his language skills. He’ll start with a thorough evaluation of your child’s communication skills. He may ask you to have your child’s hearing checked to rule out poor hearing as a root cause. Appropriate goals will be written with your input. Therapy will consist of activities designed to build on your child’s strengths in a fun, positive manner, and to target the needed areas.
What parents do at home is just as important, or more important, than what the therapist can accomplish in the therapy session. Working together is the key to success. Your child’s therapist will help you with activities to do at home to accomplish your child’s goals.
Pragmatic Language Disorder
Is your child having trouble navigating social situations? Does he hang back, or stand too close, or say too much, or the wrong things?
Pragmatic language involves the way we use language socially and practically to navigate our world. We all go through a complex process of figuring out what to say in various social, school, or work situations, and most of us still end up stumped or flustered once in a while. For some children, this is an area of life where they could use some serious help.
Pragmatic language involves three major communication skills:
• Using language for different purposes, such as greeting, informing, demanding, promising, and requesting
• Changing language according to the needs of a listener or situation, such as speaking differently in a classroom than on a playground
• Following rules for conversations and storytelling, such as taking turns in a conversation, introducing topics, staying on topic, using verbal and nonverbal signals, standing a certain distance from someone else during a conversation, and using facial expressions and eye contact
A lot of pragmatics comes down to being able to put yourself in the other person’s shoes, which is not easy for some children, and being able to notice what another person may be feeling.
Pragmatic skills include:
• Knowing it’s polite to answer when someone has asked you a question.
• Participating in a conversation by taking turns with the other speaker.
• Noticing and responding to the nonverbal aspects of language (body language, etc.).
• Introducing topics of conversation that the other person will share an interest in.
• Knowing how to initiate a conversation or respond to someone else’s initiation.
• Maintaining or appropriately changing a topic, or interrupting politely.
• Maintaining appropriate eye-contact during a conversation.
• Knowing how to talk and behave with a variety of people (formally with some, informally with others).
How can I help my child who needs help with pragmatics?
We work on how to use language effectively in every session. Depending on the child’s age and needs, we might start addressing pragmatic language use in individual sessions. Often, however, it becomes obvious that we need to involve peers. We facilitate home based programs that will help children with using language socially and pragmatically with peers, matching children with appropriate communication partners.
Monroe
Counseling Center
1105 Hudson Lane,
Monroe, LA 71201
318-322-6500
CenturyLink Counseling
100 CenturyLink Drive,
Monroe, LA 71203
318-362-1500
Pediatric Therapy
1300 Hudson Lane, Ste. 7,
Monroe, LA 71201
318-361-7180
Autism Center
1300 Hudson Lane, Ste. 9,
Monroe, LA 71201
(318) 600-6640
West Monroe
Autism Center
107 McMillan Road
West Monroe, LA 71291
(318) 600-6640
Ruston
Counseling Center
206 E. Reynolds Drive
Ste E1
Ruston, LA 71270
318-255-2922
AutismCenter
206 E. Reynolds Drive
Ste C3
Ruston, LA 71270
(318) 600-6640
Pediatric Center
206 E. Reynolds Drive
Ste C3
Ruston, LA 71270
318-224-9177
WINNSBORO
Autism Center
4279 Front Street
Winnsboro, LA 71295
318-605-2636
Olla
Autism Center
3036 Robert Street
Olla, LA 71465
(318) 600-6640 | {
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6,474,645,668,629,473,000 | Will Losing Weight Help Type 2 Diabetes
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Dr-A-Greene
Dr-A-Greene, Doctor
Category: Mental Health
Satisfied Customers: 190
Experience: Clinical and Forensic Psychologist
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What has a bigger inpact on Children envoriment or genics?
Customer Question
What has a bigger inpact on Children envoriment or genics?
Submitted: 1 year ago.
Category: Mental Health
Expert: Dr-A-Greene replied 1 year ago.
Dr-A-Greene :
It depends on what you're asking about specifically. Can you give me some more details?
Dr-A-Greene :
For example, in illnesses like Schizophrenia, genetics has a bigger impact. In things like personality disorders, it's environment.
Customer:
My son is 16 and I had him when I was 15. His biological father is a registered sex offender and has made many bad decision. My son has never met him yet I see so much of his father in him its scares me. I'm tried to raise him to be kind and a good person with a good heart but he tells me my standards are too high. He now lives with my brother who is a great responsiblie man who works and own a new home. My brother has no children yet so my son is very happy and so is my brother they seem to be doing well.
Dr-A-Greene :
Ah, okay. So you're worried about that component from his biological father seeping in. It's strange. There are definitely correlations when it comes to things like little mannerisms and emotional ways of responding that appear to have a genetic component. However, when it comes to criminality or being an offender, that does NOT seem to be genetically linked. I can say this with some confidence because I have worked with it and studied it for the first 10 years of my career. While some of his minor behaviors may remind you of his father, his major decision making in life should be borne out of environment. That's where he will learn right from wrong.
Customer:
My son Markus says he wants to become a cop and most parents would be happy about it but me it scares because I afraid hes just looking for the loop holes to break the law. I know that sounds terrible but Markus is so adorable it just seens to get away with walking the edge of I didn't do anything bad but I'm not going to try and do anything good either. His father was the same way till he got caught. Then he spent 9 years in prison for transportation of a minor across stste line with the intent to have sex. The girl was 15 he was 32.
Dr-A-Greene :
It's possible, but just to offer a little perspective: most cops I work with have a fascination with criminality. They often have interesting histories and I think it makes them better cops, not worse. Being able to think like the people they're trying to catch isn't a bad thing. That said, have you seen anything in his behavior that concerns you like truancy from school, fighting, manipulation of his friends?
Dr-A-Greene :
Anything to be worried about in his sexual behavior either?
Customer:
Well he's living with my brother 300 miles away because he turned 15 and started cutting himself, cutting classes, having sexual relations on school property durning school hours with a girl who parents both worked for the school district, cutting school and failed math and had to take summer school. the rest of his grades were barley D's it was a rough year. He was also inpacting his younger brothers badly they are 10 & 11 he stole porn and show it to them.
Dr-A-Greene :
Okay, everything gels except for one thing - the cutting himself. Cutting class, sexual promiscuity, and theft could be part of what you've been concerned about and seem to indicate that he is gravitating toward more of a criminal path in life. But the cutting doesn't mesh with that. That's a self-abuse behavior seen mostly in Borderline Personality Disorder (which he is too young to be diagnosed with yet). So, there's a disconnect here. As a psychologist I have to try to get all the evidence together. My hunch is that while the prior behaviors have a criminal component to them, they're not generally in line with typical acting out (defacing property, indescriminate violence) - they're more in line with attention getting behaviors that also just happen to be more antisocial in nature. For instance, I don't think its a coincidence that the firl's parents both worked for the school district or that he tried to corrupt his younger brothers....
Dr-A-Greene :
So, my best guess is that he is engaging in behaviors that will get everyone's attention and that the cutting on himself is an extension of that. Boys with patently criminal behavior aren't necessarily seeking attention, but are doing it only for their own gain. What are your thoughts about that?
Customer:
Could this all just be bad teenage years? My brother says he's doing better. The cutting himself I put a stop to right away I told him I'd put him in a mental hospital if he did it agasin and he stopped. I don't think he's stealing anymore cause my brother made it clear to him he will buy him what he want he just has to ask. I don't agree but it seems to be working. He's not cutting school anymore cause it to far for him to walk home or go to friends houses. His grades haven't improved much but he looks a lot happier mentally how ever he still studders when he talks to me. I'm not sure if it's out of fear? He's only been with my brother since school started this year and we go see him every month. I try to call once a week cause I don't want to be to over bearing. I've fought for this kid for over half my life and I love him sooo much and I sent him to live with my brother to give him another chance he seens to be doing well I'm just sooo scard for him with all that kids face these days.
Dr-A-Greene :
I hear that. There's a lot of temptation and bullying and god know what out there! But if he seems to be doing better, then maybe he truly is. If the cutting has stopped that's a great sign and it sound like maybe he was just going through a bit of a rebellion there. Just a question, has he ever been tested for any learning disorders by the school?
Customer:
Yes he was diagnosed ADD/ADHD in 3rd grade he also has learning disablities in 3 out of 5 areas.
Customer:
He is on concerta
Dr-A-Greene :
Okay, well that might explain some of the difficulty with the grades and the truancy from before. All in all, I think you are doing everything you can for him and are being quite selfless in the process, I might add! It must be soooo difficult to have him so far away. But sometimes a change in environment can do a lot and it sounds like its working. I wouldn't be too worried about the genetics. Either way, you're doing what you can in the environment and you love him. That's what counts.
Dr-A-Greene :
When I talk to my guys (my inmates), the biggest complaint is that they had bad relationships with parents - not that the parents were criminals or had some disease. What it all boils down to is, "did my mother love me?" - If the answer to that question is always "yes" - they often don't end up coming my way.
Customer:
Its been a year with him but all in all good parents have to make hard selfless decisions and as hard as it was it has saved me and all 3 of my boys. The others boys father and I divorced 3 years ago and all the boys were on a bad downward sprial now there doing much better but I love them all and fight the battles for them everyday as parents should. They know they are loved.
Dr-A-Greene :
Perfect. You're doing everything you can then. It will make a difference in the long run (and sounds like it is now too). I admire your ability to do that and I wholeheartedly think that its the right thing. Kudos to you. Are there any more questions that you have?
Customer:
No andThank you for all your help I'm just going to keep loving my boys as I always have.
Dr-A-Greene, Doctor
Category: Mental Health
Satisfied Customers: 190
Experience: Clinical and Forensic Psychologist
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-8,525,760,351,722,074,000 | Home / Personal Empowerment / Is it really a medical emergency? Here’s how to be sure
Is it really a medical emergency? Here’s how to be sure
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How do you know if the symptoms you are experiencing are serious or if you can just ride them out?
When you are experiencing symptoms say, for instance, chest pain, almost everyone with a phone will start to Google and will try to find out what is happening to them and if they should phone an ambulance. Many doctors have, however, told me that Google isn’t really a reliable source of medical information and will cause you to stress even more.
Symptoms you should never ignore
Meningitischecking your head resize
You should get medical attention if you are experiencing the following symptoms: fever, severe headaches, neck pain and stiffness, nausea and sluggishness. The last symptom of meningitis is a rash, but it is best not to wait until you get a rash before going to the doctor.
You don’t need to panic if you are only experiencing one of the following symptoms: fever, severe headaches, neck pain and stiffness, nausea and sluggishness. But always trust your instincts; if you feel something is wrong go to the doctor, particularly if you have small children or teenagers because meningitis is more common with them.
Appendicitis
Get medical attention if you have pain in the lower right side of the abdomen, between the navel and the right hip. The pain is usually accompanied by diarrhoea, blood in your stools and vomiting. You should go to the hospital before the pain turns very sharp, which could happen in just a few hours.
You don’t need to panic if you are only experiencing stomach pain but without any of the other symptoms; you might just be suffering from irritable bowel syndrome. But if the cramping doesn’t go away in a few days you should cosult your GP.
Broken bonefalling-at-caution-sign-hazard
You should get medical attention if you see swelling and you are struggling to move that part of your body, or if you heard a snap or grinding noise at the time of the injury.
Most of the time, ankle or wrist injuries are sprains; if you didn’t hear a sound at the time of the injury it’s most likely to be a sprain. Anti-inflammatories should help you see an improvement in just a few days. You will also notice some swelling but you will still have some movement.
Heart attackheart-attack
You should get medical attention when you have pain that feels tight and heavy on your chest with the following symptoms: shortness of breath, dizziness, sweating and feeling cold and clammy. The pain in your chest might start to spread down your left arm or both your arms. Women might not even experience chest pain but they will have other symptoms like nausea and vomiting, upper back and jaw pain, and extreme fatigue; don’t ignore any of these symptoms and get to a hospital as soon as possible.
If you have chest pain but it feels like it is getting worse after eating or when lying down it’s possible that it might just be very bad heartburn so there is no need to stress. But as soon as you feel any of the other symptoms above go to a hospital.
No one likes to go to hospital but if your body is telling you that something is not right you should listen to it and go to the hospital.
Words: Natassha Burrell
Trusted Tenant - #TenantPower
hometimes@pixelbaste.com
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Radiology. 2020 Mar 24:192013. doi: 10.1148/radiol.2020192013. [Epub ahead of print]
Diffusion-weighted Imaging Voxelwise-matched Analyses of Lung Cancer at 3.0-T PET/MRI: Reverse Phase Encoding Approach for Echo-planar Imaging Distortion Correction.
Author information
1
From the Dept of Biophysics and Nuclear Medicine-Molecular Imaging, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, CHU Bicêtre, 94270, Le Kremlin-Bicêtre, France (F.L.B., E.D.); Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France (F.L.B., O.M., A.S., S.B., S.M., F.P., D. Montani, D. Mitiliian, E.F., V.L., E.D.), Université Paris-Saclay, CEA, CNRS, Inserm, BioMaps, Orsay, 91401, France (F.L.B., C.C., V.L., E.D.); Applications and Workflow, GE Healthcare, Buc, France (B.F.); Laboratoire de Mathématiques d'Orsay, Université Paris-Saclay CNRS, 91405 Orsay, France (S.F.); Dept of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Hôpital Marie Lannelongue, 92350 Le Plessis Robinson, France (O.M., S.M., D. Mitilian, E.F.); Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, CHU Bicêtre, 94270, Le Kremlin-Bicêtre, France (A.S., X.M., S.B., F.P., D. Montani); Inserm UMR_S999 Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, 92350 Le Plessis Robinson, France (A.S., D. Montani); Service Hospitalier Frédéric Joliot (SHFJ), CEA/Université Paris-Saclay, Orsay, France (É.B., A.C., F.B., V.L.); Dept of Pathology, Hôpital Marie Lannelongue, 92350 Le Plessis Robinson, France (M.R.G.B.); NeuroSpin, CEA Saclay, Université Paris-Saclay, Gif-sur-Yvette, France and Parietal, INRIA, Palaiseau, 91120, France (H.C.).
Abstract
Background PET/MRI has drawn increasing interest in thoracic oncology due to the simultaneous acquisition of PET and MRI data. Geometric distortions related to diffusion-weighted imaging (DWI) limit the evaluation of voxelwise multimodal analyses. Purpose To assess the effectiveness of reverse phase encoding in correcting DWI geometric distortion for multimodal PET/MRI voxelwise lung tumor analyses. Materials and Methods In this prospective study, reverse phase encoding method was implemented with 3.0-T PET/MRI to correct geometric distortions related to DWI. The method was validated in dedicated phantom and then applied to 12 consecutive patients (mean age, 66 years ± 13 [standard deviation]; 10 men) suspected of having lung cancer who underwent fluorodeoxyglucose PET/MRI between October 2018 and April 2019. The effects on DWI-related image matching and apparent diffusion coefficient (ADC) regional map computation were assessed. Consequences on multimodal PET/MRI voxelwise lung tumor analyses were evaluated. Spearman correlation coefficients (rs) between the standardized uptake value (SUV) and ADC data corrected for distortion were computed from optimal realigned DWI PET data, along with bootstrap confidence intervals. Results Phantom results showed that in highly distorted areas, correcting the distortion significantly reduced the mean error against the ground truth (-25% ± 10.6 to -18.4% ± 12.6; P < .001) and the number of voxels with more than 20% error (from 85.3% to 31.4%). In the 12 patients, the coregistration of multimodal PET/MRI tumor data was improved by using the reverse phase encoding method (0.4%-44%). In all tumors, voxelwise correlations (rs) between ADC and SUV revealed null or weak monotonic relationships (mean rs of 0.016 ± 0.24 with none above 0.5). Conclusion Reverse phase encoding is a simple-to-implement method for improved diffusion-weighted multimodal PET/MRI voxelwise-matched analyses in lung cancer.
PMID:
32208099
DOI:
10.1148/radiol.2020192013
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10 Injury Treatment Priorities at the Emergency Room
Health | ER
Patients with life-threatening injuries receive first priority by the emergency staff.
Photodisc/Thinkstock
In 2007, roughly 117 million Americans went to the emergency room [source: Niska, Bhuija and Xu]. What's sending them there? The top 10 reasons why we visit the ER may surprise you. Accidents and critical injuries aren't the main drivers. Instead we seek help for everything from abdominal and chest pain to fever, cough and sore throat [source: McCaig and Burt].
But the way emergency departments work is not first come, first serve. While your back pain may feel like a critical injury to you, the emergency team may have a different set of priorities. How quickly you are seen depends on how severe your condition is.
Patient priority is determined by a triage staff once the patient arrives at the ER. Symptoms are assessed and the triage staff takes a medical history. Those with the most critical injuries or symptoms, such as patients with multiple traumas or those unconscious or not breathing, are first priority. These patients are seen immediately.
Patients with urgent symptoms that could deteriorate quickly into an emergency are typically seen in 15 minutes to one hour, while patients with semi-urgent symptoms are generally seen by a physician in one to two hours. Non-urgent patients are given the lowest priority, and could wait as long as two hours or more in a crowded ER [source: McCaig and Burt].
"High-acuity patients are taken straight to the ER," explains Dr. Tarlan Hedayati, a physician in the department of emergency medicine at John H. Stroger Hospital of Cook County in Chicago. "Others will wait in the waiting room where they will be reassessed during that time. It's a very dynamic process, and patients might increase or decrease in priority while they wait."
Additionally, the entire patient, not just the immediate complaint, is taken into account during the triage process. Other conditions, such as cancer or HIV, are considered in the assessment, as well as how long the patient's symptoms have been going on. For example, explains Hedayati, a patient who has experienced stomach pain for six months may be less of a priority than a patient who has complained of severe stomach pain for a few days.
So what types of symptoms or injuries are at the top of the emergency department's priorities? Let's look at the reasons why people visit the emergency room and prioritize them through the eyes of the triage staff, starting with the least urgent and working our way to the most critical. | {
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3,970,143,088,170,446,000 | tocopherol
(redirected from alpha-tocopherol)
Also found in: Dictionary, Medical, Encyclopedia, Wikipedia.
• noun
Synonyms for tocopherol
a fat-soluble vitamin that is essential for normal reproduction
References in periodicals archive ?
Serum alpha-tocopherol levels of 1,168 subjects between the ages of 65 to 79 who suffered hip fractures during up to 11 years of follow-up were compared to those of 1,434 control subjects from the same cohort.
They randomly assigned participants into four treatment groups: 2000 IU/d of alpha-tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or a placebo (n = 152).
Cook-Mills had done previous allergy research in mice showing alpha-tocopherol decreased lung inflammation, protecting healthy lung function and gamma-tocopherol increased lung inflammation and airway hyperresponsiveness, a characteristic of asthma.
Miia Kivipelto, director of the research from University of Eastern Finland, vitamin E exists in eight different natural forms (fat-soluble compounds) and the entire vitamin E family plays a role in protecting against memory disorders, not only alpha-tocopherol.
Alpha-Tocopherol in human spermatozoa and seminal plasma: relationships with motility, antioxidant enzymes and leukocytes.
Unlike the regular vitamin E alpha-tocopherol, tocotrienol exists scarcely in nature and is especially low in Western diet.
There were small but significant increases in the proportion of alpha-tocopherol in beans from the same genetic line grown in warmer, full-season Eastern Shore locations compared to beans that matured under slightly cooler conditions.
5-fold increase in relative alpha-tocopherol content, compared to the other years during which rainfall was adequate.
The scientists attempted to form and characterize cyclodextrin inclusion complexes with the natural antioxidants alpha-tocopherol and quercetin.
The authors do not recommend vitamin E supplements to increase levels, since the approximately 15mg to 30mg per day of dietary alpha-tocopherol (a component of vitamin E) needed can easily be reached through diet, from sources such as almonds, tomato sauce and sunflower seeds, among others.
Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group.
Alpha-tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-[alpha].
The alpha-tocopherol source used was Roche ROVIMIX E50, an alpha-tocopheryl acetate containing 500 mg [alpha]-tocopherol [g.
Another form of vitamin E, known as alpha-tocopherol, found naturally in olive oil, almonds, and sunflower seeds, appeared to be harmless.
However, just a few weeks later, results from the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Trial showed that men with high blood levels of alpha-tocopherol (a form of vitamin E) had a lower risk of prostate cancer, reports Harvard Men's Health Watch. | {
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5,304,327,064,895,536,000 | What Does Anatomical Variation Mean
The purpose of the NGSP is to standardize Hemoglobin A1c test results to those of the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) which established the direct relationships between HbA1c levels and outcome risks in patients with diabetes.
Full Answer. Any behavior that helps ensure the survival of an organism specifically, and its species generally, can be considered a behavioral adaptation, so examples of behavioral adaptation are numerous. Two common, opposite behavioral adaptations are diurnality and nocturnality, which refer to being active during the day and during the night,
a. Date ranges are from Du et al. (2018) except for Australopithecus prometheus: for Sterkfontein Member 2 and StW 573, we use Granger et al., 2015, and for Member 4 Pickering and Kramers (2010) minimum age of 2.01.We note, however, that the stratigraphic association of the flowstones used to date the upper limit of Member 4 is more complex than proposed in Pickering and Kramers (2010) and.
Measurement of the Normal Optic Chiasm on Coronal MR Images Andrew L. Wagner, F. Reed Murtagh, Ken S. Hazlett, and John A. Arrington PURPOSE: To develop an objective method for measuring the optic chiasm and to document its normal range in size.
Notes on Genital Dimensions (2004) By Anne A. Lawrence, M.D., Ph.D. Men commonly boast about and exaggerate their genital dimensions. Some male-to-female transsexuals engage in this kind of behavior after undergoing SRS: "My surgeon gave me six inches of vaginal depth."
Mar 08, 2014 · Now including HGTV, Food Network, TLC, Investigation Discovery, and much more.
When the out-of-Africa migrations of anatomically modern humans are taken into consideration, a window is opened that points towards the emergence and nature of such variations and their attendant diseases.
We report on 3D statistical modeling and analysis performed in 80 clinical CT data of adult European Whites with unaffected calvarial bones to establish an anatomical background for the development.
Full Answer. Any behavior that helps ensure the survival of an organism specifically, and its species generally, can be considered a behavioral adaptation, so examples of behavioral adaptation are numerous. Two common, opposite behavioral adaptations are diurnality and nocturnality, which refer to being active during the day and during the night,
Evolution is a change in the gene pool of a population over time. A gene is a hereditary unit that can be passed on unaltered for many generations. The gene pool is the set of all genes in a species or population. The English moth, Biston betularia, is a frequently cited example of observed evolution.
What does it really mean for the brain to experience pleasure. rules about pleasure that have persisted throughout history in any number of forms and variations: Pleasure should be sought in.
This approach requires knowledge of placental structure and its variations in different species. This view is probably too simplistic because it does not take into consideration the anatomical fact.
120 µm/m root mean square error (RMSE) compared to intact bone in Gruen zone 1 and >60 µm/m RMSE in Gruen zones 2, 6, and 7. Geometrical changes (ribs, grooves, cross sections, stem length, anatomic.
What Are Empirical Studies Ecologist Jobs In Japan Hepatitis E Epidemiology And Natural History The primary objective was to describe the early “natural history” of pulmonary hypertension (PH. 2012;129:e682–e689. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. The global burden of hepatitis B virus (HBV) infection is profound. Around 250 million people are
The hominin skeletons were found with the bones either in partial articulation or in close anatomical association. early human origins of any site on the planet. What does Australopithecus sediba.
And – okay, so you’re seeing these small physiological changes or small anatomical changes. And PALCA: What does that mean, polymorphic? Dr. SCHAEFER: That there is a lot of variation in these.
Humans. Studies on human brain size, largely based on participants of European ancestry, tend to find an average adult brain volume of 1260 cubic centimeters (cm 3) for men and 1130 cm 3 for women. There is, however, substantial variation between individuals; one study of 46 adults, aged 22–49 years and of mainly European descent, found an average brain volume of 1273.6 cm 3 for men, with a.
Biological diversity – biodiversity – is reflected in the vast number of species of organisms, in the variation of individual characteristics within a single species and in the variation of cell types within a single multicellular organism.
Estimates suggest that almost two out of every 100 people in the world have a genetic, hormonal or anatomical sex variation from the. relatively small segment of the world’s population does not.
This lesson is designed to be accomplished in two 90-minute blocks with the groups working simultaneously at the seven stations for about 20 to 25 minutes each.
What, pray tell, does that mean, exactly? Well, according to the press materials. The line is apparently the result of "years of research" into the "anatomical and acoustic differences between men.
There is also a high rate of second cancers observed at the same anatomical site (acknowledging that it is. given their relative incidence. It does mean that the majority of data included in our.
He delighted in etymology, synonyms and antonyms, slang, swear words, palindromes, anatomical terms. “What the hell does that mean?” I said while making coffee. Oliver chuckled, then went on to.
But what is gender identity exactly, and how does it differ from the sex a person is. But this term doesn’t fully capture the complex biological, anatomical, and chromosomal variations that can.
But just because your vagina burns after sex, it doesn’t necessarily mean doomsday. In fact. it can definitely cause some pain issues. "Due to anatomic variations between partners, the friction.
Phylogenetic trees are diagrams of evolutionary relationships among organisms. Scientists can estimate these relationships by studying the organisms’ DNA sequences. As the organisms evolve and diverge, their DNA sequences accumulate mutations. Scientists compare these mutations using sequence.
presentation rates 10 Hz (Foster et al., 1985; Chance et al., 1998), while neuronal firing rates in IT decrease for slower rates 4Hz(Keysersetal.,2001).Second,informationaccumulation
Misconceptions about evolutionary theory and processes. MISCONCEPTION: Evolution is a theory about the origin of life. CORRECTION: Evolutionary theory does encompass ideas and evidence regarding life’s origins (e.g., whether or not it happened near a deep-sea vent, which organic molecules came first, etc.), but this is not the central focus of evolutionary theory.
What Social Science Entails A flood of online information has given the public unprecedented access to elite individuals in politics, media, academia, science, business, and an array of other fields. Thanks to tools like social. It means that a person has the ability to describe, explain, and predict natural phenomena. Scientific literacy entails being able to read with understanding
x In a survey of all female U.S. radiation oncology residents in 2017-2018 with 125 respondents (74% response rate), half agreed that gender-specific bias existed in their programs and a quarter reported experiencing sexual harassment. Half reported that lack of mentorship affected career ambitions, and 90% expressed interest in joining a professional group for women in radiation oncology.
What does the name change mean for the museum, in practical terms. Tschopp’s study discovered at least seven different anatomical characteristics separating Brontosaurus from Apatosaurus. The.
A new study shows it also applies to the health of your heart—not your broken, pining for Ben & Jerry’s, heart, but your real anatomical heart. What the heck does that mean, you ask? Well, as the.
Jan 16, 2019 · Human evolution. Human evolution is the lengthy process of change by which people originated from apelike ancestors. Scientific evidence shows that the physical and behavioral traits shared by all people originated from apelike ancestors and evolved over a.
Magnetic resonance angiography (MRA) can capture the variation. as it typically does not require any contrast agent and offers a good blood-to-background contrast of arteries. The TOF MRA sequence.
It can be unsettling to get unusual health or anatomical. ‘What does it mean?’ ” says Jha, adding that symptoms are often better than test results as indicators of illness. “Literally, it means.
Best Zoology Colleges In Nc Note: This Draft Panel (as on ) is based on the data received from the Colleges. If any clarification or correction is needed, you are requested to meet the Controller of Examinations on any working day with the relevant certificates. Size : Medium-sized. Unique Facilities : marine laboratory, museum of art, forest, teaching and research
Only inferences on anatomical organization from resting state data paradigms. The interhemispheric functional connectivity variations depending on the visual motion percept were also estimated with.
Does Darwin Airport Have A Curfew Social Science Gk Questions With Answers CBSE class 10 students will write their Social Science exam tomorrow. Students can know here the tips to write perfect answers in Social Science paper to help in scoring maximum marks. Gad Saad On Jordan Peterson Utvalda bloggar, tidningar, videokanaler med skarp och intressant vinkel, både svenska och internationella.
How Does Epidemiology Help Public Health "It does not. by a national health survey improved awareness and management of these conditions. The persistent limited awareness of diabetes and hypertension remains a major public health concern, Using Epidemiology in Public Health Practice. Epidemiology is a key science that underpins public health. It is most useful when the scientific evidence is presented in
30. How does natural selection result in changes in gene frequencies in a population? Natural Selection – You should be able to summarize the main points of evolution by natural selection. 1. The members of a population have variation which can be passed down to their offspring (Pigeon Breeders) 2.
Anatomical study of the digastric muscle: variations in the anterior belly/Estudio anatomico del musculo digastrico: variacion en el vientre anterior Tim Hannagan, a Chicago-based trader and analyst with Alaron Trading, cautions investors that pork bellies are thinly traded and fluctuate a great deal in price on a weekly and daily basis.
Complementarily, the measure of hierarchy is a variation on the ignition-based hierarchical measures. we analysed resting state neuroimaging MEG data which has the right timescale and thus does not.
In all anatomical compartments, both host and environment influence. sequencing resulted in a total of 9,441,738 microbial reads (per sample median: 14,010; per sample mean: 13,664) partitioned.
May 24, 2019 · Mean clustering coefficient (C). of muscle reversions in primate phylogeny and their implications for the understanding of the ontogeny, evolution, and anatomical variations of.
A very special example of anatomical variation During her lifetime. And while acknowledging that the unusual case of Rose Marie Bentley "does appear to be the exception, rather than the rule", | {
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-6,777,410,768,467,133,000 | Skip to content Skip to sidebar Skip to footer
Substitute For Squats
Dear Nick,
I would appreciate very much if you could answer these two honest questions about training (a substitute to squatting and dips/chins). It will not come as a surprise to you that the so called ‘expert’ personal trainers I asked could not answer them.
Here goes:
1) If one has no means to do free weight barbell squats (i.e. no rack available, gym management bars Zercher squats as unsafe (!?!?), current working weight too heavy to simply clean off the ground and press over head onto traps, etc) how good a substitute are deadlifts, if they are substitute to squats at all?
2) If one can dip body-weight for more reps to failure than one can chin/pull-up body-weight to failure, is this a sign of a muscular un-balance?
I thank you in advance for your time while reading this and look forward to hearing from you.
As always, wishing you all the best.
Misha
1) Deadlifts would be an acceptable substitute to regular barbell squatting, but in your situation for muscle building purposes a better alternative by far would be to perform barbell hack squats. Although we are all used to modern hack squat machines, the original exercise simply consisted of holding a barbell behind your back and squatting down low with it. If you are very flexible it will be necessary to use weight plates that are smaller than the regular 45lbs. This movement takes a bit of practice, isn’t suited to higher reps (15 plus) as biomechanics tend to break down, and benefits from the use of lifting straps. There are many substitutes to regular squats – don’t forget dumbell squats can also be very effective for bodybuilding the legs, as are weighted step ups.
2) No – it is a sign that you are normal! The only people I have encountered who can pull up more than they can dip are world class climbers. The rest of us are always better at dipping than chinning, and the normal ratio of dips to chins is about 2.75:1.
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-3,398,461,305,589,288,000 | The Knowledge Of Hypothetical Low Carb News
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Stasis Dermatitis And Ulcers
What Is Stasis Dermatitis?
Highlights
1. Stasis dermatitis is a skin condition that develops in people with poor circulation. It typically occurs in the lower legs. In serious cases, stasis dermatitis can progress into ulcers.
2. People over the age of 50 are most at risk for developing stasis dermatitis, especially if they have heart disease, are very overweight, or frequently sit for long periods of time.
3. Preventing swelling in your lower legs, or peripheral edema, is the best way to avoid getting stasis dermatitis.
Stasis dermatitis is skin inflammation that develops in people with poor circulation. It most often occurs in the lower legs because that’s where blood typically collects.
When blood collects or pools in the veins of your lower legs, the pressure on the veins increases. The increased pressure damages your capillaries, which are very small blood vessels. This allows proteins to leak into your tissues. This leakage leads to a buildup of blood cells, fluid, and proteins, which causes your legs to swell. This swelling is called peripheral edema.
People with stasis dermatitis usually experience swollen legs and feet, open sores, or itchy and reddish skin. A protein called fibrinogen may be responsible for the changes you see in your skin. When fibrinogen leaks into your tissues, your body converts it to the active form of the protein, which is called fibrin. As it leaks out, the fibrin surrounds your capillaries, forming what are known as fibrin cuffs. According to the Cleveland Clinic, these fibrin cuffs may prevent oxygen from entering your tissues. When your cells don’t receive enough oxygen, they can become damaged and die.
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Risk Factors
What Are the Risk Factors for Stasis Dermatitis?
Stasis dermatitis affects people with poor circulation. It’s common among adults over the age of 50. Women are more likely to get it than men.
A number of diseases and conditions can increase your risk for developing stasis dermatitis, including:
• high blood pressure
• venous insufficiency, which occurs when your veins have difficulty sending blood from your legs to your heart
• varicose veins, which are swollen and enlarged veins that are visible under your skin
• congestive heart failure, which occurs when your heart doesn’t pump blood efficiently
• kidney failure, which occurs when your kidneys can’t remove toxins from your blood
• obesity
• injury to your lower legs
• numerous pregnancies
• a deep vein thrombosis in your leg, which is a blood clot in your leg vein
Your lifestyle can also affect your risk. You may be at a higher risk of getting stasis dermatitis if you’re very overweight, don’t get enough exercise, or if you sit or stand without moving for long periods of time.
Causes
Common Causes of Stasis Dermatitis
Poor circulation causes stasis dermatitis. Typically, poor circulation is the result of a chronic, or long-term, condition called venous insufficiency. Venous insufficiency occurs when your veins have trouble sending blood to your heart. There are one-way valves inside your leg veins that keep your blood flowing in the right direction, which is toward your heart. In people with venous insufficiency, these valves become weak. This allows blood to flow back toward the feet and pool in your legs instead of continuing to flow toward your heart. This pooling of blood is what causes stasis dermatitis.
Varicose veins and congestive heart failure are also known causes of leg swelling and stasis dermatitis.
Most of the conditions that cause stasis dermatitis usually develop in people as they get older. However, there are also several causes that are unrelated to age, including:
• surgery, such as using a leg vein for bypass surgery
• deep vein thrombosis in your leg
• traumatic injury to your lower legs
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Symptoms
Symptoms of Stasis Dermatitis
The symptoms of stasis dermatitis include:
• skin discoloration
• itching
• scaling
• ulcers
You may also experience symptoms of venous insufficiency, including:
• leg swelling
• calf pain
• calf tenderness
• a dull ache or heaviness in your legs that gets worse when you stand
In the early stages of stasis dermatitis, the skin on your legs may look thin. Your skin may also itch, but try not to scratch it. Scratching can cause the skin to crack and fluid to seep out.
Over time, these changes can become permanent. Your skin may eventually thicken, harden, or turn dark brown. This is called lipodermatosclerosis. It may also look lumpy. In the final stages of stasis dermatitis, your skin breaks down and an ulcer, or sore, forms. Ulcers from stasis dermatitis usually form on the inside of your ankle.
When to See Your Doctor
When to See Your Doctor
You should see your doctor if you notice leg swelling or any symptoms of stasis dermatitis, especially if the symptoms include:
• pain
• redness
• open wounds or ulcers
• pus-like drainage
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Diagnosis
How Is Stasis Dermatitis Diagnosed?
To diagnose stasis dermatitis, your doctor will closely examine the skin on your legs. Your doctor may also order a venous Doppler ultrasound. This is a noninvasive test that uses sound waves to check the blood flow in your legs.
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Treatments
How Is Stasis Dermatitis Treated?
There are several things you can do at home to treat stasis dermatitis. You should:
• avoid standing and sitting for long periods of time
• prop up your feet when sitting
• wear compression stockings
• wear loose-fitting clothing to avoid irritating your skin
Ask your doctor about the types of skin creams and ointments you can use. You should avoid using the following products:
• lanolin
• calamine and other lotions that dry your skin
• topical antibiotic ointments such a neomycin
• benzocaine and other numbing medications
Your doctor might tell you to put wet bandages on your skin and might prescribe topical steroid creams and ointments. Your doctor may also prescribe antibiotics if your skin becomes infected. Surgery may be recommended to correct varicose veins if they become painful.
Treating conditions that cause venous insufficiency, such as high blood pressure and congestive heart failure, can also help control your stasis dermatitis.
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Complications
What Are the Possible Long-Term Complications of Untreated Symptoms?
If it’s left untreated, stasis dermatitis can result in:
• chronic leg ulcers
• osteomyelitis, which is a bone infection
• a bacterial skin infection, such as abscesses or cellulitis
• permanent scarring
Prevention
How Can Stasis Dermatitis Be Prevented?
Stasis dermatitis is usually the result of a chronic illness, such as congestive heart failure, so it’s difficult to prevent if you’re already ill. However, you can reduce your risk by preventing the swelling in your legs, or peripheral edema, that causes it. You can also lower your risk by exercising. Exercise is a great way to improve your circulation and reduce your body fat. Limiting the amount of sodium you consume can also help.
Article resources
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7,482,218,281,884,476,000 | TY - JOUR T1 - Rational Combination of Immunotherapies with Clinical Efficacy in Mice with Advanced Cancer JF - Cancer Immunology Research JO - Cancer Immunol Res SP - 1279 LP - 1288 DO - 10.1158/2326-6066.CIR-15-0103-T VL - 3 IS - 11 AU - Bransi, Ali AU - Salgado, Oscar Camilo AU - Beffinger, Michal AU - Milo, Karim AU - Silina, Karina AU - Yagita, Hideo AU - Becher, Burkhard AU - Knuth, Alexander AU - van den Broek, Maries Y1 - 2015/11/01 UR - http://cancerimmunolres.aacrjournals.org/content/3/11/1279.abstract N2 - In the context of cancer, naïve T cells are insufficiently primed and become progressively dysfunctional. Boosting antitumor responses by blocking PD-1 or CTLA-4 results in durable clinical responses only in a limited proportion of cancer patients, suggesting that other pathways must be targeted to improve clinical efficacy. Our preclinical study in TRAMP mice comparing 14 different immune interventions identified anti-CD40 + IL2/anti-IL2 complexes + IL12Fc as a uniquely efficacious treatment that prevents tolerance induction, promotes priming of sustained, protective tumor-specific CD8+ T cells, and cures late-stage cancer when given together with adoptively transferred tumor-specific T cells. We propose that improving signals 2 (costimulation) and 3 (cytokines) together with fresh tumor-specific, rather than boosting of dysfunctional preexisting memory, T cells represents a potent therapy for advanced cancer. Cancer Immunol Res; 3(11); 1279–88. ©2015 AACR. ER - | {
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3,176,381,541,243,761,700 | Hier wird die unterschiedliche Magnetisierbarkeit der Gewebe ausgenutzt, um Bilder der Körperorgane zu erzeugen. Unter Anwendung eines starken Magnetfeldes kann man die Strukturen des Herzens und der herznahen Gefäße darstellen und beurteilen. Die Herzuntersuchung wird mit EKG-Kontrolle gemacht, hier ist zeitweise das Anhalten des Atems notwendig. Die sogenannte Stress-MRT Untersuchung wird mit einem Stress-Medikament (Adenosin) und Kontrastmittel (Gadolinium) durchgeführt, um mögliche Durchblutungsstörungen des Herzens zu demaskieren.
Bei manchen Krankheitsbildern (zum Beispiel Herzmuskelentzündung) kann man mithilfe der MRT Ort und Ausdehnung der Erkrankung genau definieren.
Auch die Narben nach einer durchgemachten entzündlichen Erkrankung oder nach einem Myokardinfarkt werden dank dieser Methode dargestellt. | {
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4,783,589,862,926,049,000 | Wheel of Health
In today’s fast-paced and increasingly complex world, medical science and the evolution of unique models for health care are bringing us closer to truly personalized medicine. Given these evolving trends, the need for a comprehensive and dynamically responsive plan for your health is even more important. For this reason we want to help you create personalized health plans that are as responsive to your current health needs as they are adaptable to your future health.
Wheel of Health
Colors around the Wheel of Health denote important areas of focus.
Yellow:
You are the central focus of the Wheel of Health. Mindful Awareness of physical, mental, social, and spiritual well-being is the key to start the process of positive change.
Green:
Self-Care resonates deeply in all aspects of your health and well-being, and is reflected in lifestyle, priorities, motivation, and habits. Recognizing the impact of lifestyle on your basic health, and how it supports basic functions in your life, allows you to rebuild a healthier life from the ground up.
Blue:
Professional Care includes therapies that are aimed at staying healthy (Prevention) as well as treating conditions that arise (Intervention). Integrative Medicine combines evidence-based therapies from both conventional (Western or Allopathic medicine) and complementary therapies. Providers include physicians, nurses, nutritionists, and other conventional health care workers, as well as integrative health coaches, acupuncturists, massage therapists, psychologists, mind-body therapists, and a wide range of other complementary health care providers.
Self-Care
Mind-Body Connection: Taking advantage of complex connections between state of mind and basic physiologic functions in the body, many mind-body skills can have a profound impact on your health. Breathing techniques, meditation, progressive muscle relaxation, guided imagery, and other therapies are used to activate the body’s automatic healing response and reduce the harmful effects of stress.
Movement, Exercise, and Rest: Exercise supports your health in maintaining weight, blood pressure, reducing lipids, releasing stress, and improving mood and focus. Developing a sustainable, appealing plan that meets your needs and keeps you strong, flexible, balanced, and happy is ideal. You must also balance physical activity with rest, healthy sleep, and restorative relaxation.
Nutrition: Attending to what you eat can boost your body’s natural healing potential. An integrative nutrition approach includes developing healthy eating habits, eating foods that support your health and fit your lifestyle, selecting dietary supplements that provide support for various issues in your health, and regulating substances you ingest that may impact health such as caffeine, alcohol, nicotine, etc.
Spirituality: Developing a deep understanding of the purpose and meaning in your life supports all aspects of physical and emotional health. Religion, prayer, and spiritual connections in traditional healing systems complement conventional medicine and offer positive effects on health and well-being.
Personal and Professional Development: An ongoing assessment of where you are with personal, career or life goals-- especially important at times of transition, milestones, and tipping points in life—can reinforce healthy behavior and lifestyle choices. Taking a deeper look at work-life balance, financial goals, and personal growth supports optimal well-being.
Physical Environment: Evolving science suggests that your surroundings can influence your health in many ways. It is important to give some thought to how your environment can support your health: creating a nurturing space that facilitates relaxation, or a special place to build your mind-body practices; arranging workspaces and selecting furniture that supports your body; exploring options for dealing with concerns you may have about toxic exposure, safety, noise, clutter and other aspects of your environment.
Relationships and Communication: Building a supportive community and maintaining healthy connections with your family, co-workers, and friends is important to your life and your health. It is vital to identify the ways in which you need support, and to communicate them effectively to those around you.
Copyright © 2010 by Duke University on behalf of Duke Integrative Medicine
All rights reserved
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1,951,696,072,075,883,300 | Skip to Content
Publications Search - Abstract View
Title: Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.
Authors: Koster R, Mitra N, D'Andrea K, Vardhanabhuti S, Chung CC, Wang Z, Loren Erickson R, Vaughn DJ, Litchfield K, Rahman N, Greene MH, McGlynn KA, Turnbull C, Chanock SJ, Nathanson KL, Kanetsky PA
Journal: Hum Mol Genet
Date: 2014 Nov 15
Branches: CGB, CGR, HREB, LTG, OD
PubMed ID: 24943593
PMC ID: PMC4204765
Abstract: Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT. | {
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-6,202,068,871,920,890,000 | facebook twitter RSS
HOT TOPICS: Drug and Alcohol Treatment Heroin
Addiction Brain Scans, Unscrambled
We're used to media splashes about so-called "holes" in the brain. But what neuroimaging really tells us about the effects of drug use is much subtler—and much more helpful.
• Fried Eggs
Even if no one took it too seriously, this was once the extent of our conceptualization of the brain on drugs. We've come a long way since; the advent and exponential development of neuroimaging techniques allows us to visualize the mind’s hardware—and how it goes awry in addiction—in increasing detail and nuance. But the media bombardment of brightly-colored brain images can be overwhelming—and important points get lost. These slides are meant as a primer on some of the biggest stories to have emerged in addiction neuroimaging, and the insights they give. Of course, these examples are only a thin sliver of the available science—and scientists are still grappling with addiction's overwhelming complexity. Without dismissing other relevant brain systems or equally important socio-cultural and environmental influences, our focus here is the striatum: a set of structures heavily involved in reward, motivation, habit formation—and the brain's dopamine system.
Photo via
• Acute Effects (1)
One of the earliest addiction imaging experiments was also one of the gutsiest: in 1989 researchers set out to find what cocaine actually did in the brain, where it went, and what that meant. They tagged cocaine with a radioactive element, injected it into healthy volunteers, and used PET (positron emission tomography) to measure the location and time-course of radioactivity emitted. The result? Coke went straight to the striatum: the home of reward signaling and the formation of consequent behaviors. Here we see a horizontal brain slice over time (in minutes). The “hotter” colors represent more cocaine (the striatum is the two sickle-shaped hot-spots near the middle). The study also investigated time-course (right), showing the rapid cocaine uptake needed for a high—this paralleled the subjective effects reported by the volunteers, suggesting the two are related. The work demonstrated in humans that cocaine’s direct effects on the striatum and time-course modulate its subjective effects. The study was later repeated using methamphetamine instead (bottom row): the binding again primarily involved the striatum, but also extended to many other areas. The time-course, again paralleling subjective experience, was much longer-lasting than cocaine—explaining differences between the two stimulants in duration, subjective experience and long-term effects.
Photo via
• Acute Effects (2)
Sometimes it's less obvious why people enjoy a drug. This recent study investigated psilocybin (magic mushrooms), a compound that binds to serotonin receptors and doesn't have obviously rewarding dopamine effects. MRI (magnetic resonance imaging) was used to measure the magnetic properties of blood flowing into the brain, with the idea that active regions need more blood. Researchers injected volunteers with the drug and placebo, and measured changes in blood flow and oxygenation. To everyone’s surprise, MRI measures decreased with psilocybin, mainly in regions other than the striatum (yellow circle), including areas involved in association, consciousness and “constraining the experience of the world.” The scatterplot shows that the amount of decrease in MRI signal predicted the intensity of subjective effects. The study also found reduced communication between brain regions, suggesting that “decreased activity and connectivity” permits “an unconstrained style of cognition.” So some drugs without a direct striatum/dopamine effect can be found enjoyable, perhaps due more to the reward of changing perceptions—a uniquely human feature that seems hard to model in animals. In a separate study, the group also found that MRI measures related to memory vividness and subjective well-being at follow-up, suggesting a biological basis to the proposed use of psilocybin in psychotherapy.
Photo via
• Dopamine Receptors in Addiction
One of the most consistent “hallmarks” of addiction is that levels of the D2 subtype of dopamine receptors (mostly found in the striatum) are lower in addicted than in non-addicted individuals. These images come from a number of PET studies which assessed D2 receptor levels, by injecting subjects with a radioactive compound that specifically binds to dopamine receptors and comparing levels between groups. The “cooler” colours indicate lower D2 levels in the addicted groups. This represents the possible identification of an addiction “biomarker”—an objective biological measure that can be investigated, monitored and perhaps manipulated for prevention or treatment. The real-world relevance of this is shown in the pink inset: in two studies (cocaine and meth), addicted subjects had their D2 levels measured, went through treatment, and were then contacted again to assess treatment success. Successful responders to treatment were found to have higher D2 levels than those who had relapsed, suggesting that D2 levels have some predictive value for success. Much remains to be filled-in in the dopamine receptor/treatment response black box. But this knowledge can help in the allocation of clinical attention and resources, or the identification of patients who may benefit from one type of treatment—like meds to increase dopamine transmission—over another.
Photo via
• Recovery of D2 Receptors With Abstinence
The D2 dopamine receptor has also been used to investigate signs of recovery after abstinence. In this PET image, the “cooler-coloured” striatum of a one-month-abstinent meth user shows lowered binding of the radioactive compound, suggesting fewer receptors. But the striatum grows “bright” again after 14 months' abstinence, suggesting increase in D2 receptor availability, or recovery of the receptors. This implies that brain cells don't necessarily disappear permanently, but may temporarily adapt (perhaps retracting receptors in response to the dopamine bombardment from drug use)—or else that the remaining brain cells can compensate. Unfortunately, behavioral tests in the same study didn't improve as much as D2 measures, and the finding has been difficult to replicate, which limits the study's implications—but it does show the importance of timing in studies, and suggests that neurochemical changes aren't necessarily permanent. (By the way, the black spots in the 14-month image are not holes in the brain, but a result of assigning colors to values, and setting the threshold at a certain level).
Photo via
• Relationship Between D2 Receptors and Personality Traits
One problem with neuroimaging is that the pictures often don't reveal much about functional relevance. How, if at all, do receptor levels translate to differences in experience, behaviour, thinking or feeling? This PET study measured the relationship between dopamine receptors and personality traits. The striatum blobs shown here don't display radioactivity indicating D2 receptor levels, but rather the strength of the correlation between receptor levels and trait impulsivity (“hotter” colors mean a tighter relationship). In both meth-dependent and healthy subjects, the measures correlated inversely: those with the lowest D2 receptor availability were the most impulsive. This shows that dopamine receptor availability in the striatum can contribute to personality traits for the entire population—and addicted individuals, who tend to be on the low end of the D2 spectrum, are more likely to act impulsively than non-addicted individuals. It's still frustratingly hard to determine what came first: drug use could cause a decrease in D2, or alternatively, low D2/high impulsivity could make people likelier to use drugs. Still, the study gives the "low D2 addiction biomarker" some behavioral meaning. It also explains some aspects of initiating or continued drug use, and raises clinical implications—as personality traits can be easily assessed and maybe used to evaluate dopamine-related intervention strategies.
Photo via
• Genetic Predisposition to Addiction
Genetic factors contribute significantly to addiction, and imaging techniques can pick up and visualize genotype effects that less sensitive behavioural or self-report measures may not. This study investigated how genetic variation in the dopamine system affects smoking. Dopamine release in a certain part of the striatum is often considered the brain’s reward signal, and can be assessed in humans using PET. This requires measurement of a dopamine receptor-binding radioactive compound at two time-points; the difference between the points shows how much dopamine was released over time, knocking the compound off the receptor. The lower the second PET signal, the more dopamine was released. Subjects were scanned before and after a smoke break, then divided by genotype for three components of the dopamine system—each of which varies in function depending on genotype. Each row on the slide is a component: top, the dopamine transporter; middle, the D4 dopamine receptor; bottom, an enzyme that removes dopamine after release. For all three components, individuals with one genotype (left two panels) released more dopamine during the smoke break than those with another genotype (right two panels). So some people, due to their genetic makeup, find smoking more rewarding than others—and are likelier to continue or escalate use. Tiny biological differences can influence addiction processes, and a better understanding of them can aid prevention and intervention.
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• Neurobiology of Behavioral Addictions
Behavioral or process addictions, like compulsive gambling, eating, or sex, have been getting lots of neuroimaging attention, partly due to their surface similarities with drug addiction, but their neurobiology remains largely unexplored. These results from several PET studies measuring D2 dopamine receptors in the striatum show that obese individuals who may be prone to compulsive overeating have low D2 levels—paralleling findings in compulsive drug users. This suggests biological commonalities between behavioural and drug addictions; it's an exciting area currently gaining research momentum. Interestingly, in compulsive gambling—the only behavioural compulsion currently proposed for re-classification to addiction—low D2 receptor levels haven't been found, although several studies have searched. This may mean that low D2 levels are sufficient, but not necessary, to drive addiction, and that other factors play a more important role here—or that the low D2 levels seen in drug addicts relate to the effects of drugs themselves, rather than addiction per se. This is a unique chance for scientists to learn about addiction without the potentially interfering effects of drugs, but clinically there are potential problems: drug addiction treatment options may have different effects when aimed at behavioural addictions. Of course, other biological parallels with drug addiction have been identified, and neuroimaging has played an important role in teasing apart the results.
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• Neuropropaganda
Neuroimaging has enabled many advances in addiction science; it's also added to the debate on personal culpability in addiction, by highlighting neurobiological factors that aren't necessarily under our control. But the emotive influence of these images can also be used to more sinister effect, manipulating audiences into knee-jerk reactions. Sometimes this is done for the sake of eyeballs and obviously overwrought (right panel)—but other uses are more serious, including court evidence to support drug-related penalties. Even if an image comes from reputable scientific sources, it's still subject to interpretation and presentation, which can easily be shifted to fit different needs. So we're well advised to approach these images with questions. What is actually being shown? What do colors (or their absence) mean? What's the behavioural significance, if any? And who is being shown? Is this a group of individuals, or one exemplar—and if the latter, is he or she representative of the population, or does the image pit the best in one group against the worst in another? How many times did they use the drug, how heavily, and how long were they abstinent? Could factors other than drug use account for the image? The answers may not be easy to come by. But posing these questions can help overcome gut responses, fostering a fuller, fairer understanding.
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• Neurohype: Smoke, Mirrors and Dead Fish
In the previous slide, even though the news article claimed to have “conclusively demonstrated severe and multiple disruptions,” the “black holes” don't indicate dropout of actual brain tissue. They're a result of threshold-setting: assigning “black vs. colour” at a particular signal value, with the choice of value entirely subjective. This is just one of the many caveats of neuroimaging. In human neuroimaging, for example, actual photographs are rare; more often, images are proxy signals for some biological event that have been digitized and computerized, reconstructed and transformed, and subjected to statistical testing and interpretation. Signals are small, assumptions are many, and at every point, a person intervenes in producing what will ultimately be displayed. The result can sometimes be utter junk—as demonstrated in a study that flashed pictures of human social interactions, and "found" associated brain activation...in a dead fish. Neuroimaging techniques, no matter how brilliant, are removed biological events, so can't always be assumed to accurately reflect them. Addiction neuroimaging is a tricky area: the field is fraught with political static and agenda. Combine this with the computational limitations of neuroimaging, and emotionally charged headlines can ensue. Ultimately, though, a tool that can visualize the hardware of the mind is extremely valuable in any mental health field. It's a privilege and a thrill to think of the possibilities ahead.
Doris Payer received her Ph.D. in Neuroscience from UCLA, where she trained in the NeuroImaging Training Program and the Center for Addictive Behaviors. She's now a Post-Doc in the Addiction Imaging Research Group at the Centre for Addiction and Mental Health in Toronto, making pretty pictures of brains with various impulse control disorders.
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2,947,792,334,718,752,000 | CameraIcon
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Question
Which of the following diseases spreads through infected needles or blood transfusion?
A
Jaundice
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B
AIDS
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C
Measles
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D
Polio
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Solution
The correct option is B AIDS
AIDS (Acquired immunodeficiency syndrome) is an infection which is caused by Human immunodeficiency virus (HIV). The causative agent of the disease is a virus and so the disease can spread from one person to the other by sexual contact. The disease alsoe spreads through the use of teh infected needles, syringes and blood transfusion from the infected person.
Thus, the correct answer is option B.
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5,679,233,294,775,131,000 | plank woman fitness working out workout Shutterstock
The INSIDER Summary:
• Working out is often better done with a plan in mind.
• Chris Jordan, an exercise physiologist, shared a short workout routine complete with foods to eat before and after a workout.
Getting ready to workout is often the hardest part of exercising. You need a plan, a place to do it, the right kind of clothes, good shoes, and enough energy.
Caffeine can help you feel more energetic — but so can certain foods.
Chris Jordan is the exercise physiologist who came up with the 7-minute workout routine designed to give you the benefits of a sweaty bike ride and a trip to the gym in just a few minutes. He says it's important to fuel your body properly before working out.
To avoid feeling burned out a few minutes into your routine or exhausted afterwards, Jordan recommends two specific snacks.
The first, which should be eaten 1-2 hours before hitting the gym, should score low on the glycemic index.
Foods with a low glycemic index score, which dietitians often refer to as "low-glycemic" foods, can help keep energy levels steady by making sure your blood sugar levels don't rise or fall too dramatically. Good low-glycemic snack options include an apple, some walnuts or almonds, a small low-fat yogurt, some hummus and carrots, a piece of whole wheat toast, or a couple of hard-boiled eggs. Some research suggests a low-glycemic diet may have other benefits as well, such as helping your body metabolize fat more efficiently.
Flickr/USDAgov
The second can be eaten at any time and should combine carbohydrates and protein. Jordan's favorite after a sweaty trip to the gym? Low-fat chocolate milk.
"Chocolate milk is an ideal post workout snack since it provides carbohydrates, protein, fluid, electrolytes," he says.
These snacks can help provide you with more energy throughout the day and assist you in pursuing fitness goals like losing body fat and building muscle, Jordan says. So what are you waiting for? Fuel up and hit it. | {
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4,430,552,149,670,357,000 | Explosions of Anger
Explosions of Anger Problems that Parents Must Address Urgently by Dr. Chonnipa Butwong, Specialist in Child and Adolescent Psychiatry at PatRangsit Hospital.
This article discusses the disruptive behavior of children, what causes irritable and easily angered children, how to take care of them, and why we should pay attention and understand them. Many disruptive behaviors often manifest as anger and frustration, which are primary symptoms of Oppositional Defiant Disorder and Conduct Disorder. However, children with other psychiatric disorders are also at risk of exhibiting disruptive, angry, and aggressive behaviors.
Research studies have found that the prevalence of disruptive behaviors ranges from 14% to 35%. Particularly in children with ADHD, the prevalence can increase to 14% to 62%, and in children with anxiety, it ranges from 9% to 45%.
However, anger is a natural part of emotions, although it involves increased physiological arousal. Anger often leads to thoughts of blame towards oneself or others, as it arises from frustration or provocation. Anger can last from minutes to hours and ranges from mild anger to extreme anger. Crying, stomping, pushing, hitting, and kicking are common expressions of anger in children aged 1-4 years, occurring 5-9 times a week on average, with durations of 5-10 minutes. However, the intensity and frequency of anger tend to decrease as children grow and age.
Uncontrolled outbursts of anger are problems that need to be addressed to help children develop emotional control skills and cope with anger and frustration effectively.
Methods that can be used to manage anger include:
1. Recognize anger quickly. Anger itself is not inherently bad, nor does it define a person as being bad. Allow yourself to acknowledge and accept your anger. However, to recognize emotions effectively, it is important to be in a calm environment that reduces emotional triggers and allows for sufficient concentration to be more aware.
2. Relaxation of the breath and muscles. Breathe in and out slowly and deeply, paying attention to comfortable breathing. Check each muscle to see if there is any tension. Start from the face, shoulders, palms, arms, and legs on both sides, gradually imagine those muscles being stretched and relaxed.
3. Once the mood has calmed down, consider where the anger comes from. Find the cause and seek ways to address the problem, such as talking to someone you trust about how you feel. Talking helps calm intense emotions, allows others to understand you better, and helps you understand things easier than when thoughts and feelings are trapped within you.
Allowing yourself to articulate your feelings honestly can help turn your anger into understanding. Self-awareness will be coupled with self-control. Dealing with anger is not easy, and anger control is something that must be practiced gradually and continuously. It may not be possible to completely manage all feelings of anger immediately, but it is important to learn to control your anger so that it doesn't overwhelm you.
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-524,010,512,737,650,750 | The Art of Anma: Unlocking Bliss By way of Therapeutic Contact
Welcome to the entire world of Anma, a Japanese form of therapeutic massage that holds the important to unlocking true bliss by means of the electricity of therapeutic touch. Dating back centuries, Anma not only aims to chill out the human body and ease tension, but also nurtures the spirit, providing a holistic method to effectively-becoming. In this report, we will delve into the prosperous heritage of Anma, investigate its rewards, and uncover the artistry driving this ancient apply. Regardless of whether you are curious to learn a lot more or seeking a new route in the direction of harmony and rejuvenation, get ready to embark on a journey of healing as we unravel the strategies of Anma therapeutic massage. Let us immerse ourselves in the serene world of Anma and embrace the profound rewards it provides for both human body and mind.
Origins and History of Anma
Anma, also acknowledged as massage in English, has a prosperous heritage that dates back hundreds of years. Its origins can be traced back again to historic China, the place it was practiced as a kind of therapeutic and peace. The techniques and principles of Anma have been later adopted and further created in Japan, evolving into the distinctive type of massage treatment that it is known for today.
In China, Anma was initially utilised as a way to promote physical and religious nicely-becoming. It was considered that the harmony and stream of power, identified as qi, played a critical part in keeping overall health. By means of the software of specific hand movements and force on key points of the human body, practitioners aimed to launch blockages in the power pathways and restore harmony in the human body.
With the introduction of Anma to Japan, the exercise underwent even more refinement and integration with Japanese lifestyle. The tactics were tailored to match the Japanese physique sorts and sensitivity, ensuing in a style of massage that prioritized deep stress and effective stimulation of the body’s pressure details.
Over time, Anma turned an vital component of Japanese society, deeply rooted in classic medicine and therapeutic procedures. It was not only used for therapeutic purposes but also turned a popular leisure approach between the standard populace. Anma practitioners were highly revered, and their expertise have been handed down through generations, ensuring the preservation and continuity of this historical art kind.
Today, Anma continues to be practiced and appreciated for its many rewards. It is acknowledged as a useful complementary therapy in advertising actual physical and psychological well-currently being. No matter whether it is employed to relieve tension, relieve muscle tension, or restore equilibrium within the human body, Anma continues to be an efficient and timeless sort of therapeutic touch.
Tactics and Concepts of Anma
Anma massage, also known as Anma therapy, originates from conventional Chinese medication and is characterized by its special methods and principles. This historical apply focuses on advertising rest, improving the flow of strength, and relieving tension inside of the human body. By way of the expert fingers of a educated practitioner, Anma brings together numerous tactics to unlock the blissful advantages of therapeutic touch.
The techniques used in Anma therapeutic massage are varied and tailor-made to personal requirements. 1 frequent approach is kneading, which requires applying force to the muscle groups and gentle tissues making use of the palms, fingers, and fists. This rhythmic motion aids to improve circulation, relieve stiffness, and soften absent muscular knots. Yet another strategy is effleurage, a gentle stroking movement that will help to relax the human body and soothe the anxious system. By gliding the palms effortlessly more than the skin, the practitioner stimulates blood and lymphatic stream, selling overall well-becoming.
An important basic principle of Anma therapeutic massage is the perception in the body’s innate potential to recover itself. It is based on the idea of Qi, the vital energy that flows via meridians inside of the body. Anma practitioners implement stress and manipulate specific factors together these meridians to stimulate the body’s natural healing mechanisms. By balancing the flow of Qi, Anma aims to restore harmony and encourage the body’s self-healing procedures.
In addition to using certain strategies and ideas, Anma therapeutic massage also incorporates the holistic strategy of viewing the entire body, brain, and spirit as interconnected. This thorough standpoint enables the practitioner to not only handle physical rigidity but also contemplate emotional and energetic imbalances. By considering the complete man or woman, Anma therapeutic massage provides a really profound and therapeutic knowledge.
Via the software of a variety of strategies and adherence to its guiding principles, Anma massage delivers a profound avenue to unlock bliss and properly-being. With its centuries-outdated roots and its concentrate on marketing relaxation and total harmony, Anma carries on to be a treasured artwork form in the realm of therapeutic contact.
Advantages and Applications of Anma
Anma, the art of therapeutic massage, is a therapeutic strategy that delivers different rewards and programs. Let’s investigate some of the techniques Anma can provide bliss and properly-becoming into your life.
To start with, Anma is identified to reduce stress and advertise leisure. Via the use of distinct methods and strain points, Anma therapeutic massage helps to launch stress in the muscle groups and promote a sense of deep leisure. This can be specially useful for individuals with high-stress life or people encountering actual physical or mental fatigue.
Next, Anma can boost circulation and increase all round actual physical wellness. seoul anma By stimulating the stream of blood and strength during the entire body, Anma assists to boost oxygen and nutrient shipping and delivery to the muscle tissues and organs. This can guide to enhanced vitality, diminished muscle mass soreness, and improved all round properly-getting.
And lastly, Anma can also tackle distinct health worries and offer aid from different ailments. The target on certain stress points and strategies in Anma massage permits for targeting of particular locations of soreness or stress in the human body. This helps make Anma suitable for addressing troubles such as again ache, head aches, digestive difficulties, and even insomnia.
In conclusion, Anma massage offers a assortment of rewards and apps that can positively affect equally bodily and mental well-getting. Whether you find peace, improved circulation, or focused relief from distinct wellness concerns, Anma supplies a therapeutic touch that can unlock bliss and boost your good quality of existence.
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-3,500,287,465,673,412,600 | Guide to Intermittent Fasting
July 05, 2019
Have you ever felt that no matter how hard you exercise or how diligent you are with your nutrition, the weight just keeps slowly creeping up? The weight increases and slows you down, causing fatigue, pain and inflammation. You are not alone in the fight against weight gain, and there is a smarter path to walk down.
Functional medicine, including techniques like intermittent fasting, helps you re-envision the weight-loss process as a set of skills you can develop to combat chronic weight-gain. These skills are focused on shifting our environment, and not fighting against our amazing bodies. Done correctly, lifestyle skills like intermittent fasting can save time and energy, promote productivity and ultimately lead to longevity.
While intermittent fasting is a very popular topic right now in the wellness community, it is important to remember that the practice of fasting dates back to our earliest human cultures and spans most religious and spiritual practices. Fasting is not new, but due to the flood of new evidence on the benefits of fasting, we have a new way of talking about it.
As a Naturopathic Doctor with more than 12 years in clinical practice helping 1000s of professionals lead with their health, I can help you understand the benefits of intermittent fasting so that you can consider using it as a tool for your success.
This guide is for information purposes only; always check with your primary care provider before you make changes to your health plan.
Why do I care so much about intermittent fasting (IMF)?
Your energy matters: it is the fuel for your success. IMF can help you make more energy by optimizing your metabolism.
Here’s how it works:
• Mitochondria are the energy manufacturing machines that live in every single cell of your body. They are highly concentrated in your brain, liver and muscle tissue.
• Your muscle mass is like an energy investment with a quick and high return, the more you have the more energy you can make efficiently and easily.
• Body fat on the other hand is like an investment that is very difficult to access, it is very difficult to get your energy out and the more you accumulate the more inflamed, tired and sluggish you feel.
• For longevity and optimal health, we want to work to increase our ratio of muscle mass to body fat, which naturally declines with age. Fasting can help us do that.
Intermittent fasting is like a genetic switch that:
• Improves insulin sensitivity, which is a key component of an increased metabolism, putting you in the fat burning versus fat storing mode. This is how we combat those long hours at a desk that promote our growing belly fat.
• Increases growth hormone, which is a powerful anti-aging hormone that does amazing work for our body. It repairs tissue and helps us grow stronger and more resilient. Growth hormone dramatically declines after the age of 25. The more we can promote it naturally as we age the younger our cells will be.
• Increases cellular repair and waste elimination. IMF promotes autophagy. Autophagy is the body’s natural process of identifying old and dysfunctional cells, breaking them down and removing them from the body. It is the ultimate detox process, like the body’s natural “KonMari” method. Let go of all of the old stuff that no longer serves us.
• Optimizes gene expression. Our DNA is not exactly our destiny. Functional medicine can support optimal gene expression, which is like putting your best genetic blueprint forward for replication. There are many negative environmental influences on our gene expression like stress and pollution. IMF can help tip the scale in favour of our best health.
The health benefits of IMF are significant, especially as we face a growing number of metabolically-linked diseases like type 2 diabetes, Alzheimer’s, dementia, cancer and heart disease. Fighting metabolically-linked disease with drugs alone is not enough to win the war. The pressures of the modern world have moved us away from our optimal rhythm, and functional medicine can help to bring us back.
What does IMF look like?
Fasting simply means not eating any energy-containing foods. You should drink water and can drink herbal tea while you fast. We already fast every night while we are sleeping. Research shows that we need to be mindful of the number of hours we spend in a fasting state. Our culture of late-night dinners, wine before bed and stress eating after long hours at the office have decreased the amount of time we spend fasting.
How long do I need to fast?
There is a large body of evidence to support the “13 hour fast”. This would mean for example eating breakfast at 7 am and having dinner by 6pm. Long term repetition of this pattern is very promising for fat lost and metabolic balance over the course of the lifespan.
• Your “feeding window” would be 11 hours.
• Your “fasting window” would be 13 hours.
Other studies show that fat loss may be more significant with a 16-18 hour fast. This might look like eating your first meal at 10 am and your last meal at 6pm.
• Your “feeding window” would be 8 hours
• Your “fasting window” would be 16 hours
Do I fast every day?
No.
While some people may feel the benefit of doing a 13 hour fast regularly, the intention behind longer periods of fasting is not meant to be daily but intermittent.
The frequency of fasting should be determined by your specific health goals. While most of us are not fasting enough, some of those who have caught on to the popular health trend are fasting beyond what the research is showing is beneficial.
A good analogy for how much fasting is right for you is to compare against running for exercise. What is your end goal and where is your starting point?
Training for a 13 hour fast is like training for a “couch to 3-5km”: it’s doable and it’s sustainable. You can do it most days to feel good, but you don’t need to do it every day to reap the health benefits on your metabolism.
Training for a 16-18 hour fast is like training for 7-10km. At first it is going to feel uncomfortable but over time your body will adapt, grow stronger and be better able to regulate. If you completed this fast every day you would certainly be “over training” and stressing your body. This type of fasting is best done 1-2 times a week.
Training for a 24 hours fast or longer is like training for a marathon. You don’t run a marathon without training and preparation first. You need to ensure you are committed to supporting your overall health though out this practice of you risk over stressing your body. You are likely completing this type of fasting 1-4 times per year to achieve the health benefits and the research is not yet clear if more is better.
What do I need to do before I start fasting?
Let’s walk you through our functional medicine checklist:
• You need to have your sleep cycle dialed in.
The benefits of fasting depend on your sleep: the two metabolic processes go hand in hand. Fasting can help to improve the quality of your sleep, but you are not going to experience the fat loss benefits if you are staying up late.
• Your nutrition game needs to be strong.
Fasting is not about starving your body. It is about cleaning house and requires nutrient optimization. Your “feeding window” needs just as much attention as your “fasting window”. Your diet needs to be nutrient dense: you need to eat well, and you will need to plan ahead.
• Your liver needs some love.
Your liver is the main controller of the fuel you use to make energy. It is an overlooked organ that plays a major role in your metabolism. Removing stressors to your liver like alcohol, sugar, hydrogenated and some saturated fats, and potentially even coffee, might be necessary to kick your metabolism into the gear it needs to be in to achieve your goals.
• Your bowels need to move daily.
Remember that this process is also about elimination. If your bowels are not moving, you might not feel good while you are fasting, and long fasts might contribute to more constipation. Address this with your Naturopathic Doctor before you start.
• You need to stay hydrated.
The process of burning fat for fuel requires water. The more you practice fasting the more your body’s need for water will increase. If your bowel movements slow down or you start feeling really tired your hydration levels are the first thing you should consider. Many people forget to drink plenty of water when they are focused on avoiding food.
• You need a plan.
A good plan considers how fasting might contribute to your overall health and also considers how it might also take away. Each person has a unique set of metabolic circumstances that should be evaluated.
When intermittent fasting might not be a good idea:
• If you are taking insulin or have been diagnosed with diabetes you should only fast under the direct supervision of your healthcare professional. Fasting will affect your blood sugar regulation and could be fatal in this circumstance if not monitored.
• If you have a history of gallstones or constipation, fasting may aggravate your condition. You can address these factors with your Naturopath.
• If you have battled eating disorders or are triggered by obsessive thinking around your nutrition or weight loss, then tracking your fasting window may exacerbate obsessive behaviour. There is certainly an argument that fasting can be a loving expression of eating in tune with our natural circadian rhythm. It can also be used as a tool for self -deprivation. A deep understanding of our motivations and how we approach selfcare should be explored before you start.
• If you are pregnant or breastfeeding, your body has a different metabolic priority. It is focused on building and feeding your baby. This is a time to build, not a time to clean house.
• If you are experiencing malnutrition or malabsorption for any reason. While fasting can play a role in the management of inflammation and autoimmunity, if you are currently experiencing malnutrition due to an IBD flare or your celiac disease is not well managed, correcting malnutrition and malabsorption must be accomplished before fasting could be beneficial. Fasting while malnourished will only add to your state of nutrient deprivation.
Intuitive fasting and mindfulness are the keys to long-term success. Working from a functional approach that considers your metabolic starting point and tracks your success using:
• Body composition analysis (BIA)
• Waist circumference and additional markers of insulin sensitivity (HBA1C)
• Preliminary lab work to establish nutrient status and liver function
• Sleep quality apps or heart rate variability monitoring as markers of stress reduction and optimal recovery
Working on a program and with a health coach will help you avoid the most common mistakes, including:
Giving up too soon:
• Many people start and stop too soon without understanding the impact they have achieved, or the success they could have if they make fasting a long-term pattern.
Unnecessary and unproductive suffering:
• Feeling angry and tired is not a badge of honour. It is a sign that you are not “fat adapted” and your liver needs support before you start fasting on a regular basis.
When fasting goes too far and becomes disordered eating:
• It can be difficult to accurately assess our own behaviours. A coach can help you stay accountable to your highest self.
Not eating enough nutritious food:
• Fasting requires nutrient optimization. Our program focuses on nutrient dense, easy to access foods that will help you nourish and recovery your best health. Our health coach will ensure the program is tailored for you based on your unique metabolic needs and activity level.
Like exercise, fasting is about improving our long-term metabolic health benefits it is not about short-term weight loss (although that is often a nice side effect).
The greatest influence on your health is you. It’s time to stop fighting your body and shift your environment in favour of your metabolism.
Get Started
Disclaimer
The advice provided in this article is for informational purposes only. It is meant to augment and not replace consultation with a licensed health care provider. Consultation with a Naturopathic Doctor or other primary care provider is recommended for anyone suffering from a health problem or looking to optimize their health.
Dr. Erin Wiley is a Naturopathic Doctor with a strong focus on preventative and integrative medicine. She is the Owner and Clinic Director of the Integrative Health Institute, an integrative medical clinic located in downtown Toronto. Erin has a strong clinical emphasis on autoimmune conditions, stress related illness, anxiety, depression and hormone balance. As a naturopathic doctor, Erin is passionate about working with people to help them better understand their health and achieve their health goals.
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-7,433,592,203,046,224,000 | What is Chronic Pelvic Pain (CPP)?
Chronic Pelvic Pain (CPP) occurs in the lower abdomen and pelvic part of the human body. The entire area surrounding the abdomen and pelvic experiences the chronic pelvic pain than at a single point. It generates mainly in the pelvic area which is below the bellybutton and in-between the hips. It causes immense pain and can last for a maximum of 6 months or even more in a person.
Chronic pelvic pain can be an indication of presence of other disease in the body. It can even grow by its own. The reasons of chronic pelvic pain are mostly unknown. The treatment is mainly based on finding the cause of the pelvic pain.
In some women it is really tough to test the real reason of the origin of chronic pain in pelvis. The treatment is done to bring the pain in control and teaching survival techniques during this period of chronic pelvic pain (CPP).
What is Chronic Pelvic Pain (CPP)?
Etiology of Chronic Pelvic Pain (CPP)
Chronic pelvic pain (CPP) is one of the common problems in women and it is a complicated problem to treat for medical practitioners due to its unknown cause of occurrence and poor medical response to treatment.
Chronic pelvic pain cannot always be successfully treated due to its poor diagnosis. The reasons of this syndrome are completely unknown. However a number of factors are paid attention to only to bring the pain in control. The nervous system, muscles and psychological treatment are done to help a person cope up with chronic pelvic pain.
Bladder or bowel dysfunction and sexual dysfunction are the constitutional symptoms which arise with chronic pelvic pain (CPP).Chronic pain in pelvic can also cause depression and / or anxiety. People tend to incline towards drug addiction due to extreme pain.
In the United States, the medical costs to treat chronic pelvic pain (CPP) for reproductive aged women are around $881.5 million in a year.
Pathophysiology of Chronic Pelvic Pain (CPP)
The pathophysiology of chronic pelvic pain is still not clear to medical practitioners. It is due to many factors and usually complex in nature.
Causes of Chronic Pelvic Pain (CPP)
Causes of Chronic Pelvic Pain (CPP)
Chronic pelvic pain does not have any specific reason of occurrence. It can cause to a person without any reason also. The psychological factors increase to the complexities of the pain in pelvic. Since this pain in pelvic is prolonged and takes much time in recovery, people tend to get emotionally distressed during the time period.
The major causes detected for chronic pelvic pain (CPP) are:
• Endometriosis in women is one of the major reasons of chronic pelvic pain (CPP). The tissues in the lining the woman's womb or uterus tends to develop outside the uterus. These effects the menstrual cycle of the woman due to accumulation of tissues. The hormones fluctuate with the thickening and breaking down of the line of tissues during each month's bleeding. Due to the gathering of tissues outside the uterus, the blood cannot flow through the vagina. The blood does not completely flow out of the body and remains in the abdomen. Thus it forms cysts and adhesions which are extremely painful in women.
• Tension or Spasms in the floor of pelvic muscles cause repeated chronic pelvic pain (CPP).
• Any chronic pelvic inflammatory disease occurred due to sexually contaminated diseases also causes pain in the pelvic organs.
• Ovarian remnant which is the cyst formed in the body in the time of hysterectomy in women causes' chronic pelvic pain (CPP). During the complete removal of uterus, fallopian tubes and ovaries in a surgery, this cyst is generally formed. This can cause chronic pelvic pain if not treated early.
• The noncancerous uterine which develops in the lower abdomen of the body called fibroids is the cause of sharp pain in the pelvic region. The pain remains till these growths remain alive due to supply of blood in them.
• Bloating tendencies, constipation, diarrhea or other symptoms of irritating bowels causes pelvic pain. When left untreated for quite some time, this pain can grow chronic and become unbearable.
• Painful bladder syndrome. Irritated bladder causes pain in the pelvic region while passing urine. The bladder generates the pain when it is full.
• Certain psychological factors like worries, anxiety, depression, physical abuse or sexual abuse increase the chances of chronic pelvic pain (CPP) in women. The emotional distress due to such turmoil causes unbearable pain.
• Pelvic congestion syndrome. Congestion in the pelvic organs also causes chronic pelvic pain (CPP). Enlarged veins in the uterus and ovaries cause such chronic pelvic pain. This pain is most recorded in women.
Signs and Symptoms of Chronic Pelvic Pain (CPP)
Chronic pelvic pain (CPP) has characteristics of its own. The signs and symptoms of chronic pelvic pain (CPP) are:
Signs and Symptoms of Chronic Pelvic Pain (CPP)
• Continuous and serious pain
• Frequent occurrence of pain
• Unbearable extreme pain
• Muscle cramping due to sharp pains
• Pelvic experience to be heavy due to extreme nature of pain
Other than the above mentioned signs and symptoms, the person may experience the following during chronic pelvic pain:
• Pain during sex.
• Pain during excretion or urinary discharge.
• Pain between the pelvic if the person has to sit in the same position for a long time.
The chronic pain in pelvis increases after the person has to sit or stand in the same position for quite some time. However, a little relief is gained if she gets to lie down for some time. The pain is sometimes very little yet irritating. Sometimes chronic pelvic pain can grow so severe that the person experiencing the pain may not be in a condition to join work for the day. It even does not allow sleeping or working out.
Epidemiology of Chronic Pelvic Pain (CPP)
Chronic pelvic pain (CPP) is a common issue in United States of America. One woman out of seven is affected with chronic pelvic pain (CPP). Around 39 percent of women are suffering from chronic pelvic pain as revealed in a study of reproductive-aged women in primary care practices. 10 percent women are recorded to be suffering from pelvic pain during their pregnancy.
Mortality/Morbidity: Chronic pelvic pain (CPP) is also prevalent in the similar way in other countries. Chronic pelvic pain (CPP) when untreated for a long time may bring to adverse medical disability forcing a lifelong therapy. It affects the personal life of the sufferer and creates marital as well as other family problems.
Prevalence of Chronic Pelvic Pain (CPP)
Generally 6 percent to 26 percent of people suffer from chronic pelvic pain (CPP). Many countries have still to be surveyed for the data. This is due to the absence of proper studies or researches on the subject in many countries on chronic pelvic pain (CPP). More students have to be engaged towards the research of chronic pelvic pain in a proper way just to reveal the occurrence of the syndrome in many nations. This would be a good initiation towards the care and treatment of chronic pelvic pain in women.
Also Read:
Written, Edited or Reviewed By:
, MD, FFARCSI
Last Modified On: September 14, 2016
Pain Assist Inc.
Pramod Kerkar
Note: Information provided is not a substitute for physician, hospital or any form of medical care. Examination and Investigation is necessary for correct diagnosis.
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10
Doctor insights on: Doctors Will Cause Pain Shoulder Arm Numbness Tingling
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1
1
What do doctors suspect will cause pain in right shoulder with arm numbness and tingling?
What do doctors suspect will cause pain in right shoulder with arm numbness and tingling?
Pinched nerve: First thought is a pinched nerve from the neck. Can be a pinched peripheral nerve as well for example in the brachial plexus or below.. Pain in shoulder may be related or a separate issue. ...Read more
See 1 more doctor answer
Dr. Bennett Machanic
2,005 doctors shared insights
Tingling (Definition)
Tingling is a pins and needle like sensation anywhere on the body. May also be termed paresthesia. Can experience when elbow is bumped (funny bone), or even from frostbite. On its own, unlikely significant but may be part of nerve pathology from ...Read more
2
2
I have neck pain that's running down my left arm numbness and tingling. What is the cause of this?
I have neck pain that's running down my left arm numbness and tingling. What is the cause of this?
PRESSURE ON NERVES: Pain in neck radiating down the arm usually is from pressure on the nerves that originate from the neck you need to be evaluated by your doctor or an ortopedic specialist, you need exam and may need MRI exam to find the cause.You are only 34 years old so see your doc. ...Read more
See 2 more doctor answers
3
3
My doc told me muscle spasm/ tension caused arm numbness/pins and needle~ How long does it last?im on Valium currently
My doc told me muscle spasm/ tension caused arm numbness/pins and needle~ How long does it last?im on Valium currently
With limited history: if cervical spasm from DJD with spinal stenosis treatment will help only control symptoms. Sometimes surgical intervention may be indicated if symptoms worsen ...Read more
See 2 more doctor answers
4
4
6 month soreness rt shoulder, upper arm; numb/tingling /cold fingers; neck soreness less so.Hist rheumatoid, not carpal tunnel?
Doesnt sound like it: Doesnt sound like it but it can be par to f the presentation or differential. A nerve study/emg may be helpful unless its an obvious case of not being so. ...Read more
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6
6
Shoulder pain and right arm numbness took B12 vit. Thngs imprved , last time i hit the gym found sudden drop of strength in right arm?
Get a check up: I would suggest to contact your physician today to undergo a detailef history of the symptoms and followed by a thorough physical exam. He may order dome x-ray or MRI of spine to get the confimative diagnosis. In mean time, i would advise you to putneck collar to prevent any further injury to spine. Good luck ! ...Read more
8
8
Pain in right shoulder & down right arm, Numbness in thumb too.
Pain in right shoulder & down right arm, Numbness in thumb too.
Neck problem: This likely a result of the nerve that goes to your arm being pinched in your neck either by a bad disc or a muscle spasm. Ibuprofen is the first line of treatment and evaluation by your physician to make sure there is nothing else going on. ...Read more
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9
9
Arm numbness, tingling, a bit of itching, typing hurts, after five days from the blood test. What can it be?
Arm numbness, tingling, a bit of itching, typing hurts, after five days from the blood test. What can it be?
Nerve irritation: Possibly there was some nerve irritation that occurred during the blood draw. Give your arm some rest, elevate at night. Heat/cold compresses can be tried to stimulate your nerve. Hopefully, it will be over with in a few days. ...Read more
10
10
Arm numbness, tingling, a bit of itching, typing or twisting hurts, after five days from the blood test. What can it be?
See below: A small clot in the vein that was stuck is the most probable cause if so it should dissolve within the 7-10 days if not then see a physician. ...Read more
Arm Numbness (Definition)
Less sensitivity to pin or light touch in the arm. May correspond to anatomical distribution such as ulnar or median nerve, or perhaps cervical anatomical correlates. May be localized using standard ...Read more
Dr. Bennett Machanic
2,955 doctors shared insights
Numbness Or Tingling (Definition)
Numbness is a clinical finding in which one is unable to detect stimuli such ...Read more | {
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Archives
In Vitro Antibacterial Activity of Rhodanine Derivatives against Pathogenic Clinical Isolates
Bacterial infections present a serious challenge to healthcare practitioners due to the emergence of resistance to numerous conventional antibacterial drugs. Therefore, new bacterial targets and new antimicrobials are unmet medical needs. Rhodanine derivatives have been shown to possess potent antimicrobial activity via a novel mechanism. However, their potential use as antibacterials has not been fully examined. In this study, we determined the spectrum of activity of seven rhodanine derivatives (compounds Rh 1-7) against clinical isolates of Gram-positive and Gram-negative bacterial strains and Candida albicans. We also synthesized and tested three additional compounds, ethyl ester and amide of rhodanine 2 (Rh 8 and Rh 10, respectively) and ethyl ester of rhodanine 3 (Rh 9) to determine the significance of the carboxyl group modification towards antibacterial activity and human serum albumin binding. A broth microdilution assay confirmed Rh 1-7 exhibit bactericidal activity against Gram-positive pathogens. Rh 2 had significant activity against various vancomycin-resistant (MIC90 = 4 μM) and methicillin-resistant (MIC90 = 4 μM) Staphylococcus aureus (VRSA and MRSA), Staphylococcus epidermidis (MIC = 4 μM) and vancomycin-resistant Enterococcus (VRE) strains (MIC90 = 8 μM). The rhodanine compounds exhibited potent activity against Bacillus spp., including Bacillus anthracis, with MIC range of 2-8 μM. In addition, they had potent activity against Clostridium difficile. The most potent compound, Rh 2, at 4 and 8 times its MIC, significantly decreased S. epidermidis biofilm mass by more than 35% and 45%, respectively. None of the rhodanine compounds showed antimicrobial activity (MIC > 128 μM) against various 1) Gram-negative pathogens (Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and Salmonella Typhimurium) or 2) strains of Candida albicans (MIC > 64 μM). The MTS assay confirmed that rhodanines were not toxic to mouse murine macrophage (J774.1A) up to 64 μM, human keratinocytes (HaCat) up to 32 μM, and human ileocecal colorectal cell (HRT-18) up to 128 μM. Overall, these data suggest that certain rhodanine compounds may have potential use for the treatment of several multidrug-resistant Gram-positive bacterial infections.
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3,164,967,471,257,939,500 | Stomach pain is a common symptom of many conditions. If you want to find out what’s causing your stomach pain, and possibly how to treat it, you need to identify any other symptoms you may be.
Stomach cancer remains the second most frequent cause of cancer-related death worldwide, with particularly high frequencies in Japan, China, Korea, parts of Eastern Europe, and Latin America.
On January 12, 2007, a 28-year old Californian wife and mother of three children died from drinking too much water. Her body was found in her home shortly after she took part in a water-drinking contest that was sponsored by a local radio show.
Barrett’s esophagus is a complication of chronic gastroesophageal reflux disease (GERD). GERD is the reflux of acidic fluid from the stomach into the esophagus, and is classically associated with heartburn. Learn more about Barrett’s estophagus, including symptoms and causes.
Acid Reflux Baby Breastfeeding Diet May 16, 2017. In babies who have GERD, the sphincter muscle becomes weak or relaxes. If you breastfeed, burp your baby after nursing from each breast. Most babies experience some degree of uncomplicated reflux. then the condition is termed gastro
CYRAMZA® (ramucirumab), combined with other medications, is used for the treatment of patients with metastatic non-small cell lung cancer (NSCLC), advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and metastatic colorectal cancer (mCRC).
Symptoms by tumor location. The symptoms a person can have from a GI carcinoid tumor often depend on where it is growing. The appendix. People with tumors in their appendix often don’t have symptoms.
Continued Subtle Signs You’re Getting Too Much "I have not seen someone off the street who was taking a toxic level of vitamin A or D — those are very unusual," says David Katz, MD, director of.
Stomach cancer is most common in people over 75. Men, smokers, and people of Asian, South Africa or Belarusian descent are more likely to develop the condition.
Peptic ulcers are sores that develop in the lining of the stomach, lower esophagus, or small intestine. They’re usually formed as a result of inflammation caused by the bacteria H. pylori, as.
With the back-to-nature movement of the 1970’s came a whole slough of New Age health prescriptions. One of those was the blanket recommendation to drink 8 glasses of water a day.
Hydrochloric acid aids digestion, fights acid reflux, protects against leaky gut and candida, supports skin health, and helps with nutrient absorption.
Vitamin A – Retinol, Retinal, Retinoic Acid, Provitamin A – Carotenoids. Our bodies require vitamin A for night vision and color vision, but that’s not all.
What is boric acid? What are some products that contain boric acid? How does boric acid work? How might I be exposed to boric acid? What are some signs and symptoms from a brief exposure to boric acid?
The Body Has Limits. The body has limits for how much it can compensate for acid imbalance. Therefore, food intake plays a critical role in maintaining the acid-alkaline balance.
Heartburn occurs when your stomach acid flows back up into your food pipe, causing a burning feeling in your chest. "Hot peppers, spicy curry, and other spicy foods trigger a reflux of gastric.
Acid Reflux: Treatment, Symptoms, Causes, Diet. – Acid reflux is a condition in which acid backs up from the stomach into the esophagus and even up to the throat, irritating their lining tissues.
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Archive for the ‘Wheat Makes you Fat-3 hidden ways-Mark Hyman M.D.’ Category
Wheat Makes you Fat-3 hidden ways-Mark Hyman, M.D.
February 15, 2012
Posted by Kevin G. Parker,D.C. from Mark Hyman, M.D.
Key points from me from article:
1. global chronic lifestyle and dietary driven disease kills more than twice as many people as infectious disease. These non-communicable chronic diseases will cost our global economy $47 trillion over the next 20 years.
2. FrankenWheat (is not the wheat of the Bible) – a scientifically engineered food product developed in the last 50 years. (1. It contains a Super Starch – amylopectin A that is super fattening. 2.It contains a form of Super Gluten that is super-inflammatory. 3.It contains forms of a Super Drug that is super-addictive and makes you crave and eat more.)
3. Two slices of whole wheat bread now raise your blood sugar more than two tablespoons of table sugar.
4. Sadly, this tsunami of chronic illness is increasingly caused by eating our beloved diet staple, bread, the staff of life, and all the wheat products hidden in everything from soups to vodka to lipstick to envelope adhesive.
5. Each American now consumes about 55 pounds of wheat flour every year.
6. Bottom line: wheat is an addictive appetite stimulant.
Okay…on with the article….
Three Hidden Ways Wheat Makes You Fat
Gluten free is hot these days.
There are books and websites, restaurants with gluten free menus, and grocery stores with hundreds of new gluten free food products on the shelf. Is this a fad, or a reflection of response to a real problem?
Yes, gluten is a real problem.
But the problem is not just gluten.
In fact, there are three major hidden reasons that wheat products, not just gluten (along with sugar in all its forms) is the major contributor to obesity, diabetes, heart disease, cancer, dementia, depression and so many other modern ills.
This is why there are now 30% more obese than undernourished in the world, and why globally chronic lifestyle and dietary driven disease kills more than twice as many people as infectious disease. These non-communicable chronic diseases will cost our global economy $47 trillion over the next 20 years.
The biggest problem is wheat, the major source of gluten in our diet. But wheat weaves it misery through many mechanisms, not just the gluten! The history of wheat parallels the history of chronic disease and obesity across the world. Supermarkets today contain walls of wheat and corn disguised in literally hundreds of thousands of different food- like products, or FrankenFoods. Each American now consumes about 55 pounds of wheat flour every year.
It is not just the amount but also the hidden components of wheat that drive weight gain and disease. This is not the wheat your great-grandmother used to bake her bread. It is FrankenWheat – a scientifically engineered food product developed in the last 50 years.
How Wheat (and Gluten) Triggers Weight Gain, Prediabetes, Diabetes and More
This new modern wheat may look like wheat, but it is different in three important ways that all drive obesity, diabetes, heart disease, cancer, dementia and more.
It contains a Super Starch – amylopectin A that is super fattening.
It contains a form of Super Gluten that is super-inflammatory.
It contains forms of a Super Drug that is super-addictive and makes you crave and eat more.
The Super Starch
The Bible says, “Give us this day our daily bread”. Eating bread is nearly a religious commandment. But the Einkorn, heirloom, Biblical wheat of our ancestors is something modern humans never eat.
Instead, we eat dwarf wheat, the product of genetic manipulation and hybridization that created short, stubby, hardy, high yielding wheat plants with much higher amounts of starch and gluten and many more chromosomes coding for all sorts of new odd proteins. The man who engineered this modern wheat won the Nobel Prize – it promised to feed millions of starving around the world. Well, it has, and it has made them fat and sick.
The first major difference of this dwarf wheat is that it contains very high levels of a super starch called amylopectin A. This is how we get big fluffy Wonder Bread and Cinnabons.
Here’s the downside. Two slices of whole wheat bread now raise your blood sugar more than two tablespoons of table sugar.
There is no difference between whole wheat and white flour here. The biggest scam perpetrated on the unsuspecting public is the inclusion of “whole grains” in many processed foods full of sugar and wheat giving the food a virtuous glow. The best way to avoid foods that are bad for you is to stay away from foods with health claims on the label. They are usually hiding something bad.
In people with diabetes, both white and whole grain bread raises blood sugar levels 70 to 120 mg/dl over starting levels. We know that foods with a high glycemic index make people store belly fat, trigger hidden fires of inflammation in the body, and give you a fatty liver leading the whole cascade of obesity, pre-diabetes and diabetes. This problem now affects every other American and is the major driver of nearly all chronic disease and most our health care costs. Diabetes now sucks up one in three Medicare dollars.
The Super Gluten
Not only does this dwarf, FrankenWheat, contain the super starch, but it also contains super gluten which is much more likely to create inflammation in the body. And in addition to a host of inflammatory and chronic diseases caused by gluten, it causes obesity and diabetes.
Gluten is that sticky protein in wheat that holds bread together and makes it rise. The old fourteen chromosome containing Einkorn wheat codes for the small number of gluten proteins and those that it does produce are the least likely to trigger celiac disease and inflammation. The new dwarf wheat contains twenty-eight or twice as many chromosomes and produces a large variety of gluten proteins, including the ones most likely to cause celiac disease.
Five Ways Gluten Makes You Sick and Fat
Gluten can trigger inflammation, obesity and chronic disease in five major ways.
Full-blown celiac disease is an autoimmune disease that triggers body-wide inflammation triggering insulin resistance, which causes weight gain and diabetes, as well as over 55 conditions including autoimmune diseases, irritable bowel, reflux, cancer, depression, osteoporosis and more.
Low-level inflammation reactions to gluten trigger the same problems even if you don’t have full-blown celiac disease but just have elevated antibodies (7% of the population or 21 million Americans).
There is also striking new research showing that adverse immune reactions to gluten may result from problems in very different parts of the immune system than those implicated in celiac disease. Most doctors dismiss gluten sensitivity if you don’t have a diagnosis of celiac disease, but this new research proves them wrong. Celiac disease results when the body creates antibodies against the wheat (adaptive immunity), but another kind of gluten sensitivity results from a generalized activated immune system (innate immunity). This means that people can be gluten-sensitive without having celiac disease or gluten antibodies and still have inflammation and many other symptoms.
A NON-gluten glycoprotein or lectin (combination of sugar and protein) in wheat called wheat germ agglutinin (WGA)(1) found in highest concentrations in whole wheat increases whole body inflammation as well. This is not an autoimmune reaction but can be just as dangerous and cause heart attacks (2).
Eating too much gluten free food (what I call gluten free junk food) like gluten free cookies, cakes and processed food. Processed food has a high glycemic load. Just because it is gluten free, doesn’t mean it is healthy. Gluten free cakes and cookies are still cakes and cookies! Vegetables, fruits, beans, nuts and seeds and lean animal protein are all gluten free – stick with those.
Let’s look at this a little more closely. Gluten, a protein found in wheat, barley, rye, spelt and oats) can cause celiac disease, which triggers severe inflammation throughout the body and has been linked to autoimmune diseases, mood disorders, autism, schizophrenia, dementia, digestive disorders, nutritional deficiencies, diabetes, cancer, and more.
Celiac Disease: The First Problem
Celiac disease and gluten related problems has been increasing and now affects at least 21 million Americans and perhaps many millions more. And 99% of people who have problems with gluten or wheat are NOT currently diagnosed.
Ninety eight percent of people with celiac have a genetic predisposition known as HLA DQ2 or DQ8, which occurs in 30% of the population. But even though our genes haven’t changed, we have seen a dramatic increase in celiac disease in the last 50 years because of some environmental trigger.
In a recent study comparing blood samples taken 50 years ago from 10,000 young Air Force recruits to samples taken recently from 10,000 people, researchers found something quite remarkable. There has been a real 400 percent increase in celiac disease over the last 50 years (3). And that’s just the full-blown disease affecting about 1 in 100 people, or about 3 million Americans. We used to think that this only was diagnosed in children with bloated bellies, weight loss and nutritional deficiencies. But now we know it can be triggered (based on a genetic susceptibility) at any age and without ANY digestive symptoms. The inflammation triggered by celiac disease can drive insulin resistance, weight gain and diabetes, just like any inflammatory trigger – and I have seen this over and over in my patients.
Gluten and Gut Inflammation: The Second Problem
But there are two ways other than celiac disease in which wheat appears to be a problem.
The second way gluten causes inflammation is through a low-grade autoimmune reaction to gluten. Your immune system creates low-level antibodies to gluten but doesn’t create full blown celiac disease. In fact 7% of the population, 21 million, has these anti-gliadin antibodies. These antibodies were also found in 18% of people with autism and 20% of those with schizophrenia.
A major study in the Journal of the American Medical Association, hidden gluten sensitivity (elevated antibodies without full blown celiac disease) was shown to increase risk of death by 35 to 75 percent, mostly by causing heart disease and cancer.(4)
Just by this mechanism alone over 20 million Americans are at risk for heart attack, obesity, cancer and death.
How does eating gluten cause inflammation, heart disease, obesity, diabetes and cancer?
Most of the increased risk occurs when gluten triggers inflammation that spreads like a fire throughout your whole body. It damages the gut lining. Then all the bugs and partially digested food particles inside your intestine get across the gut barrier and are exposed your immune system, 60% of which lies right under the surface of the one cell thick layer of cells lining your gut or small intestine. If you spread out the lining of your gut it would equal the surface area of a tennis court. Your immune system starts attacking these foreign proteins leading to systemic inflammation that then causes heart disease, dementia, cancer, diabetes and more.
Dr. Alessio Fasano, a celiac expert from the University of Maryland School of Medicine discovered a protein made in the intestine called “zonulin” that is increased by exposure to gluten (5).
Zonulin breaks up the tight junctions or cement between the intestinal cells that normally protect your immune system from bugs and foreign proteins in food leaking across the intestinal barrier. If you have a “leaky gut” you will get inflammation throughout your whole body and a whole list of symptoms and diseases.
Why is there an increase in disease from gluten in the last 50 years?
It is because, as I described earlier, the dwarf wheat grown in this country has changed the quality and type of gluten proteins in wheat, creating much higher gluten content and many more of the gluten proteins that cause celiac disease and autoimmune antibodies.
Combine that with the damage our guts have suffered from our diet, environment, lifestyle, and medication use, and you have the perfect storm for gluten intolerance. This super gluten crosses our leaky guts and gets exposed to our immune system. Our immune system reacts as if gluten was something foreign and sets off the fires of inflammation in an attempt to eliminate it. However, this inflammation is not selective, so it begins to attack our cells—leading to diabesity and other inflammatory diseases.
Damage to the gastrointestinal tract from overuse of antibiotics, anti-inflammatory drugs like Advil or Aleve, and acid-blocking drugs like Prilosec or Nexium, combined with our low-fiber, high-sugar diet, leads to the development of celiac disease and gluten intolerance or sensitivity and the resultant inflammation. That is why elimination of gluten and food allergens or sensitivities can be a powerful way to prevent and reverse diabesity and so many other chronic diseases.
The Super Drug
Not only does wheat contain super starch and super gluten – making it super fattening and super inflammatory, but it also contains a super drug that makes you crazy, hungry and addicted.
When processed by your digestion, the proteins in wheat are converted into shorter proteins, “polypeptides”, called “exorphins”. They are like the endorphins you get from a runner’s high and bind to the opioid receptors in the brain, making you high, and addicted just like a heroin addict. These wheat polypeptides are absorbed into the bloodstream and get right across the blood brain barrier. They are called “gluteomorphins” after “gluten” and “morphine”.
These super drugs can cause multiple problems including schizophrenia and autism. But they also cause addictive eating behavior including cravings and bingeing. No one binges on broccoli, but they binge on cookies or cake. Even more alarming is the fact that you can block these food cravings and addictive eating behaviors and reduce calorie intake by giving the same drug we use in the emergency room to block heroin or morphine in an overdose called naloxone. Binge eaters ate nearly 30% less food when given this drug.
Bottom line: wheat is an addictive appetite stimulant.
How to Beat the Wheat, and Lose the Weight
First you should get tested to see if you have a more serious wheat or gluten problem.
If you meet any of these criteria then you should do a six-week 100% gluten free diet trial to see how you feel. If you have 3 out of 5 criteria, you should be gluten free for life.
You have symptoms of celiac (any digestive, allergic, autoimmune or inflammatory disease including diabesity).
You get better on a gluten free diet.
You have elevated antibodies to gluten (anti-gliadin, AGA, or tissue transglutaminase antibodies, TTG).
You have a positive small intestinal biopsy.
You have the genes that predispose you to gluten (HLA DQ2/8).
Second, for the rest of you who don’t have gluten antibodies or some variety of celiac, the super starch and the super drug, both of which make you fat and sick, can still affect you. So go cold turkey for six weeks. And keep a journal of how you feel.
The problems with wheat are real, scientifically validated and ever present. Getting off wheat may not only make you feel better and lose weight, it could save your life.
My personal hope is that together we can create a national conversation about a real, practical solution for the prevention, treatment, and reversal of our obesity, diabetes and chronic disease epidemic. Getting off wheat may just be an important step.
To learn more and to get a free sneak preview of The Blood Sugar Solution where I explain exactly how to avoid wheat and what to eat instead go to http://www.drhyman.com.
Please leave your thoughts by adding a comment below.
To your good health,
Mark Hyman, MD
Other good articles:
1. Wheat Belly-William Davis, M.D.-Cardiologist-NY Times Bestseller
2. Gluten-Top 12 Reasons Gluten Should Be ELIMINATED From Your Diet-Poliquin
3. Gluten: What You Don’t Know Might Kill You-Mark Hyman M.D.
References
———————————————————–
(1) Saja K, Chatterjee U, Chatterjee BP, Sudhakaran PR. Activation dependent expression of MMPs in peripheral blood mononuclear cells involves protein kinase A. Mol Cell Biochem. 2007 Feb;296(1-2):185-92
(2) Dalla Pellegrina C, Perbellini O, Scupoli MT, Tomelleri C, Zanetti C, Zoccatelli G, Fusi M, Peruffo A, Rizzi C, Chignola R. Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol. 2009 Jun 1;237(2):146-53.
(3) Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, Brantner TL, Kim WR, Phelps TK, Lahr BD, Zinsmeister AR, Melton LJ 3rd, Murray JA. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009 Jul;137(1):88-93
(4) Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F. Small-intestinal histopathology and mortality risk in celiac disease. JAMA. 2009 Sep 16;302(11):1171-8.
(5) Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol. 2008 Nov;173(5):1243-52.
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-2,313,468,218,959,347,000 | Symptoms and Treatments of Phobias
What are phobias?
Specific Phobias
Many people experience specific phobias, intense, irrational fears of certain things or situations-dogs, closed-in places, heights, escalators, tunnels, highway driving, water, flying, and injuries involving blood are a few of the more common ones. Phobias aren’t just extreme fear; they are irrational fear. You may be able to ski the world’s tallest mountains with ease but panic going above the 10th floor of an office building. Adults with phobias realize their fears are irrational, but often facing, or even thinking about facing, the feared object or situation brings on a panic attack or severe anxiety.
Specific phobias strike more than 1 in 10 people. No one knows just what causes them, though they seem to run in families and are a little more prevalent in women. Phobias usually first appear in adolescence or adulthood. They start suddenly and tend to be more persistent than childhood phobias; only about 20 percent of adult phobias vanish on their own. When children have specific phobias-for example, a fear of animals-those fears usually disappear over time, though they may continue into adulthood. No one knows why they hang on in some people and disappear in others.
If the object of the fear is easy to avoid, people with phobias may not feel the need to seek treatment. Sometimes, though, they may make important career or personal decisions to avoid a phobic situation.
When phobias interfere with a person’s life, treatment can help. Successful treatment usually involves a kind of cognitive-behavioral therapy called desensitization or exposure therapy, in which patients are gradually exposed to what frightens them until the fear begins to fade. Three-fourths of patients benefit significantly from this type of treatment. Relaxation and breathing exercises also help reduce anxiety symptoms.
There is currently no proven drug treatment for specific phobias, but sometimes certain medications may be prescribed to help reduce anxiety symptoms before someone faces a phobic situation.
Social Phobia
Social phobia is an intense fear of becoming humiliated in social situations, specifically of embarrassing yourself in front of other people. It often runs in families and may be accompanied by depression or alcoholism. Social phobia often begins around early adolescence or even younger.”
If you suffer from social phobia, you tend to think that other people are very competent in public and that you are not. Small mistakes you make may seem to you much more exaggerated than they really are. Blushing itself may seem painfully embarrassing, and you feel as though all eyes are focused on you. You may be afraid of being with people other than those closest to you. Or your fear may be more specific, such as feeling anxious about giving a speech, talking to a boss or other authority figure, or dating. The most common social phobia is a fear of public speaking. Sometimes social phobia involves a general fear of social situations such as parties. More rarely it may involve a fear of using a public restroom, eating out, talking on the phone, or writing in the presence of other people, such as when signing a check.
Although this disorder is often thought of as shyness, the two are not the same. Shy people can be very uneasy around others, but they don’t experience the extreme anxiety in anticipating a social situation, and they don’t necessarily avoid circumstances that make them feel self-conscious. In contrast, people with social phobia aren’t necessarily shy at all. They can be completely at ease with people most of the time, but particular situations, such as walking down an aisle in public or making a speech, can give them intense anxiety. Social phobia disrupts normal life, interfering with career or social relationships. For example, a worker can turn down a job promotion because he can’t give public presentations. The dread of a social event can begin weeks in advance, and symptoms can be quite debilitating.
People with social phobia are aware that their feelings are irrational. Still, they experience a great deal of dread before facing the feared situation, and they may go out of their way to avoid it. Even if they manage to confront what they fear, they usually feel very anxious beforehand and are intensely uncomfortable throughout. Afterwards, the unpleasant feelings may linger, as they worry about how they may have been judged or what others may have thought or observed about them.
About 80 percent of people who suffer from social phobia find relief from their symptoms when treated with cognitive-behavioral therapy or medications or a combination of the two. Therapy may involve learning to view social events differently; being exposed to a seemingly threatening social situation in such a way that it becomes easier to face; and learning anxiety-reducing techniques, social skills, and relaxation techniques.
The medications that have proven effective include selective serotonin reuptake inhibitors, MAO inhibitors and high-potency benzodiazepines. People with a specific form of social phobia called performance phobia have been helped by drugs called beta-blockers. For example, musicians or others with this anxiety may be prescribed a beta-blocker for use on the day of a performance.
Quick Facts
Phobias are persistent, irrational fears of certain objects or situations. Phobias occur in several forms; the fear associated with a phobia can focus on a particular object (specific phobia) or be a fear of embarrassment in a public setting (social phobia). People who have phobias are often so overwhelmed by their anxiety that they avoid the feared objects or situations. Specific phobias involve a fear of an object or situation, such as small animals, snakes, closed-in spaces, or flying in an airplane. Social phobia is the fear of being humiliated in a social setting, such as when meeting new people, giving a speech, or talking to the boss. Most people experience these fears with mild to moderate intensity, and the fear passes. For people with social phobia, however, the fear is extremely intrusive and can disrupt normal life, interfering with work or social relationships in varying degrees of severity.
Fortunately, through research supported by the National Institute of Mental Health (NIMH), effective treatments have been developed to help people with phobias.
How Common Are Phobias?
Approximately 4 to 5% of the U.S. population has one or more clinically significant phobias in a given year.
Specific phobias occur in people of all ages. The average age of onset for social phobia is between 15 and 20 years of age, although it can often begin in childhood.
What Causes Phobias?
Traumatic events often trigger the development of specific phobias, which are slightly more prevalent in women than men. Research shows that social phobia may have a hereditary component and occurs in women and men in equal proportions. However, men may seek treatment for social phobia more frequently than women.
What Treatments Are Available for Phobias?
Social phobia can be effectively treated with medications including, MAOIs, SSRIs, and high potency benzodiazepines. People with a specific form of social phobia called performance phobia have been helped by drugs called beta blockers. There is no proven drug treatment for specific phobias, but certain medications may help reduce symptoms of anxiety before one faces a phobic situation. A type of cognitive-behavioral therapy known as “exposure therapy” is also a very useful treatment for phobias. It involves helping patients become gradually more comfortable with situations that frighten them. Relaxation and breathing techniques are also helpful.
Can People with Phobias Also Have Other Physical and Emotional Illnesses?
People with phobias, particularly social phobia, may also have problems with substance abuse. Many people with social or a specific phobia become so anxious that they experience panic attacks, which are intense and unexpected bursts of terror accompanied by physical symptoms. As more situational panic attacks occur, people with phobias may take extreme measures to avoid situations where they fear another attack might happen or where help would not be immediately available. This avoidance, similar to that in many panic disorder patients, may eventually develop into agoraphobia, an inability to go beyond known and safe surroundings because of intense fear and anxiety. Appropriate diagnosis and treatment of other disorders are important to successful treatment of phobias.
Treatment
Many people with anxiety disorders can be helped with treatment. Therapy for anxiety disorders often involves medication or specific forms of psychotherapy.
Medications, although not cures, can be very effective at relieving anxiety symptoms. Today, thanks to research by scientists at NIMH and other research institutions, there are more medications available than ever before to treat anxiety disorders. So if one drug is not successful, there are usually others to try. In addition, new medications to treat anxiety symptoms are under development.
For most of the medications that are prescribed to treat anxiety disorders, the doctor usually starts the patient on a low dose and gradually increases it to the full dose. Every medication has side effects, but they usually become tolerated or diminish with time. If side effects become a problem, the doctor may advise the patient to stop taking the medication and to wait a week-or longer for certain drugs-before trying another one. When treatment is near an end, the doctor will taper the dosage gradually.
Research has also shown that behavioral therapy and cognitive-behavioral therapy can be effective for treating several of the anxiety disorders.
Behavioral therapy focuses on changing specific actions and uses several techniques to decreases or stop unwanted behavior. For example, one technique trains patients in diaphragmatic breathing, a special breathing exercise involving slow, deep breaths to reduce anxiety. This is necessary because people who are anxious often hyperventilate, taking rapid shallow breaths that can trigger rapid heartbeat, lightheadedness, and other symptoms. Another technique-exposure therapy-gradually exposes patients to what frightens them and helps them cope with their fears.
Like behavioral therapy, cognitive-behavioral therapy teaches patients to react differently to the situations and bodily sensations that trigger panic attacks and other anxiety symptoms. However, patients also learn to understand how their thinking patterns contribute to their symptoms and how to change their thoughts so that symptoms are less likely to occur. This awareness of thinking patterns is combined with exposure and other behavioral techniques to help people confront their feared situations. For example, someone who becomes lightheaded during a panic attack and fears he is going to die can be helped with the following approach used in cognitive-behavioral therapy. The therapist asks him to spin in a circle until he becomes dizzy. When he becomes alarmed and starts thinking, “I’m going to die,” he learns to replace that thought with a more appropriate one, such as “It’s just a little dizziness-I can handle it.”
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3,965,077,224,198,813,000 | Category:
What is the Bundle of His?
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• Written By: Heather Scoville
• Edited By: Susan Barwick
• Last Modified Date: 10 November 2017
• Copyright Protected:
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The bundle of His is the part of the heart's electrical system that controls the beating of the cardiac muscle. It is made up of myocardial cells that contract when an electrical impulse passes through them, and also contains pacemaker cells that produce those electrical impulses. This bundle is located in the interventricular septum that separates the left and right ventricles from each other.
Directly before the bundle of His in the electrophysiological pathway of the heart is the atrioventricular (AV) node. Together, they make up the area of the heart called the AV junction. The AV node contains only myocardial cells, no pacemaker cells. The bundle of His connects the AV node to the left and right bundle branches that control the contraction of the ventricles. The pacemaker cells within in the bundle can send electrical pulses at an accelerated rate of 40 to 60 beats per minute.
The electrical impulse in the heart originates in the sinoatrial (SA) node, located in the right atrium of the heart. After stimulating the atria, it travels into the AV node and continues through the bundle of His to the right and left bundle branches so that it can reach the ventricles. The contraction of the ventricles then pumps the blood away from the heart through arteries so that it can travel throughout the body.
The bundle of His was named for Wilhelm His, a cardiologist from Switzerland, who discovered the bundle in 1893. His was also the first to study the idea of bundle branch blocks which can cause the natural pacemaker in the heart to stop functioning correctly due to a blockage in the electrophysiological pathway. These blocks can be caused by cholesterol buildup or congenital heart defects.
Bundle branch block is diagnosed when tests show the blockage on an electrocardiogram (EKG). Most often, bundle branch blocks are treated, if they are found along with other heart problems, by inserting an artificial pacemaker that can control the electrical impulses necessary for the heart to contract at a normal pace. The pacemaker wires are inserted directly into the ventricles where they can stimulate the right and left bundle branches to contract at the same time.
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6,909,668,007,967,821,000 | Notre Dame Integrated Imaging Facility
Anesthetic procedures
The mice will be anesthetized using isoflurane inhalation for 2-5 minutes in a covered glass bell jar or vaporizer-controlled tank. The waste isoflurane will be trapped with a commercial filter and the amount trapped will be monitored by the increase in weight. Mouse breathing will be checked once every minute by visual inspection. The anesthetic dose will be lowered for animals that are observed to be struggling for a normal breathing pattern. The anesthetic dose will be raised for animals that retract their feet after a firm toe pinch. | {
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5,586,527,128,454,286,000 | Survival
Figure 2: Survival curves of WT and TRPV4-/- (KO) mice up to 7 days post-MI. Twenty wild-type and seventeen TRPV4-/- mice were subjected to permanent left anterior descending (LAD) coronary artery ligation to induce myocardial infarction at day 0. The survival time course was analysed using the log-rank (Mantel-Cox) test. | {
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3,293,222,462,950,983,000 | Skip to main content
Advertisement
Table 1 Blood smears classification criteria (Adapted from Kiggundu et al.[15])
From: Impact of a training course on the quality of malaria diagnosis by microscopy in Angola
Classification Criteria
Thick blood smear Thin blood smear
Bad - Smear too big (diameter greater than 1 cm) or too small (diameter less than 0.5 cm); - Smear too big (more than half of the slide) or too small (smaller than 0.5 cm);
- Smear very close from the edge of the slide (less than 1 cm) which enables the use of immersion oil; - Smear spread unevenly with patchy distribution, streaky and with many tails (greasy slides or edge of the spreader slide chipped);
- Very thick smear (fine print cannot be read through it); - Very thick smear that fine print cannot be read through it or too thin with few red blood cells;
- Poorly stained (red blood cells are not lysed and parasites have a green, red, or blue colour). - Many red blood cells lysed and lightly stained cells (red and white blood cells) and parasites.
Satisfactory Smear well-made regarding size and location but moderately stained (red blood cells are partially lysed and parasites are lightly stained). Smear well-made regarding size and location but moderately stained (red blood cells are partially lysed and parasites are lightly stained).
Good - Smear round in shape with a diameter of approximately 1 cm; - Smear with the right dimension (half of the slide leaving space for thick blood);
- Smear at least 1 cm away from the edge of the slide; - Smear spread evenly (without patchy or streaky distribution);
- Smear density that fine print can be read through it; - Smear density that fine print can just be read through it;
- Smear with all of the red blood cells lysed, and the malaria parasites are well-exposed with a bluish pink coloration. - Smear with intact red blood cells and pink coloration, intact white blood cells properly stained, and malaria parasites are well-exposed with a bluish pink coloration. | {
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-7,627,386,199,085,782,000 | 1. Supraventricular arrhythmias, diagnosis and therapy
Definition
Supraventricular arrhythmias are those which originate from the SA node, atria, or AV junction. They include the following:
• Sinus arrhythmias
• Sinus bradycardia
• Sinus tachycardia
• Sick sinus syndrome
• Supraventricular premature beats
• Atrial tachycardia
• Atrial fibrillation
• Atrial flutter
• AV nodal reentry tachycardia (AVNRT)
• AV reciprocating tachycardia (AVRT)
Atrial fibrillation
Definition
Atrial fibrillation (Afib) is the most important supraventricular arrhythmia. The characteristic ECG findings of atrial fibrillation is the lack of normal P-waves in all leads, and irregularly irregular ventricular rate. The ventricular rate is often high. We can distinguish three types of Afib:
• Paroxysmal Afib – Afib that terminates spontaneously within 48 hours
• Persistent Afib – Afib which lasts more than seven days or requires electrical cardioversion to restore sinus rhythm
• Permanent Afib – Afib where a decision has been made to no longer try to achieve sinus rhythm, either because cardioversion or drugs have failed, or because a rhythm-control strategy is used instead
Afib usually progresses from paroxysmal to persistent to permanent with time.
Afib is problematic because of the following:
• It increases the risk for stroke
• It can cause tachycardia-induced heart failure (= arrhythmia-induced cardiomyopathy)
• It can cause symptoms
Etiology
Afib can be multifactorial and idiopathic, but in some cases it’s caused by treatable etiologies:
• Hyperthyroidism
• Hypovolaemia
• Hypervolaemia
• Intoxication
• Heart failure
• Respiratory failure
Clinical features
Most patients are asymptomatic, and Afib is discovered incidentally. Patients may also present with palpitations, syncope, dyspnoea, or symptoms of heart failure.
Treatment
ESC uses an ABC pathway for the management of Afib:
• Anticoagulation/avoid stroke
• Better symptom control
• Comorbidity management/cardiovascular risk factor reduction
In some cases, Afib is caused by a reversible etiology and does not return when the etiology is managed.
Anticoagulation
Stroke risk is increased in patients with atrial fibrillation, due to the Afib’s tendency to form thrombi in the atria which can embolise to the brain. All patients with Afib should have the CHA2DS2-VASc score calculated.
A score of 1 or more in men and 2 or more in women is an indication for anticoagulation. A score of 0 in males, or 1 or 0 in females has low risk for stroke and does not require anticoagulation. The bleeding risk (with the HAS-BLED score) should be calculated and considered, and risk factors for bleeding should be treated if possible. Anticoagulation should be with a DOAC, and it should be continued indefinitely.
Better symptom control
The symptoms of Afib can be controlled with either a rate-control strategy or a rhythm-control strategy. Choosing between them can be difficult. Generally, we use rhythm-control for patients who are young, have heart failure, have significant symptoms, have high cardiovascular risk, or if rate-control has failed. Rate-control is generally used for older or asymptomatic patients.
Rate control involves not doing anything to convert the rhythm to sinus rhythm, but to use drugs to reduce the ventricular rate. This improves symptoms and prevents development of heart failure. The first choice is a beta blocker, often metoprolol. Second choices include verapamil, amiodarone, or digoxin.
Rhythm control involves measures to convert the rhythm to sinus rhythm, and to maintain it. It’s usually tried if adequate rate control can’t be achieved, or if the onset of the Afib is recent (< 2 days). It can be performed in cases when it’s known that the Afib has lasted < 2 days, or if it’s lasted longer but the patient has been properly anticoagulated for 3 – 4 weeks, or if a TEE has been performed and excluded the presence of cardiac thrombus (which could embolise during cardioversion).
Usually, electrical cardioversion is performed to convert the rhythm back to sinus. Patients must usually remain on antiarrhythmic drugs after conversion to prevent recurrence. In some cases, electrical cardioversion cannot be performed. However, antiarrhythmic drugs alone may convert the rhythm to sinus as well. Antiarrhythmic drugs most commonly used include flecainide and amiodarone. In some cases the ectopic focus can be ablated, preventing further recurrence.
Comorbidity management/cardiovascular risk factor reduction
Tachycardia-induced heart failure should be treated like other types of heart failure, with ACEi/ARB, beta blockers, diuretics, etc. Other cardiovascular risk factors, like hypertension, diabetes, atherosclerosis, etc., should be managed as well.
Atrial flutter
Atrial flutter is generally managed similarly as atrial fibrillation, and in many cases it progresses to Afib. It requires anticoagulation and either rate or rhythm control. There are two types:
• Typical atrial flutter
• Atypical atrial flutter
On the ECG, P-waves are replaced by F-waves which have a frequency of about 300/minute. There is a fixed pattern of atrial:ventricular conduction (P-waves:QRS-complexes), usually 2:1 or 4:1.
Typical atrial flutter can be treated effectively with ablation because it’s caused by a macro-reentry circuit along the tricuspid anulus, which can be ablated.
AVNRT
AV nodal reentry tachycardia (AVNRT) is caused by the presence of an additional electrical pathway in the AV node, which forms a reentry circuit in the AV node. On the ECG there are fast, narrow, regular QRS complexes without normal P-waves. In some leads, small P-waves may be visible at the end of the QRS complex (retrograde P).
AVNRT can often be terminated by vagal manoeuvres or adenosine. Some patients can be managed by only performing vagal manoeuvres when they feel the AVNRT. Others require antiarrhythmic treatment with beta blockers, verapamil, or flecainide.
AVRT
AV reciprocating tachycardia (AVRT) occurs in patients with an accessory pathway which circumvents the AV node, which causes pre-excitation of the ventricles. This occurs most commonly in patients with Wolff-Parkinson-White syndrome. It is triggered by a premature atrial or ventricular beat. Treatment involves ablation of the accessory pathway.
In patients with WPW (but not currently in AVRT), pre-excitation is visible as delta-waves, and the PQ-interval is decreased.
Other supraventricular arrhythmias
Sinus arrhythmias
Sinus bradycardia is a sinus rhythm with < 60 bpm. It’s physiological in well-trained persons but can be pathological in some cases.
Sick sinus syndrome (SSS) or sinus node dysfunction refers to the condition where the SA node is dysfunctional. This causes intermittent sinus bradycardia, sinus pauses, sinus arrest, or SA block, and is typically due to old age. Patients present with intermittent complaints of fatigue, dizziness, palpitations, syncope, etc. Patients often require implantation of a pacemaker.
Atrial tachycardia
Atrial tachycardia may be focal (originate from one focus in the atria) or multifocal (originate from multiple foci). The typical symptom is palpitations. In the focal type all P-waves have the same morphology, while in the multifocal type there are multiple P-wave morphologies.
Atrial tachycardia is associated with heart surgery, like CABG. Multifocal atrial tachycardia is associated with COPD.
Supraventricular premature beats
Supraventricular premature beats, also called supraventricular extrasystoles (SVES), are atrial contractions triggered by ectopic foci in the atria or AV node. They include atrial premature beats and junctional premature beats. Supraventricular premature beats rarely cause symptoms and therefore rarely require treatment.
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-5,309,740,093,978,575,000 | 1 what are two parts of a physical fitness program?
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Daisy Mosciski asked a question: 1 what are two parts of a physical fitness program?
Asked By: Daisy Mosciski
Date created: Sat, Apr 24, 2021 4:52 AM
Date updated: Sun, May 22, 2022 7:15 PM
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Video answer: Different main types of exercises - cardio, strength training, flexibility, balance and coordination
Different main types of exercises - cardio, strength training, flexibility, balance and coordination
Top best answers to the question «1 what are two parts of a physical fitness program»
A: The five components of physical fitness are cardiovascular endurance, muscular strength, muscular endurance, flexibility and body composition, according to Fit Day.
FAQ
Those who are looking for an answer to the question «1 what are two parts of a physical fitness program?» often ask the following questions:
💄 What are the two parts of physical fitness program?
Physical fitness has two components: general fitness (a state of health and well-being) and specific fitness (the ability to perform specific aspects of sports or occupations).
💄 What is physical fitness program?
Physical fitness is a state of health and well-being and, more specifically, the ability to perform aspects of sports, occupations and daily activities. Physical fitness is generally achieved through proper nutrition, moderate-vigorous physical exercise, and sufficient rest.
💄 1. what are the two important parts of physical fitness program?
From the question, two important parts of physical fitness program are Physical-related and mental related.
Video answer: Action words, part 1 (classroom physical activity breaks)
Action words, part 1 (classroom physical activity breaks)
9 other answers
A physical fitness program is a systematic approach to attain physical development, health, and fitness. A sound physical fitness program is key to optimum functioning in daily living. It involves...
1. What are the two important parts of a physical fitness program? (1 point) ° (1 pt) Skill-related and health-related ° (0 pts) Physical-related and mental-related ° (0 pts) Heart-related and skeletal-related ° (0 pts) Cardio-related and strength-related ° 2. Cardiovascular efficiency, muscular strength and endurance, flexibility, and body composition are all considered_____ related factors.
A complete fitness and exercise program should incorporate three basic components: Endurance (Aerobic), Flexibility, and Strength. Each of these components has specific guidelines, which govern their effectiveness.
What are two important parts of physical fitness program? Skill-related and health-related factors Cardiovascular efficiency, muscular strength and endurance, flexibility, and body composition are all considered____ related factors
All good fitness programs must include cardiovascular exercise. Revving up your heart and breathing improves circulation and oxygen delivery to your muscles and tissue, which ultimately makes it...
The 11 Components of Physical Fitness include: Agility; Balance; Body Composition; Cardiovascular Endurance; Coordination; Flexibility; Muscular Endurance; Muscular Strength; Power; Reaction Time; Speed; All 11 components of fitness are present in everyone’s daily lives. You just may not realize it.
This is an excerpt from Fitness: Steps to Success by Nancy Naternicola. Components of Fitness. Each of the five areas of physical fitness plays an important role in being fit, and one is not more important than another. Think about the components of a car: What's the use in having a nice-looking exterior if the motor is shot or the tires are flat?
The three components of physical fitness are strength, endurance and flexibility. Most exercise and fitness programs combine these three elements. It is important to incorporate these three elements in your exercise program to achieve a healthy and energetic lifestyle.
weight management. better coordination, agility and flexibility. improved balance and spatial awareness. increased energy levels. improved immunity. increased physical confidence. reduced risk of chronic disease (such as type 2 diabetes and heart disease) improved sleep. improved brain function and health.
Your Answer
We've handpicked 26 related questions for you, similar to «1 what are two parts of a physical fitness program?» so you can surely find the answer!
What does the command physical fitness program do?
• The command physical fitness program is the command’s action plan to maintain and/or improve the fitness and health of the entire crew. 2. Program Strategies Key program strategies enhance opportunities for physical activity, increase knowledge, increase availability/access to nutritious foods and decrease availability to foods with
Planks are parts of what physical fitness components or?
An example of muscular endurance would be doing planks for duration of one minute. Muscular strength allows for increased strength and ability to lift heavier weights, while muscular endurance improves posture and daily activities. What are the 5 components of fitness? There are five components of physical fitness you need to consider: Muscular ...
How to make a physical fitness program?
How to Develop a Physical Fitness Program
• Identify Your Goal (s) Before you can create a physical fitness program, determine your goals. That is, what do you hope to achieve through your commitment to exercise?
• Create a Routine. Once you've defined your goals, you're ready to design your physical fitness program
• Increase Difficulty Over Time…
• Track Progress…
What are the components of a physical fitness program?
• Components include cardio-respiratory endurance, muscle strength endurance, flexibility, and body composition. Skill-related physical fitness
What is the definition of a physical fitness program?
• What Is a Physical Fitness Program? Physical fitness is measurement of the performance of your lungs, heart and muscles both during exercise and while at rest. An exercise routine designed to increase or maintain your performance in these areas is commonly known as a physical fitness program.
Video answer: Fat burning cardio workout - 37 minute fitness blender cardio workout at home
Fat burning cardio workout - 37 minute fitness blender cardio workout at home How are the parts of physical fitness related?
• Physical fitness is made up of 11 parts - 6 of them health related and 5 skill related. All of the parts are important to good performance in physical activity, including sports.
How many parts are there in physical fitness?
Considering the total body, there are six elements of fitness: aerobic capacity, body structure, body composition, balance, muscular flexibility and strength.
Video answer: Train to grow | full body workout
Train to grow | full body workout What are the different components or parts of physical fitness?
A: The five components of physical fitness are cardiovascular endurance, muscular strength, muscular endurance, flexibility and body composition, according to Fit Day.
What are the five parts of skill related physical fitness?
Skill-related fitness is broken down into six different components; agility, speed, power, balance, coordination, reaction time. These skill-related components are movements that are necessary for an individual to successfully demonstrate a variety of motor skills and movement patterns.
What are the three man parts of any physical fitness?
A: The five components of physical fitness are cardiovascular endurance, muscular strength, muscular endurance, flexibility and body composition, according to Fit Day.
Video answer: Live: 2 for 1- lower body burn/arms back & abs(11/19/20)
Live: 2 for 1- lower body burn/arms back & abs(11/19/20) What is physical physical fitness?
Physical fitness is to the human body what fine tuning is to an engine. It enables us to perform up to our potential. Fitness can be described as a condition that helps us look, feel and do our best. ● Physical fitness involves the performance of the heart and lungs, and the muscles of the body.
How does the army physical fitness program work?
• Army Physical Fitness Program. It is a simple way to measure your physical strengths, abilities, and cardio-respiratory fitness. The intent of the APFT is to provide a baseline assessment regardless of your Military Occupational Specialty. The APFT is to be taken at least twice a calendar year and you must be able to meet...
In what decade did pepsico establish its physical fitness program?
In the 1970s, the Foundation began to support fitness research, and by the 1980s, the Foundation established a focus on preventive medicine, underwriting research in this field at major medical schools at Duke, Harvard and Stanford, as well as at the Mayo Clinic.
What are the components of a good physical fitness program?
• The five components of physical fitness are cardiovascular endurance, muscle strength, muscle endurance, flexibility and body composition. Schools and gyms use the components to measure the level of a person's fitness. Cardiovascular endurance is associated with the way the heart and lungs work together to provide the body with oxygen.
What items are included in a sound physical fitness program?
5 Components of a Sound Fitness Program. December 26, 2017. January 5, 2017 by BAC Staff. 1. Mobility. – Tissue: Fascial Tissue that is able to move freely. – Joints: Bones able to articulate freely through the Range of Motion. Achieved through Foam Rolling, Massage Stick, Therapy Ball, or Massage Therapist. 2.
How do mini goals help a physical fitness program?
The entire piece of equipment is easy to assemble, and when not in use it can be folded into a compact unit that is easy to store. A group of fitness experts have tested the equipment and have provided rave reviews. Company executives believe that this product, called.
Why is fitness important in a physical education program?
• High quality physical education programs have demonstrated a direct impact on student knowledge, fitness and attitudes when appropriate pedagogies are utilised (Cale and Harris, 2005, 2006). The development of fitness knowledge, competence and confidence is of utmost importance and is an important objective of any HPE program.
Physical fitness is made up of how many different parts?
A: The five components of physical fitness are cardiovascular endurance, muscular strength, muscular endurance, flexibility and body composition, according to Fit Day.
Video answer: Live: total body conditioning / full body workout / 1 hour (1/7/21)
Live: total body conditioning / full body workout / 1 hour (1/7/21) What is physical fitness and components of physical fitness?
A: The five components of physical fitness are cardiovascular endurance, muscular strength, muscular endurance, flexibility and body composition, according to Fit Day.
What defines physical fitness?
Physical fitness involves the performance of the heart and lungs, and the muscles of the body. And, since what we do with our bodies also affects what we can do with our minds, fitness influences to some degree qualities such as mental alertness and emotional stability.
What is physical fitness?
Mental health Physical activity has been linked to the alleviation of depression and anxiety symptoms. In patients suffering from schizophrenia, physical fitness has been shown to improve their quality of life and decrease... Being fit can improve one's self-esteem. Working out can improve one's ...
What means physical fitness?
Physical fitness is a state of health and well-being and, more specifically, the ability to perform aspects of sports, occupations and daily activities. Physical fitness is generally achieved through proper nutrition, moderate-vigorous physical exercise, and sufficient rest.
Video answer: Affiliate roundup, part 11: “programming for gpp”
Affiliate roundup, part 11: “programming for gpp” | {
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-2,577,002,196,295,424,000 | Fludarabine Compared with CVP Chemotherapy in Newly diagnosed Patients with Stages III and IV Low Grade Malignant Non-Hodgkin?s Lymphoma. Final Analysis of a Prospective Randomized Phase III Intergroup Study in 381 Patients
Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 13 de diciembre de 2001
Presenter: A. Hagenbeek
Presenter's Affiliation:
Type of Session: Scientific
Background
In 1993, the EORTC lymphoma group initiated a prospective randomized trial in newly diagnosed, low grade non-Hodgkin?s lymphoma (NHL) patients to investigate the efficacy and toxicity of Fludarabine compared to the conventional regimen of cyclophosphamide, vincristine and prednisone (CVP). This report is the final analysis of that trial.
Materials and Methods
381 patients from 60 centers in 9 countries with Grade III or IV low-grade NHL were enrolled on this trial.
Eligible histologies were NHL Working Formulation class A (CLL excluded), B or C.
Patients were either started on treatment immediately after diagnosis (n=248), or observed until either the development of B symptoms, progression over a 3 month period, or the involvement of a critical organ (n=133).
At the start of treatment, patients were randomized to either 8 cycles of Fludarabine or 8 cycles of CVP.
Staging with CT scans and bone marrow biopsy was performed at the time of study entry and after completion of the last cycle of chemotherapy.
Primary endpoints of this study were rate of response to treatment, duration of response, and toxicities.
Results
Central pathology review declared 78 patients (20%) ineligible for review.
In the Fludarabine group, overall response rate (ORR) was 75%, complete response (CR) rate was 39%, partial response (PR) 36%, stable disease (SD) 2%. Seventeen percent of patients in the CV group achieved a CR and 41% achieved a PR.
There was no difference in overall response rate between patients who were treated immediately and those who were observed until progression. In the immediate treatment group, ORR in was 76% in the Fludarabine group and 58% in the CVP group. In the observed group ORR was 74% for Fludarabine and 58% for CVP.
There was no significant difference in time to progression (TTP) or overall survival (OS) between the Fludarabine and CVP treatment groups; median TTP 21 months vs 15 months, 5 year OS 68% vs 60%. Median OS has not yet been reached in either group.
Granulocytopenia and thrompbocytopenia (Grade 2 or above) were significantly more common in the Fludarabine group; 28% vs 12 %, p < .001 and 8% vs 1%, p=.002 respectively. The frequency of severe infections was not significantly different between the two groups.
Only multivariate analysis, only elevated serum LDH was a significant adverse prognostic factor (p < .001) for TTP. For OS; age, elevated LDH, and evidence of liver involvement were significant as adverse prognostic factors.
Author's Conclusions
There was a significant increase in overall response and more CRs in the Fludarabine group with no difference in life-threatening toxicities between the two groups. There was no difference in TTP or OS.
The authors conclude that Fludarabine is a safe and effective therapy for low grade NHL that can contribute to new treatment modalities such as immunotherapy and stem cell transplant.
Clinical/Scientific Implications
This randomized Phase III study demonstrates the safety and efficacy of Fludarabine as first-line treatment for low-grade NHL. Fludarabine will likely be part of many first-line strategies, and should be studied further in combination with other modalities.
Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Amgen.
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9,128,799,113,175,451,000 | Definición de exsanguination en inglés:
exsanguination
Silabificación: ex·san·gui·na·tion
Pronunciación: /ekˌsaNGgwəˈnāSHən
/
sustantivo
Medicine
• 1The action of draining a person, animal, or organ of blood.
Más ejemplos en oraciones
• After measuring mechanics, animals were killed by exsanguination.
• Animals then were killed by further exsanguination through the abdominal aorta.
• After exsanguination, the lungs were fixed by intratracheal instillation with 10% neutral phosphate-buffered formalin at a pressure of 20 cm H2O for 72 hours.
• 1.1Severe loss of blood.
Más ejemplos en oraciones
• Disruption of vessels in the cord can lead to exsanguination of blood that, if confined to the cord, forms a hematoma.
• Fatalities are rare and usually a consequence of exsanguination at the scene or penetration of a vital organ.
• All three types of subadventitial aortic disruption are at high risk for exsanguination and should be managed with emergent surgery.
Derivativos
exsanguinate
Pronunciación: /ekˈsaNGgwəˌnāt/
verbo
Más ejemplos en oraciones
• They have never seen how white a woman's body is when she's exsanguinated by a post-partum hemorrhage.
• The dream had forced me to confront the fact that I had been at the hospital seeing a patient in consultation who was close to exsanguinating after an operation.
• Following arthroscopy, the extremity is elevated, exsanguinated, and the rest of the procedure carried out under tourniquet control.
Origen
early 20th century: from Latin exsanguinatus 'drained of blood' (from ex- 'out' + sanguis, sanguin- 'blood') + -ion.
Más definiciones de exsanguination
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Palabras cercanas
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autopsy bleed cesarean crash cart distress
Palabra del día astrogation
Pronunciación: ˌastrə(ʊ)ˈgeɪʃ(ə)n
noun
(in science fiction) navigation in outer space | {
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High levels of incidental physical activity are positively associated with cognition and EEG activity in aging
• Javier Sanchez-Lopez ,
Contributed equally to this work with: Javier Sanchez-Lopez, Juan Silva-Pereyra
Roles Conceptualization, Methodology, Project administration, Writing – original draft, Writing – review & editing
Affiliations Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
• Juan Silva-Pereyra ,
Contributed equally to this work with: Javier Sanchez-Lopez, Juan Silva-Pereyra
Roles Conceptualization, Formal analysis, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing
Affiliation Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, México
• Thalía Fernández ,
Roles Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing
thaliafh@yahoo.com.mx
Affiliation Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
• Graciela C. Alatorre-Cruz,
Roles Investigation, Project administration, Writing – original draft, Writing – review & editing
Affiliations Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, México
• Susana A. Castro-Chavira,
Roles Investigation, Writing – original draft, Writing – review & editing
Affiliations Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México, Institutt for psykologi, Det helsevitenskapelige fakultet, Universitetet i Tromsø –Norges arktiske universitet, Tromsø, Norway
• Mauricio González-López,
Roles Investigation, Writing – original draft, Writing – review & editing
Affiliation Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
• Sergio M. Sánchez-Moguel
Roles Investigation, Writing – review & editing
Affiliations Departamento de Neurobiología Conductual y Cognitiva, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México, Escuela Superior de Atotonilco de Tula, Universidad Autónoma del Estado deHidalgo, Hidalgo, México
High levels of incidental physical activity are positively associated with cognition and EEG activity in aging
• Javier Sanchez-Lopez,
• Juan Silva-Pereyra,
• Thalía Fernández,
• Graciela C. Alatorre-Cruz,
• Susana A. Castro-Chavira,
• Mauricio González-López,
• Sergio M. Sánchez-Moguel
PLOS
x
Abstract
High levels of physical activity seem to positively influence health and cognition across the lifespan. Several studies have found that aerobic exercise enhances cognition and likely prevents cognitive decline in the elderly. Nevertheless, the association of incidental physical activity (IPA) with health and cognition during aging has not been studied. Thus, the aim of this study was to evaluate the association of IPA level with cognitive functions and resting electroencephalogram (EEG) in healthy old participants. Participants (n = 97) with normal scores on psychometric and neuropsychological tests and normal values in blood analyses were included. A cluster analysis based on the scores of the Yale Physical Activity Scale (YPAS) allowed the formation of two groups: active, with high levels of IPA, and passive, with low levels of IPA. Eyes-closed resting EEG was recorded from the participants; the fast Fourier transform was used offline to calculate absolute power (AP), relative power (RP), and mean frequency (MF) measures. There were no differences in socioeconomic status, cognitive reserve, general cognitive status, or lipid and TSH profiles between the groups. The results of cognitive tests revealed significant differences in the performance variables of the WAIS scores (p = .015), with advantages for the active group. The resting EEG exhibited significantly slower activity involving the frontal, central, and temporal regions in the passive group (p < .05). Specifically, higher delta RP (F7, T3), lower delta MF (F4, C4, T4, T6, Fz, Cz), higher theta AP (C4), higher theta RP (F4, C4, T3, Fz), lower alpha AP (F3, F7, T3), lower alpha RP (F7), and lower total MF (F3, F7, T3, T5, Fz) were found. Altogether, these results suggest that IPA induces a neuroprotective effect, which is reflected both in behavioral and electrophysiological variables during aging.
Introduction
Aging is accompanied by a normal decline in important cognitive functions, such as processing speed, executive control, inhibition, working memory, and episodic memory [1]. These declines in the cognitive status of the elderly are associated with structural and functional modifications in the brain [2]. Different studies have found age-related changes in the resting electroencephalogram (EEG) and EEG during the performance of cognitive tasks [310]. According to Giaquinto & Nolfe [9], a slower resting EEG is characteristic of old age. This EEG slowing is evidenced by a decrease in frequency [3] and amplitude [4] of the occipital alpha rhythm, associated with a decrease in posterior alpha power; the appearance of dispersed theta waves, related to a diffuse increase in theta power [10]; and the occasional presence of delta waves, mainly in the temporal sites [10]. In contrast with the idea that these changes are the result of normal aging, some authors [3] have proposed that these changes may be a result of an ongoing subclinical pathological process. In fact, a large increase in the theta activity may predict cognitive impairment in the elderly [6]. A recent multimodal study in the elderly using both structural magnetic resonance imaging (MRI) and EEG found associations among the activity in the theta frequency band, cortical thickness, and performance in a visuospatial task [8]. Furthermore, these aforementioned EEG changes are exacerbated in patients with mild cognitive impairment and dementia [11]. Besides these results, some previous studies have also reported increased alpha activity in frontal areas [5], which might be related to compensatory mechanisms against cognitive decline [7].
Several studies have suggested that lifestyle significantly influences overall health, particularly cognition, during aging [12] in association with modifications in the recruitment of brain networks [13]. As a component of the lifestyle, physical activity seems to positively influence several body systems, such as the respiratory, circulatory and muscular systems [14], producing variations in hematological [15] and hormonal parameters [16] and improving cognitive function [1,17]. Furthermore, the increase in the level of physical activity, acting as a neuroprotective mechanism, may reduce declines in cognitive functions and offer protection against dementia during normal aging [18]. A study by Barnes and colleagues in old adults [19] reported that the level of aerobic fitness (i.e., the capacity of the cardiorespiratory system to use oxygen), which is positively related to the practice of aerobic physical activity, predicts performance on a cognitive task involving working memory, processing speed, attention, and general mental functioning up to six years later. In a meta-analysis, Colcombe and Kramer [20] reported similar results in seniors, where aerobic fitness was strongly associated with executive processes and performance in controlled, spatial, and speed tasks. Therefore, the processes that undergo age-related decline seem to be also enhanced by aerobic physical activity; for this reason, several interventions in the elderly are based on programs of physical activity aiming to provide physical and cognitive wellness among this population.
There are two main approaches to the study of the associations of physical activity with health and cognition: a) the effects of structured physical activity either acute or long-term [2022], which is the most common approach, and b) the association of incidental physical activity (IPA) with fitness quality [e.g., 18,22]. IPA, as opposed to structured physical activity, is the result of unstructured daily activities, such as working, housekeeping, transportation, leisure, etc. [1,12,23].
Our study, which pertains to the second approach, is focused on the association of IPA with cognition and brain electrical activity. Since IPA comprises daily activities, it involves an ecological environment that is easily accessed by everyone, including seniors who less frequently practice structured physical activity [24]. To our knowledge, there are no previous studies that relate IPA to EEG and cognition. Nevertheless, few electrophysiological studies have investigated the relationship between structured physical activity, cognition, and aging, and even fewer have examined the changes in resting EEG associated with physical activity in the elderly [2531]. Most of these studies included populations of old adults, although not all participants coursed with normal aging [e.g., 25,28]. In general, these studies considered structured physical activity, and the time of training ranged from 15 min to eight weeks. A common feature of most of the studies is an increase in alpha absolute power (AP) and/or alpha relative power (RP) of the resting EEG as a consequence of the training [25,27,28,31]. A delta decrease [27] and a theta [27,31] and beta [25,27] increase were also observed. The training effects were more evident in younger than in old adults [28] and occurred mainly in frontal channels.
Therefore, considering that a) age-related cognitive decline is identified by a decay in several cognitive processes, which are related to a lower-frequency EEG [e.g., 31]; b) that structured physical activity promotes positive effects on cognition, EEG [e.g., 26] and physiological measurements [14]; and c) that IPA and structured physical activity have similar physiological effects [32], the main purpose of this study was to evaluate the relationship of the IPA level with cognitive function and resting EEG; as a secondary objective, we proposed to investigate the association of IPA with anthropometrics and blood variables. We expected that if IPA and structured physical activity have similar neuroprotective mechanisms, IPA will also be positively associated with cognition and quantitative EEG (QEEG) (i.e., seniors with higher levels of IPA will exhibit lower delta and theta and higher alpha and beta activities).
Materials and methods
Participants
Through a nonprobability judgment sampling, 114 elderly individuals were invited to participate in the study. After an initial screening based on the inclusion/exclusion criteria (described below), this study involved 97 participants aged 60 years and older (mean age = 66.80 years old, SD = 4.30); there were 64 female and 33 male participants. The inclusion criteria considered participants, who at least completed middle school (mean of years of schooling = 15.65, SD = 4.09) and lacked cognitive impairments or clinical symptoms of cognitive deterioration. None of them had major socioeconomic disadvantages (The Mexican Association of Marketing Research and Public Opinion Agencies; AMAI 8 x 7 questionnaire) or evidence of depression as indirectly measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), which is a self-reported measure of satisfaction in seven daily-functioning domains: bodily health, subjective feelings, job, housekeeping, leisure activities, social relationships, and general satisfaction. Responses were scored on a 5-point scale, from “Never” to “All the time”, with higher scores implying more enjoyment and satisfaction [33]. The scores of participants in the Global Deterioration Scale (GDS) [34] did not show signs of cognitive decline. All participants had normal scores on the brief neuropsychological test battery in Spanish (Neuropsi) [35], a standardized test for the Mexican population with norms by age and educational level. This neuropsychological battery briefly assesses a wide spectrum of cognitive functions, including orientation, attention, memory, language, visuoperceptual abilities, and executive functions.
Participants with neurological or psychiatric disorders were excluded from this study. In addition, individuals with untreated anemia or metabolic, cardiac or thyroid diseases were not included.
The Ethical Committee of the Institute of Neurobiology at the National Autonomous University of Mexico approved this study. The main incentive for volunteers was that free access to their results of the clinical screening was provided. All volunteers signed informed consent forms. The entire study was conducted in the Psychophysiology Laboratory of the Institute of Neurobiology at the National Autonomous University of Mexico, in Juriquilla, Queretaro, Mexico.
Phase one: Participant classification according to physical activity level
Physical activity instrument.
To know the level of physical activity, all participants completed the Yale Physical Activity Survey (YPAS) in its Spanish version [36]. The YPAS assesses physical activity in adults aged 60 and older. This questionnaire has shown acceptable reliability (test-retest R from .19 to .66, p < .05) and validity (Spearman correlations with anthropometric and physiological measures from .20 to .29, p < .05) in old adults [36] and diverse patient populations across different cultures [e.g., 36,37,38]. The YPAS is divided into two parts. The first part asks the participants about the time spent on specific activities across different domains (i.e., housework, working, yard work, care-taking and leisure activities). Three values are obtained for each specific activity: time (minutes/week), energy expenditure in MET (Metabolic Equivalent of Task-MET-*time) and energy expenditure (MET*time*weight), measured in kilocalories; finally, a sum of the values for each domain and a total sum are calculated. The second part of the questionnaire asks about the frequency and time spent in vigorous activities, leisurely walking, standing, moving and sitting. The partial indices are calculated by multiplying the frequency score by the duration score for each specific activity and multiplying again by a weighting factor. The total index is obtained when partial indices are added.
Data analysis for group formation.
To perform further analysis on cognitive, physiological, and electroencephalographic variables, a hierarchical cluster analysis was applied to identify possible homogeneous subgroups of old adults according to the variables from the YPAS. The total kcal/week, vigorous activity index, and moving index were used for a cluster analysis, which was performed using the Ward method with a measure of squared Euclidean distance [39], since this distance is sensitive to the variable metrics, standardized Z scores were used. A visual inspection of the dendrogram revealed two independent clusters that were equal in size and with different characteristics (see Fig 1). Finally, the following two groups were obtained: Active Elderly: n = 48 (31 females) and Passive Elderly: n = 49 (33 females).
thumbnail
Fig 1. Dendrogram resulting from a hierarchical cluster analysis.
Two clusters were observed: one with high levels of IPA (cyan color) and other with low levels of IPA (magenta color). After to remove participants with extreme values in age into each cluster, two homogeneous groups were obtained (Active Elderly: n = 48 and Passive Elderly: n = 49) for the further analyses.
https://doi.org/10.1371/journal.pone.0191561.g001
Sociodemographic description and group comparisons for possible confounding variables.
To rule out the possible differences between groups not related to physical activity, the groups were compared considering the following variables: cognitive reserve, age, years of schooling, and gender.
Cognitive Reserve is an important factor to consider in studies where cognition and brain activity are implicated because better cognitive performances and changes in brain activity pattern when have been observed cognitive reserve proxy measures are high. In a similar approximation to assess cognitive reserve as reported previously [40], a questionnaire was applied to obtain information about the activities of daily living. The Cognitive Reserve questionnaire (CRq) includes items that assess a diverse variety of activities, such as reading, playing a musical instrument, collecting things, practicing other language or dialects, traveling, or taking part in sports. The CRq is organized into four categories: everyday activities (EA), leisure activities (LA), social environment (SE), and training information (TI). A two-way ANOVA was performed to analyze differences between the groups regarding the different CRq categories. Group (active versus passive) was included as a between-subjects factor, and CRq (EA, TI, LA, and SE) was included as a within-subjects factor. The results of the ANOVA did not showed significant main effect of group (F < 1), or a significant group by CRq interaction (F < 1). As shown in Table 1, no significant differences between the groups were observed in years of schooling, gender, and socioeconomic level; only differences in age were found. Posterior statistical analyses were conducted on variables standardized by age or by using ANCOVA including age as a covariate.
Phase two: Comparisons between active and passive groups with respect to physical activity, cognition, EEG, and hematological variables
Physical activity analyses.
Cluster analysis is an exploratory and descriptive method and not an inferential statistical tool. We forced the analysis to obtain two groups, but this does not mean that there was any significant difference between the groups across physical activity variables. So, once the two clusters were obtained, a mixed two-way ANCOVA was performed to assess differences between the groups in daily physical activity measured through energy expenditure in kilocalories and using age as a covariate. Group (actives and passives) was included as a between-subjects factor, and the YPAS domains (house work, work, yard work, care taking and leisure), as a within-subject factor. A mixed two-way ANCOVA was also performed to assess differences between the groups in frequency and time spent for every index of physical activity. Group was included as a between-subjects factor and physical activity indices (vigorous activity index, leisurely walking activity index, standing index, moving index and sitting index) as a within-subject factor. The Greenhouse- Geisser correction was applied to correct for violations of sphericity when there was more than one degree of freedom in the numerator. Tukey’s honest significant difference (HSD) post-hoc tests were completed after the ANCOVA.
Instruments for cognitive assessment.
The Wechsler Adult Intelligence Scale in Spanish (WAIS-III-R) [41] was administered to the participants. WAIS-III-R is designed to measure intelligence, understood as IQ (normal or superior scores above 90), in participants between 16 and 89 years of age of any race, intellectual, educational and reading level, and any socioeconomic and cultural background. The scale is standardized, and measures of reliability (R from .88 to .97) and criterion validity with respect to the WAIS-III-R (R from .86 to .94) were obtained in the Mexican population [41]. It is administered individually and consists of 14 subtests: vocabulary, similarities, information, digit span, arithmetic, letter-number sequencing, comprehension, symbol search, coding, picture completion, block design, matrix reasoning and picture arrangement. By grouping the different subtests into a full-scale IQ, 2 sub-indices, verbal and performance IQs, and 4 secondary index scores, verbal comprehension index (VCI), working memory index (WMI), perceptual organization index (POI) and processing speed index (PSI), are obtained.
A series of mixed two-way ANOVAs were performed to analyze the differences between groups regarding different cognitive measurements from the WAIS-III-R. Group (Active and Passive) was included in the ANOVA model as a between-subjects factor, and domains were assessed using the WAIS-III-R full-scale and verbal and performance IQs or WAIS secondary indices (VCI, WMI, POI, and PSI) as a within-subjects factor. Two more mixed, two-way ANOVAs were also performed considering group as a between-subjects factor and 1) verbal IQ subscales (vocabulary, similarities, information, comprehension, arithmetic, digit span, and letter-number sequencing) as a within-subjects factor and 2) performance IQ subscales (picture completion, block design, matrix reasoning, digit symbol-coding, symbol search, and picture arrangement) as a within-subjects factor. The effect sizes (η2p) were reported. The Greenhouse-Geisser correction was applied to correct for violations of sphericity when there was more than one degree of freedom in the numerator (ε is reported). Tukey’s Honestly Significant Difference (HSD) method was used for post-hoc pairwise comparisons in the repeated-measure analyses.
EEG.
Participants were seated in a comfortable chair in a dimly lit room. Digital resting EEG was recorded with eyes closed using a Medicid™ IV system (Neuronic Mexicana, S.A.; Mexico) and Track Walker TM v5.0 data system, for 30 min from the 19 channels of the 10–20 system (ElectroCap™, International Inc.; Eaton, Ohio) referenced to the linked earlobes (A1A2). The amplifier bandwidth was set between .50 and 50 Hz. All electrode impedances were at or below 10 kΩ, the sampling rate was 200 Hz, and the signal was amplified with a gain of 20,000. An expert electroencephalographer selected twenty-four artifact-free segments of 2.56 s by visual editing for quantitative analysis.
The QEEG analyses were performed off-line. The fast Fourier transform and cross-spectral matrices were calculated every .39 Hz; the following QEEG measures were calculated for each subject: 1) AP, 2) RP and 3) MF, within the delta (1.56–3.89 Hz), theta (3.90–7.50 Hz), alpha (7.51–12.50 Hz) and beta (12.51–19.15 Hz) frequency bands for each referential channel [6,11,4244]; in addition, total MF was computed. The geometric power [45] of each individual was subtracted from his/her cross-spectral matrix to obtain the AP value in each band for each electrode; this correction reduces 42% of the variance that is not associated with physiological factors.
This software has a normative database [46,47] by age, and EEGs in the database were recorded in the 19 channels of the 10–20 system using A1A2 as a reference. When norms by age are used, the effect of age is removed. To obtain normative measures, 24 segments of 2.56 s were considered for analysis and bandwidths equal to those mentioned above. Using this normative database [46], Z values were obtained with the formula: Z = [Xi - μ] / σ, where X is the raw value of the ith subject, and μ and σ are the mean value and the standard deviation, respectively, of the normal subjects of the same age as the ith subject. In all, a total of 247 QEEG Z values were calculated for each subject.
Because of the multivariate nature of the EEG data, a non-parametric, multivariate permutation test [48] was used to explore whether there were differences between active and passive groups. The global test was performed using the permutation distribution of the maximum of the t-Student statistics. The distribution estimated by permutation techniques for max t was used to set significance levels that controlled the experiment-wise error for the simultaneous univariate comparisons. Thus, one can simultaneously test EEG differences for all the electrodes and avoid the inflation of type I errors [48]. AP, RP and MF for each frequency band were independently compared between the groups; MF was also calculated for the total frequency range between 1.56 and 19.14 Hz. In each case, a global probability (that simultaneously includes all electrodes) and 19 marginal probabilities (one per electrode) were reported in the results.
Anthropometrics and blood analyses
Additionally, anthropometrics and blood analysis variables were compared between the groups by means of t-tests. Body mass index (BMI) was determined in each participant using BMI = Weight (kg) / Squared Height (m2). Blood samples were collected in the morning after an overnight fast from each subject. Blood biochemical analyses, including a lipid profile comprising total cholesterol, HDL, LDL, VLDL, and triglyceride and basal glucose levels, were determined for each patient. Hematic biometry and the level of thyroid-stimulating hormone (TSH) were also determined.
Results
Physical activity
We compared actives versus passives in terms of kcal/week of the YPAS variables using age as a covariate. The ANCOVA showed a significant main effect of the group (F(1, 94) = 4.90, p = .03, η2p = .05), which indicates a greater kcal/week expenditure in actives than in passives. Significant differences were observed in the interaction group by physical activity (kcal/week) (F(4, 376) = 3.15, p = .04, ε = .57, η2p = .03). The multiple-comparison, post-hoc analyses are displayed in Fig 2A. ANCOVA regarding physical activity indices showed a significant main effect of group (F(1, 94) = 109.40, p < .0001, η2p = .54), indicating greater scores for active people than passives. There was also a significant group by physical activity indices effect (F(4, 376) = 83.50, p < .0001, ε = .45, η2p = .47). Fig 2B shows the post-hoc analyses results, where actives had greater scores than passives in vigorous and moving activity.
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Fig 2. Post-hoc comparisons between the groups in the YPAS variables.
* p < .05, ** p < .01, *** p < .001.
https://doi.org/10.1371/journal.pone.0191561.g002
WAIS
The ANOVA results showed no significant main effect of group (active versus passive; F(1, 95) = 2.23, p = .13, η2p = .02), but an important significant group by IQ-subscale (verbal versus performance IQs) interaction (F(1, 95) = 8.98, p < .01, η2p = .09) was found. These results mean that actives had higher performance IQ scores than passives, which is shown in Fig 3A. In terms of the secondary indices (VCI, WMI, POI and PSI), the ANOVA results showed no significant main effect of group (F(1, 95) = 3.1, p = .08, η2p = .03), but a significant group by secondary-index interaction (F(3, 285) = 5.70, p < .01, η2p = .05 ε G-G = .66). Fig 3A also displays greater scores of actives than those of passives in PSI.
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Fig 3.
Comparisons between active (n = 48) and passive (n = 49) groups for the WAIS-III-R variables: a) Indices, IQ scales and total IQ; b) verbal WAIS subtests; and c) performance WAIS subtests; * p < .05; ** p < .01. IQ: Intelligence quotient; VCI: verbal comprehension index; WMI: working memory index; POI: perceptual organization index; PSI: processing speed index.
https://doi.org/10.1371/journal.pone.0191561.g003
Subtests belonging to the verbal IQ category were included as within-subject factors in one separate ANOVA (vocabulary, similarities, information, comprehension, arithmetic, digit span, and letter-number sequencing). The results showed no significant main effect of group (F < 1) nor group X verbal IQ subtests (F(6, 570) = 1.40, p = .24, η2p = .02, ε = .77), as is shown in Fig 3B. The ANOVA with the performance IQ subtests (picture completion, block design, matrix reasoning, digit symbol-coding, symbol search and picture arrangement) included as within-subject factors revealed a significant main effect of group (F(1, 95) = 6.20, p = .02, η2p = .06). Actives displayed larger scores than passives. There was a significant group by performance IQ subtests interaction (F(5, 475) = 3.53, p < .01, η2p = .04, ε = .88), where actives displayed larger scores on matrix reasoning (MD = 1.6, p = .02), digit symbol-coding (MD = 1.99, p < .01), and picture arrangement (MD = 1.7, p = .01), but not in picture completion (MD = -.16, p = .77), block design (MD = 1.05, p = .09) or symbol search (MD = .88, p = .07), as is shown in Fig 3C.
EEG
When the spectral EEG variables of the active group were compared with variables of the passive group, some differences were observed: a) less theta AP at C4 (p < .05) and more alpha AP at F3, F7 and T3 (p < .05); b) less delta RP (Global p = .04) at F7 and T3 (p < .05), less theta RP at F4, C4, T3 and Fz (p < .05), and more alpha RP at F7 (p < .05); and c) higher total and delta MF at F3, F7, T3, T5, Fz (p < .05) and at F4, C4, T4 T6 (p < .05), respectively. The results are shown in Table 2 and Fig 4.
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Fig 4.
Mean Z values of absolute power (A), relative power (B) and mean frequency (C) in the active (upper, n = 48) and passive (bottom, n = 49) groups. Note that all values are within normal limits; however, the passive group has a slower EEG activity, which corresponds to higher power values in the delta and theta bands and lower power values in the alpha band. Mean frequency of the delta band indicates faster delta activity in the active group.
https://doi.org/10.1371/journal.pone.0191561.g004
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Table 2. EEG spectral differences between the active and passive groups.
https://doi.org/10.1371/journal.pone.0191561.t002
Anthropometrics and blood analyses
Differences between the groups in mean corpuscular hemoglobin concentration (MCHC), with higher values in the Active group (Mean = 33.6±1.15) compared with the Passive group (Mean = 32.8±.8; t(90) = 2.1, p = .04, CI .26–1.46), were found. Also, higher mean corpuscular hemoglobin (MCH) values in the Active group (Mean = 31.05±1.5) in comparison with the Passive group (Mean = 30.3±1.9; t(90) = 3.6, p = .001, CI .34–1.2) were observed (see Table 3).
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Table 3. Group comparisons for anthropometrics and blood analyses.
https://doi.org/10.1371/journal.pone.0191561.t003
Discussion
In our study, comparisons on cognition, brain electrical activity, and blood variables between physically active and passive healthy seniors were conducted. Significant differences were observed for WAIS scores, where the active group obtained higher scores on the performance IQ, processing speed index, matrix reasoning, digit-symbol coding, and picture arrangement subtests. In addition, the active group showed less EEG delta and theta activity, and more alpha activity than the passive group, mainly in frontotemporal areas. Finally, higher values in the MCHC and MCH variables of the blood testing were observed in the active group. Our findings showing that higher levels of IPA are positively associated with cognition and brain electrical activity are similar to the findings of studies evaluating the influence of structured physical activity [25,27,29,4952]. It is known that the effects of physical activity on health and cognition depend upon the variation in type, frequency, duration, and intensity of physical activity [23]. Several studies have postulated that old adults can enhance their cognitive performance by practicing aerobic structured physical activity, showing improvements in executive control [52,53], inhibitory control [54], and general cognitive capacity [55]. The effects of structured physical activity on cognitive processes have also been observed in young adults, and these effects are larger when there is an increase of intensity, which generates improvement in attention, cognitive control [49], and processing speed [51]. The presence of similar mechanisms may explain the positive associations of IPA and aerobic structured physical activity with cognition and brain functions. In fact, improvements in perceptual organization subtests associated with higher levels of IPA could be a result of amelioration in visual sequencing that requires the retrieval of visual aspects from the tasks; therefore, visual information may be used for planning, sequencing, and organizing processes, which, in turn, improves task performance [56,57].
Functional changes in the prefrontal cortex have been observed when subjects regularly practice structured aerobic physical activity; these changes are interpreted as adaptations related to improvements in working memory, inhibition, and executive functions [50]. In our study, old adults with higher levels of IPA showed higher left frontotemporal alpha power and lower delta and theta power in the left frontotemporal and right frontocentral areas, respectively, than passive old participants. Additionally, the delta MF in the right frontal, central, and temporal regions and the total MF in the left frontotemporal areas were higher in the active group. These topographical differences are in agreement with previous studies investigating the relationship between structured physical activity and resting EEG [2631] and are related to the aforementioned cognitive processes [57,58]. The EEG pattern of the passive participants was more similar to the EEG pattern exhibited by individuals who developed cognitive decline seven years after this pattern presentation, according to Prichep et al. [6]; this suggests that IPA could be protective against cognitive deterioration.
To our knowledge, the association of IPA with EEG had not been previously explored despite its great importance, since IPA does not require an additional time expense or special resources like structured physical activity does; IPA is linked to a more active lifestyle in individuals independently of structured physical activity practice.
The physiological mechanisms mediating the relationship of IPA with cognition and EEG may be similar to the mechanisms proposed for aerobic structured physical activity. First, a higher level of aerobic physical activity has an important effect on cardiovascular health [59], which has been related to an increase in both, gray and white matter [60], accompanied by increases in brain activation during cognitive tasks in healthy elderly [20,60]. These cognitive improvements may result from enhanced blood flow following physical activity. Ross and McGuire [32] found that the duration and intensity of IPA were positively associated with the cardiorespiratory function; these results suggest physiological effects of IPA that are similar to the effects of the structured physical activity. Therefore, our results regarding the association of IPA with cognition and resting EEG may be partially explained by the mechanism mentioned above, which is supported by the hematological differences between the groups, i.e., the higher mean concentration of hemoglobin and mean corpuscular hemoglobin in the active group. Notice that no evidence of nutritional deficits across the participants was observed. However, on average, active persons tended to show clinically healthier cardiovascular risk profiles (i.e., lower blood glucose and lower total cholesterol and triglycerides) than passives but showed no significant differences. Clinical criteria are based on the normative ranges; therefore, using a strict clinical criterion, the mean values of LDL-Cholesterol, Total-Cholesterol, and Glucose in the passive group were above these limits; while in the active group, these mean values were within the normative limits.
A limitation of the present study could be the use of a self-reported survey to assess the level of IPA of the participants since it constitutes a subjective measurement. Another weakness is the use of a solely behavioral (psychometric) test to evaluate cognition; instead, psychophysiological tools, such as event-related potentials, should be utilized to conduct further studies. Considering the complexity of the physiology of physical activity, future research may be conducted to investigate other physiological mechanisms associated with the benefits of IPA, such as neurotrophic factors [61] or neuroprotective effects [62].
The relevance and novelty of this study rely on unraveling the importance of IPA without detracting the benefits that structured physical activity provide to health and cognition in old adults. Hence, the increase of incidental physical activity may be an alternative to structured physical activity when environmental, personal or motivational conditions hinder the practice of the latter.
Conclusion
This study presents, for the first time, an analysis of the association between incidental physical activity, cognitive performance, resting EEG, and anthropometric and blood variables in old adults. The obtained results show that incidental physical activity is associated with better scores on cognitive tasks, an increased EEG frequency, and better physiological status, which suggests that incidental physical activity may be protective against age-related deterioration.
Acknowledgments
The authors acknowledge Leonor Casanova, Teresa Álvarez and Bertha Esquivel for administrative support and Héctor Belmont for technical assistance.
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3,730,159,588,329,792,500 | Get How To Get The Biggest Discount On Betterhelp
practical|useful and brand-new} resources to improve yourself while challenging your psychological difficulties How To Get The Biggest Discount On Betterhelp
yes well it’s a big concern to begin with sure well let me simply just reassociate about that a bit I’ve been doing treatment for a long time of all the various schools of therapy I would say did one end of the continuum of those who believe that the nature of the relationship the intimacy of the relationship the the work on the process suggesting what’s happening between is there isn’t a is the most essential issue so I focus very much on taking a look at what’s going on in between the clients and me attempting to give very intimate so I would be the person who would probably be least thinking about a context therapy format and and I have been for several years I indicate one so my colleagues do telephone terapy for instance I understand an expert who transferred to California would capital for New york city analysis and would do her analysis of the phone I felt extremely crucial that you’re missing all these visual cues how can you do that but whatever changed for me a few years ago when I got a call an email from from a patient who I can’t even
mention the the place where she was but she was on another continent where it was absolutely ice-cold in the northern hemisphere and there wasn’t another therapist or MD within five or six hundred miles of her and asking whether I would just do some Skype work with her considering that there was no other option I I agreed to do that she couldn’t see anyone else and she needed treatment so I started working with her and I ended up having a great experience with her in fact she had moved to that location to escape everybody and there is no way that she would have been willing to consult with me in a space in person there was no other option in a sense and so it wound up it was surprisingly well I was really satisfied with that and since then I have actually had a genuine had a genuine modification of focus on that and among the important things that has actually been most intriguing to me about talks face is the truth that of a it’s just it’s counterproductive I would have thought the major problem with talk area is that they would not be focusing on the here and now what was taking place between therapist and patient and yet compared to a lot of the new movements in psychiatric therapy with cognitive behavioral therapy they’re even more involved in the nature at least the method it’s carried out in this clothing it’s they’re even more interested and nurturing of the here and now and with patient relationship so that’s.
that’s been a change of heart for me completely moved I was also shocked to see how much intimacy you can get back at by composing in some cases even some of the patients are more able to expose themselves that is a little bit confidential that that’s been very important finding for me also I have actually been working with Nicole Eames and monitoring rather routinely now in the last number of years which’s that is among the important things that I really found in my work with her as she spoke about her patient they expose things what has shocked me is several times I have actually heard her state the patients have actually stated that they reveal things to her they never ever exposed to their to their face-to-face therapist which’s quite exceptional among the important things is naturally the anonymity that that we don’t quite find however here they deal with face to face therapist for a year or more and never ever exposed certain of these things that were that were very disgraceful there’s another thing too which is that a patient can have an anxiety attack in the middle of the night and right away text the therapist. How To Get The Biggest Discount On Betterhelp
How To Get The Biggest Discount On Betterhelp – Get Some Help Today
Looking for How To Get The Biggest Discount On Betterhelp…
How much will BetterHelp treatment cost? How do the expenses compare to what you ‘d pay for competitors’ services or for standard, in-person therapy?
Just how much does BetterHelp expense monthly?
Costs compare positively both to in-person treatment and to matching services, especially when you think about the value of weekly live sessions included for every single customer (not simply readily available at a premium rate). Pricing info on the website is more opaque than we ‘d choose; normally, you would not understand your most likely expenses prior to finishing the survey unless you’ve read our review here. We’ll lay out the pertinent pricing information and factors below so that you can understand BetterHelp’s series of possible expenses and discount rate alternatives.
hi my name is hey take legal action against and today we’re gon na be talking about high functioning depression so for those of you that are actually knowledgeable about psychological health and a few of the conditions that we can find in the DSM you might know this as dysthymia so we’re gon na talk a bit more about indications that you could be trying to find whether you might be experiencing high operating anxiety or somebody that you understand and care about is going through this obstacle and struggle
so initially let’s consider anxiety in general when you think about somebody that’s depressed what comes to mind for me I’m thinking about somebody that has a hard time rising has a difficult time leaving their home perhaps they’ve disliked things they utilized to really delight in like pastimes or particular types of food restaurants things that they liked to do with their spare time maybe they’re not actually so proficient at maintaining relationships with their household their good friends maybe they’ve lost their task since they’ve lost inspiration and this will in this drive to live their life so on the flip side let’s think of individuals in your life that are really high-functioning you might have a co-worker for instance or have had a co-worker that appears to somehow manage to get up early every day before work to exercise keeps
Insurance protection likewise will not be an option. However, unless you have great insurance coverage with a low deductible, the cost of treatment will likely be a fantastic value to you compared to options.
Client care and personal privacy
Grade: 9
How does BetterHelp stack up? What measures does BetterHelp take to safeguard your sensitive info?
In a nutshell, BetterHelp is dedicated to personal privacy, security, and quality– and it shows. The customer service group replies promptly to problems you raise– appealing to respond within 24 hr however, in our experience, replying in far less time than that– and responses your concerns with the appropriate level of personalized care. And the company makes sure that its therapists stick to HIPAA guidelines and protect your privacy. You can even more secure your personal privacy using a label with your therapist. Since BetterHelp does not work with insurance or employers, there isn’t even a standard level of information-sharing between such entities, which indicates maximum privacy for you.
What is the BetterHelp controversy? How To Get The Biggest Discount On Betterhelp
BetterHelp is the biggest online treatment platform worldwide. Ad tech professional, Alon Matas, established the business in 2013 after seeking therapy for depression. He found out that the majority of people who need it weren’t getting assistance. Factors such as lack of gain access to, schedule, expense, trouble, and fear make in-person treatment challenging for many individuals. Online therapy platforms like BetterHelp aim to offer a much easier, more comfortable, and more budget-friendly way to get help.
The demand for online therapy has actually skyrocketed in the last few years. While online therapy became the only choice for the majority of during this time, favorable experiences assisted many individuals acknowledge that it’s a viable choice in a post-pandemic world, too.
Everyone can take advantage of talking with a therapist. Everybody deals with challenges in life that can obstruct of our joy or become obstructions to our goals. And in some cases, when goals themselves change, we need assistance coping and navigating with challenging feelings.
BetterHelp therapists are all extremely certified to help you as you seek to enhance your life. The business also deals with therapists who focus on particular areas of concern, consisting of however not restricted to:
Anxiety
Tension
Stress and anxiety
Self-confidence
Life modifications
Parenting
Relationships
Religion
Sexuality
Identity
Anger
Addiction
Consuming
Sleep
PTSD
Sorrow
Household conflict
Attempt BetterHelp
Additional services
In addition to specific treatment, the BetterHelp homepage lists Couples and Teenager counseling choices. Each of these services sends you to a sister site when picked– Regain.us for couples and TeenCounseling.com for teenagers. Prices for these services is similar to BetterHelp, and all therapists satisfy the same high standards and undergo the very same strenuous screening. How To Get The Biggest Discount On Betterhelp
Better help reviews
BetterHelp has a separate site dedicated to LGBTQIA counseling, called Pride Counseling. Its services are just as structured and budget-friendly as the moms and dad business, however therapists with Pride Counseling specialize in offering treatment to individuals in the LGBTQIA neighborhood. Pride Therapy likewise protects your personal privacy and anonymity as rigorously as BetterHelp.
perhaps someone else that you have actually understood in the past great work ethic really an assertive communicator just appears usually like he knows what’s happening with life has whatever found out so now that we have these images in mind of someone with anxiety and someone that relatively does not want to move equipments a little bit to speak with you about an operating alcoholic we have actually all heard this term so what does it imply when we say someone’s a functioning alcoholic or normally describing somebody that most likely does have some sort of issue with alcohol but they’re able to maintain their job they’re able to preserve relationships family but the issue I guess is that sometimes they’re unable to maintain those things in healthy methods and it’s extremely hard sometimes to identify an operating alcoholic due to the fact that they are able to keep some elements of their life together so leaping back to the original topic here of somebody with high functioning anxiety otherwise known as dysthymia it’s really tough to identify these individuals often and sometimes it’s us in some cases we can’t even identify when it’s us that we’re suffering from these things so today once again we wish to talk about things that you can be looking for or things that you might have discovered in yourself that could be an indication that you’re experiencing high-functioning anxiety so individuals with high-functioning anxiety or experiencing dysthymia are often difficult to recognize we’re not seeing these overt traits of a really depressed person no catatonic states in fact individuals with high-functioning anxiety are frequently able to keep really healthy way of lives good relationships with other people and that and it vertically almost makes the risk a bit scarier in a various type of method why someone with overt signs of anything we can discover them we can get them into some kind of services or try to help them as best as we can for individuals flying under the radar for people experiencing symptoms that we don’t see it’s really difficult to identify them and after that get them help it’s really challenging to interact to them that perhaps they must consider finding help on their own so when we think of mental health services in general there currently is a quite big stigma around this a lot of individuals out there adults in the United States for example have a hard time looking for treatment because of you know the idea that if you seek out therapy you’re insane or you can’t manage things by yourself or something
Is BetterHelp legit?
Yes, BetterHelp is a legit, trustworthy business and a leader in online treatment with over 22,000 therapists and nearly two million clients up until now. Many people choose it to their standard in-person therapy. As a company, it seems to comprehend that trust is an important part to its success. The company makes sure:
A protected and safe platform
Complete compliance with HIPAA law
Greater cost for some individuals, compared to in-person therapy
The choice of anonymity
High requirements for its therapists
An uncomplicated experience whether you use the site or the app
Who are the therapists?
The most important resource BetterHelp provides is its wide selection of highly certified therapists. It was gotten by Teladoc, Inc. in 2015, the company continues to employ the same rigorous therapist application procedure in order to veterinarian therapists and preserve quality. BetterHelp reports that just 15% of therapists who apply to the platform are approved.
The therapist application process comprises:
An evaluation of each therapist’s background, experience, and references
Confirmation of credentials
A case study examination evaluated by a certified clinician; a video interview
A platform abilities test
Therapists are likewise based on continuous quality tracking, enhancement, and client feedback throughout their tenure at BetterHelp.
greater for them due to the fact that they do not wish to clue individuals in their lives in to the truth that they might be fighting with something or that they might require help with something and so for people experiencing this we have a hard time finding them and they have a tough time finding help since you know maybe some part of them does not actually wish to be recognized where this other part does but we do not know how to find them so what are we looking for in order to identify whether we ourselves are having a tough time with this or someone that we care about might be going through a difficult time with this there are some things that you can be looking for or tuning into in yourself to identify whether you might be having some sort of difficulty with high working anxiety so among the first things to look for is this general sense of sadness going back to this image you might have of this depressed individual you could be thinking someone sobbing all day just having a tough time with life dropped over catatonic even maybe stagnating quite you’re not going to really see this with somebody with high functioning depression however rather like I said a subtle and general sense of unhappiness the majority of the time practically every day if not every day and it’s a little bit mysterious sometimes you can’t really tell where this feeling is coming from or determine any particular trigger that hurt your sensations or anything like that some other things to be searching for and considering is the inability or you know the loss of ability to experience joy loss of interests and things that you used to really find to be something that makes you feel excellent or bring some sort of complete satisfaction to your life you may also discover reduced energy so like How To Get The Biggest Discount On Betterhelp.
I stated not necessarily not having the ability to get out of bed but just lessened you feel fatigued a lot of the time where perhaps before you didn’t experience it that way other things to be looking for is being truly self-critical which results in perfectionism which can likewise contribute to blowing things out of proportion finding actually small things in your life to develop into substantial issues so I believe there’s a saying making a mountain out of a molehill a lot of individuals fighting with high operating anxiety experienced these things like I stated actually self-critical feeling a great deal of guilt and pity about the past and even the future things that have not even happened yet this is something that a great deal of people could not be struggling with you may also be considering this depressed person who seems unfortunate all the time however there’s other sensations involved in anxiety. | {
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8,327,984,154,439,799,000 | Considered pills for weight loss are absorption the conducted
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-2,558,880,929,613,501,400 | Office Hours: Monday - Thursday 8-4 | Friday 8-3 | Saturday 8-12
3701 South Clarkson Street, Suite 320, Englewood, CO 80113
303.740.4883
720.542.7726
How Do You Get Plaque Psoriasis?
Man with psoriasisPlaque psoriasis is one of the most common forms of the condition, making up around 90% of all cases. Plaque psoriasis is an autoimmune disease where the skin’s cells build up rapidly, creating dry and itchy patches or scales on the body. Though the underlying cause of this condition is still unknown, specific factors such as stress, smoking, and obesity can trigger an outbreak.
What are the Symptoms of Plaque Psoriasis?
Chronic plaque psoriasis usually appears on the skin as raised, inflamed patches covered with white or silvery scales or plaques. These plaques are commonly found on the elbows, knees, scalp, and back, but it can also affect the nails, causing discoloration, pitting, and detachment of the nail from the nail bed.
These symptoms will often worsen when a person is stressed, experiencing an infection, or if the skin is injured. Symptoms of plaque psoriasis can come and go and will usually stay in remission for months or even years before a sudden flare-up occurs.
Is Plaque Psoriasis Contagious?
Plaque psoriasis is not contagious. In fact, genetics play a significant role as to how the condition is passed along. About one-third of people with this skin condition will have a family history of it. Usually, people will have around a 20% chance of experiencing psoriasis in some form per each side of the family. If it runs on both sides, then the likelihood of psoriasis increases.
If you or someone in your family is experiencing symptoms of plaque psoriasis, contact Colorado Skin Care to schedule an appointment. Our Denver skin clinic will help you determine the severity of your condition, as well as recommend a treatment plan.
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3,865,275,863,394,751,000 | Abstract Title:
Effects of supplemental fish oil on resting metabolic rate, body composition, and salivary cortisol in healthy adults.
Abstract Source:
J Int Soc Sports Nutr. 2010;7:31. Epub 2010 Oct 8. PMID: 20932294
Abstract Author(s):
Eric E Noreen, Michael J Sass, Megan L Crowe, Vanessa A Pabon, Josef Brandauer, Lindsay K Averill
Article Affiliation:
Department of Health Sciences, Gettysburg College, Gettysburg Pennsylvania, USA. enoreen@gettysburg.edu.
Abstract:
ABSTRACT: BACKGROUND: To determine the effects of supplemental fish oil (FO) on resting metabolic rate (RMR), body composition, and cortisol production in healthy adults. METHODS: A total of 44 men and women (34± 13y, mean+SD) participated in the study. All testing was performed first thing in the morning following an overnight fast. Baseline measurements of RMR were measured using indirect calorimetry using a facemask, and body composition was measured using air displacement plethysmography. Saliva was collected via passive drool and analyzed for cortisol concentration using ELISA. Following baseline testing, subjects were randomly assigned in a double blind manner to one of two groups: 4 g/d of Safflower Oil (SO); or 4 g/d of FO supplying 1,600 mg/d eicosapentaenoic acid (EPA) and 800 mg/d docosahexaenoic acid (DHA). All tests were repeated following 6 wk of treatment. Pre to post differences were analyzed using a treatment X time repeated measures ANOVA, and correlations were analyzed using Pearson's r. RESULTS: Compared to the SO group, there was a significant increase in fat free mass following treatment with FO (FO = +0.5 ± 0.5 kg, SO = -0.1 ± 1.2 kg, p = 0.03), a significant reduction in fat mass (FO = -0.5 ± 1.3 kg, SO = +0.2 ± 1.2 kg, p = 0.04), and a tendency for a decrease in body fat percentage (FO = -0.4 ± 1.3% body fat, SO = +0. 3 ± 1.5% body fat, p = 0.08). No significant differences were observed for body mass (FO = 0.0 ± 0.9 kg, SO = +0.2 ± 0.8 kg), RMR (FO = +17 ± 260 kcal, SO = -62 ± 184 kcal) or respiratory exchange ratio (FO = -0.02 ± 0.09, SO = +0.02 ± 0.05). There was a tendency for salivary cortisol to decrease in the FO group (FO = -0.064 ± 0.142 μg/dL, SO = +0.016 ± 0.272 μg/dL, p = 0.11). There was a significant correlation in the FO group between change in cortisol and change in fat free mass (r = -0.504, p = 0.02) and fat mass (r = 0.661, p = 0.001). CONCLUSION: 6 wk of supplementation with FO significantly increased lean mass anddecreased fat mass. These changes were significantly correlated with a reduction in salivary cortisol following FO treatment.
Study Type : Human Study
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3,118,986,307,741,575,000 | HYBRID EVENT: You can participate in person at Paris, France or Virtually from your home or work.
6th Edition of World Congress on Infectious Diseases
June 24-26, 2024 | Paris, France
June 24 -26, 2024 | Paris, France
Infection 2024
Sukki Ho
Speaker at Infection Conference - Sukki Ho
The Hong Kong Polytechnic University, Hong Kong
Title : Effect of a multimodal infection control programme in the reduction of bacterial contamination in the nasogastric feeding tube hubs in residential care homes for elders
Abstract:
Nasogastric tube (NG tube) feeding in residential care homes for the elderly (RCHEs) carries the risk of contamination at the NG tube hub, a crucial connection point in the enteral feeding process. This contamination can lead to the spread of harmful microorganisms, potentially resulting in serious complications such as mortality. However, there is limited research on the effectiveness of infection control programs (ICPs) in reducing NG tube hub contamination.
This study aimed to assess the impact of a comprehensive ICP on reducing bacterial contamination in NG tube hubs, enteral milk, and the hands of RCHE staff, while also evaluating its effectiveness in enhancing the staff's knowledge and skills in NG tube feeding. The research utilized a single-blinded cluster-randomized controlled trial involving eight RCHEs. The intervention group received a 12-week multimodal ICP, including educational sessions on infection control measures related to NG tube feeding, while the control group did not receive this intervention.
The ICP sessions, which involved various teaching methods such as PowerPoint presentations, videos, group discussions, and practical workshops, were tailored to accommodate the staff's shift schedules. Bacterial samples were collected from residents' NG tube hubs, enteral milk, and staff's fingertips for analysis. Pre- and post-intervention data on NG tube feeding knowledge and skills were also gathered and compared between the two groups.
Eight RCHEs with 140 residents and 250 RCHE staff participated in the study. Results showed a significant reduction in the total bacterial counts of the NG tube hubs within the intervention group before and after the intervention (p=0.04), as well as between groups (p=0.001). Both groups had 19 contaminated NG tube hubs at baseline. After intervention, the number of contaminated NG tube hubs was reduced to 13 in the intervention group but no changes were found in the control group. In addition, the total bacterial counts of the enteral milk was significantly reduced between groups (p=0.001) while there was no enteral milk contamination in either group before and after intervention.
The knowledge and skills in NG tube feeding was increased significantly in the intervention group (p=0.001) and was significantly improved compared with the control group after intervention (p=0.001). There were significant reductions in the total bacterial counts in right and left fingertips of the RCHE staff of the intervention group within group (p=0.001) and between groups (p=0.001) after intervention. Also, the number of fingertips contaminated was significantly reduced within the intervention group (p=0.001) and between groups (p=0.001). These findings underscore the effectiveness of the multimodal ICP in minimizing bacterial contamination and enhancing infection control practices in NG tube feeding.
In conclusion, the study highlights the positive impact of the ICP on reducing bacterial contamination in NG tube hubs and promoting proper hand hygiene among RCHE staff. Continuous implementation of such programs in RCHEs is recommended to sustain and further improve infection control practices in NG tube feeding.
Biography:
Sukki Ho is a Associate Professor of Practice of the School of Nursing, The Hong Kong Polytechnic University (The PolyU). Her expertise is infection control nursing, teaching and research. She has contribution in nursing research with publications in the areas of N95 respirator fit test. Her doctoral research topic is related to infection control nursing care for chronically ill patients in the residential care homes for elders. Besides, she obtained the outstanding academic awards during her doctoral study in infection control specialty. Dr HO has reinforced and brought new information of the hospital infection control practice specific to the prevention of COVID-19 infection to the staff and students of The PolyU during COVID-19 pandemic. She obtained Faculty Award/ Prizes for outstanding achievement in services (Team member) from the Faculty of Health and Social Sciences, The PolyU. She also serves as clinical coordinator of the Master of Nursing Programme.
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752,289,632,698,455,000 | Breastfeeding | Hepatitis B virus | Dr Krishan Yadav BlogParas Bliss
Feedback!
Breastfeeding of Infants born to Hepatitis B Mother
Breastfeeding of Infants born to Hepatitis B Mother
by: Dr. Krishan Yadav
HOD & CONSULTANT - NEONATOLOGY
What is Hepatitis B?
Hepatitis B can be defined as the viral infection of the liver. It is caused by Hepatitis B virus (HBV). It is the most common type of virus and can affect a person adversely if left undetected and untreated.
What are the risks to the baby born to Hepatitis B mother?
If the mother has Hepatitis B, there are chances of transfer of virus to the baby. Transmission can occur while the baby is in utero, during delivery and in postpartum period. Most of the cases are due to transmission of virus at the time of delivery due to exposure to blood. That virus can infect the baby and can cause hepatitis in the baby. Baby can become a chronic carrier and can develop liver cirrhosis and hepatocellular carcinoma in later life.
breastfeed the baby
Does breast milk contain Hepatitis B Virus?
Yes, HBV can be found in the breast milk of 70% of carrier mothers, but there is no evidence of transmission of Hepatitis B through mother’s milk.
Can Hepatitis B Positive mother give breastfeed to her baby?
Yes, according to WHO and UNICEF guidelines breastfeeding can be given, as breast milk is the natural and optimal feed to the baby. Mother feeding in hepatitis B positive mother infant can be made more safe by immunisation of the baby with Hepatitis B Vaccine and Hepatitis B immunoglobulin . Hepatitis B vaccine and immunoglobulins are to be given within 12hrs of delivery and the vaccine should be repeated after 1 month and 6 months. This will substantially reduce perinatal transmission and virtually eliminate any risk of transmission through breastfeeding or breast milk feeding. Immunization of infants will also prevent infection from all other modes of HBV transmission. Exclusive breast feeding is to be continued till 6 months of age .Start complementary feeds at 6 months of age and along with that continue breast feeding for two years.
What to do if Hepatitis B positive mother has sore or cracked or bleeding nipples?
Mothers should breastfeed the baby carefully so that she would not get cracked or sore nipple. In case she gets sore or cracked or bleeding for nipple ,stop breast feeding and take treatment for sore nipples. Because sore nipples or cracked nipples can transmit the virus through exposure to blood . During that period she should express the milk and discard it. She should resume the feeding after the nipples are healed .
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6,817,172,840,245,808,000 | the collecting duct is impermeable to water in the presence of adh
Nephron
Its loop of Henle is brief, and also its efferent arteriole branches right into peritubular veins that border the nephron sections of its very own and surrounding nephrons. A couple of varieties, consisting of humans, also possess very short surface nephrons whose Henle’s loopholes never get in the medulla. , boosted circulation of tubule liquid in the gathering air duct is a strong stimulus for K+ secretion.
Since salt is quantitatively the major osmotically energetic solute, the total result is to maintain the fluid that continues to be in the tubular lumen, though much reduced in volume, about isosmotic with the initial glomerular filtrate. If ADH is lacking or is produced at much less than 80% of normal degrees, water elimination from the accumulating air ducts fails, as well as the body secretes large quantities of pee– typically greater than 4L/day. This problem is called diabetes mellitus insipidus and also is accompanied by fantastic thirst and dehydration in the absence of raised fluid intake. Less usual sources of diabetes insipidus are congenital diseases impacting the water channels in the gathering ducts.
the collecting duct is impermeable to water in the presence of adh.
Representation describing motion of ions in nephron, with the collecting ducts on the right. The cells that consist of the air duct itself are similar to remainder of the collecting system. The air duct is lined by a layer of simple columnar epithelium hing on a thin cellar membrane.
As opposed to originating from the metanephrogenic blastema, the collecting duct originates from the ureteric bud. As Na+ is pumped from the forming pee, water is passively recaptured for the circulation; this conservation of vascular volume is seriously crucial for the maintenance of a typical blood pressure. Aldosterone is produced by the adrenal cortex in feedback to angiotensin II excitement. As an extremely potent vasoconstrictor, angiotensin II features instantly to raise high blood pressure.
Carcinoma of the gathering duct is a reasonably uncommon subtype of kidney cell carcinoma, making up much less than 1% of all RCCs. Many reported instances have actually taken place in more youthful people, usually in the 3rd, 4th, or 5th years of life. Gathering air duct carcinomas are originated from the medulla, yet several are infiltrative, and expansion into the cortex is common.
Angiotensin II is a compound made by the body to reduced high blood pressure during tension. Required water reabsorption involves the movement of water along an osmotic slope.
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-1,669,631,627,416,499,500 |
Does eating too much sugar can affect your breast milk?
It is well established that breastfeeding is the superior method of feeding an infant. Companies that manufacture infant formula have tried to mimic the composition of human breast milk, but there is no substitute. The American Dietetic Association recommends that mothers breastfeed exclusively for six months and complementary feeding for 12 months. One of the greatest benefits of breast milk is that it is designed to meet perfectly the needs of a child, regardless of the mother’s diet.
affect your breast milk
Composition of breast milk
Each milliliter of milk provides about 0.65 calories, although this varies as the fat content in the milk changes. Fifty percent of total calories derived from milk fat. The fat content is lowest at the start of feeding and gradually increases as the continuous feeding. The protein content is generally lower than that of commercial infant formula. Most of the carbohydrates are lactose milk, commonly known as “milk sugar.” The vitamins and minerals in highly bioavailable forms and immunoglobulins are other important components of human milk.
Mother’s diet and breast milk composition
Although good nutrition is very important for a nursing mother, the composition of breast milk is relatively stable despite the mother’s diet. The most significant factor that affects the production of breast milk is the baby’s demand. Unless a woman is severely malnourished, even a woman who has no calories and protein in your diet can produce milk that meets all your baby’s nutritional needs.
Fats, carbohydrates and proteins
The types of fats you eat the mother influence the types of fat that are present in milk. If you eat primarily saturated fat, a higher percentage of fat in your milk will be saturated. However, the total fat content, along with carbohydrate and protein content are not affected by maternal diet. Eating a lot of sugar in your diet will not change the composition of breast milk.
Maternal Nutrition
The Breastfeeding is a completely natural and healthy, but very demanding on your body. You need more calories, vitamins and minerals while breastfeeding a baby. Although this will get the nutrients it needs, it is important that you get proper nutrition for yourself. Eating a lot of empty calories from foods from sugar and snacks instead of other foods more nutritious could prevent you get the important nutrients your body needs. Be filled with fruits, vegetables, whole grains, lean meats and vegetables, nuts and low-fat dairy products to be well nourished.
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7,533,564,500,338,867,000 | The Warning Signs of Suicide: How to Tell if Someone is Suicidal
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Anxiety vs. Depression: Do I Have Both?
Anxiety vs. Depression: Do I Have Both?
"I'm not afraid of storms, for I'm learning how to sail my ship."
Louisa May Alcott
Sometimes it seems like our lives are wrapped in storm clouds that bring frightful thunder and drape our world in gray tones. The storms keep us tense as we anticipate the next lightning strike and hopeless because there is no joy in a colorless world. If you feel like you are constantly under these rain clouds? Exhausted but can't sleep, obsessively worried? Do you feel like the sun will never shine again? You are likely experiencing the symptoms of a mood disorder. But is it anxiety or depression? Are you wondering, “Do I have both?”
The short answer is yes. You likely have both anxiety and depression, and this is exceptionally common. Almost half of the people diagnosed with a depressive disorder are also diagnosed with an anxiety disorder. Conversely, feeling anxious all the time leads to deep depressive episodes.
The trick to managing these mental health disorders is to learn which one is the driving force in your everyday life and which is a symptom of the other. There are ways mental health professionals, like those at Goodman Psychologist Associates, can help by first assessing your symptoms, diagnosing specific disorders, and offering treatment options.
Anxiety vs. Depression: Are They the Same Thing?
Everyone experiences feelings of sadness, grief, fear, and depression. When these normal emotions persist and interfere with average day-to-day living, work, or relationships, they become mental health conditions usually called Depressive Disorder or Anxiety Disorder. Depression and anxiety can come from genetics, current circumstances, each other, or even medical conditions. While these disorders often go hand-in-hand, they are two distinct mental health issues. So, how do you know if you have anxiety, depression, or both? The key differences are in the diagnostic definition and criteria.
Anxiety Disorder
People with anxiety have intense and excessive fear and worry. Often thoughts start with the question, "What if?" Anxiety disorders are distinguished by symptoms involving anxious thoughts, unexplained physical sensations, and avoidant or self-protective behaviors experienced most of the time for at least six months.
Depressive Disorder
A person whose primary diagnosis is depression often doesn't show the same fear and uncertainty that people do with anxiety disorders. People with depression don't worry about their future because they already believe it will be full of the same bad stuff that is happening now. Instead, they have feelings of hopelessness and intense sadness. A depressive disorder is diagnosed when a person experiences symptoms for most of the day, every day, for at least two weeks.
Shared Symptoms of Anxiety and Depression
Depression and anxiety can be hard to tell apart because they have many overlapping effects on mental and physical health. You could have depression, anxiety, or both if you experience these common symptoms:
• Crankiness and irritability or feeling out of control
• Trouble concentrating or thinking
• Lowered motivation
• Trouble making decisions
• Poor memory or a foggy feeling
• Weight changes or a reduction or increase in appetite
• Sleeping too much or too little or insomnia
• Digestive issues
• Muscle tension, aches, pains, or headaches
• Exhaustion and fatigue
• Restlessness
What Causes Anxiety and Depression?
Both anxiety and depression can result from trauma, a physical injury, stress, inherent genetic predispositions, drugs or other substances, physical changes like menstruation, pregnancy, disability, or another mental health condition. Anxiety, depression or both can also stem from the same medical condition, such as:
• Cancer.
• Premenstrual dysphoric disorder (PMDD).
• Heart disease.
• Diabetes.
• Thyroid problems.
• Respiratory disorders like asthma and Chronic Obstructive Pulmonary Disorder (COPD).
• Drug or alcohol withdrawal.
• Chronic pain or irritable bowel syndrome.
How Are Anxiety and Depression Different?
When comparing anxiety vs. depression, they can clearly have the same symptoms and causes. A good way to distinguish anxiety from depression is to examine the prompting events that may have triggered one or both of the disorders and learn if there is a family history of mood disorders. Another way to tell these conditions apart is to look at symptoms that are unique to each.
Additional Mental Symptoms of Anxiety:
• Feeling overwhelmed with worry, fear, and dread
• Fear of the future, injury, sickness, and death
• Rapid, intrusive, or frightening thoughts
• Hypervigilance
• Disassociation or detachment from reality, or depersonalization
Additional Physical Symptoms of Anxiety:
• Elevated or fast heart rate and palpitations
• Shortness of breath or rapid breathing
• Tightness or pressure in the chest
• Dizziness or lightheadedness
• Sweating and shakiness
• Dry mouth
• A choking or strangling feeling
• Hot flashes or chills
• Tingling in the arms and legs
• Avoidance of typical situations or events
Please Note: Many physical anxiety symptoms mimic the symptoms of a heart attack. If you are unsure what you are feeling, call a medical professional or 911.
Additional Mental Symptoms of Depression:
• Intense and persistent sadness, sorrow, or grief; feeling tearful
• Feeling empty, guilty, or hopeless
• Persistent thoughts about worthlessness or guilt
• Lack of interest and enjoyment in activities that used to be fun and interesting
• Thoughts of self-harm, death, and suicide
Please note: If you have thoughts of self-harm or suicide, call the Suicide and Crisis Hotline by dialing 988. All calls are confidential, and the phone lines are available 24 hours a day.
Types of Anxiety Disorders
The differences between these mental health conditions are more apparent when looking at the types of disorders relating to either anxiety or depression.
There are multiple types of anxiety disorders. You can have one or more of these disorders, including:
Generalized Anxiety Disorder
Generalized anxiety disorder (GAD) is common. An estimated 5.7% of Americans experience GAD at some time in their lives. GAD is characterized by chronic anxiety and worry that is often not triggered by external circumstances.
Panic Disorder
Panic disorder includes feelings of intense anxiety and is characterized by the repetition of unexpected and sudden moments of extreme fear and panic. These feelings are often accompanied by physical sensations such as palpitations, hyperventilation, chest pain, lightheadedness, and gastrointestinal problems like diarrhea or pain.
Post-Traumatic Stress Disorder (PTSD)
PTSD is an anxiety disorder that develops after a frightening ordeal or event in which physical harm was threatened or occurred. Military combat, physical or sexual assault, and disasters are examples of PTSD-inducing traumatic events.
Social Anxiety Disorder
Sometimes called social phobia, this anxiety disorder manifests with intense symptoms of anxiety accompanying social interactions.
Phobias
A phobia is an intense fear of something or someone that is unlikely to cause harm or that is unlikely to be encountered. For example, a fear of spiders (arachnophobia), small spaces (claustrophobia), or dolls (pedophobia) are common examples of phobias. Encountering a phobia, or even thinking about it, can cause severe anxiety and panic attacks.
Obsessive-Compulsive Disorder (OCD)
OCD is an anxiety disorder characterized by unwanted and uncontrolled thoughts or feelings and ritualistic-like behaviors used in an attempt to alleviate stress caused by thoughts.
Types of Depressive Disorders
Just like anxiety, depression also has multiple disorders, categorized as follows:
Major Depressive Disorder
Major depression is what most of us think of when we envision depression. It is the most common type and involves an overarching feeling of darkness and sadness. It can lead to thoughts or actions of self-harm and suicide.
Persistent Depressive Disorder
Persistent depressive disorder is less intense than major depressive disorder and allows many people to function daily despite their low mood. However, people with this disorder often have mild depression that has lasted for two or more years and have trouble experiencing joy or feelings of optimism and general happiness.
Seasonal Affective Disorder (SAD)
SAD occurs as the nights get longer as winter approaches. Changes in emotional status from feeling ok to being depressed can occur from disruption to our circadian rhythm, as well as our serotonin and melatonin production. Often this depressive disorder can be treated simply with light therapy but can also be managed with talk therapy and medication. SAD generally gets better as the nights get shorter and more natural sunlight is available.
Bipolar Disorder
Bipolar disorder, once called manic depression, differs from anxiety and depression. Bipolar disorder is characterized by intense highs (mania), moderate highs (hypomania), and severe lows (depression). These mood changes may come on suddenly and last for several days.
Treatment for Anxiety and Depression: The Same, But Different
Treatment for any mental health condition is tailored to the individual's diagnosis and needs. Anxiety and depression disorders each have their own treatment recommendations, although these plans often overlap in both medications used and the types of psychological assistance given.
Medications
Both anxiety and depression are regulated by serotonin. Serotonin is a neurotransmitter that acts like a hormone. According to Cleveland College, "Serotonin plays several roles in your body, including influencing learning, memory, happiness as well as regulating body temperature, sleep, sexual behavior, and hunger. Lack of enough serotonin plays a role in depression, anxiety, mania, and other health conditions."
When it comes to medication for anxiety and depression, there is little distinction. Both disorders have been shown to improve using selective serotonin reuptake inhibitors (SSRIs). You will likely receive a prescription for an antidepressant SSRI medication for an anxiety disorder, which can be confusing.
Examples of SSRI medication for the treatment of both anxiety and depression include:
• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil)
• Sertraline (Zoloft)
• Vilazodone (Viibryd)
You could also be prescribed serotonin-norepinephrine reuptake inhibitors (SNRIs). Like SSRIs, these medications work to increase serotonin. Unlike SSRIs, they also increase the levels of norepinephrine. Examples of popular SNRIs include:
• Desvenlafaxine (Pristiq)
• Duloxetine (Cymbalta)
• Levomilnacipran (Fetzima)
• Venlafaxine (Effexor XR)
Therapies
Cognitive behavioral therapy (CBT) is the most effective treatment for depression and anxiety disorders. CBT is a form of talk therapy (also called psychotherapy) that aids in managing mental health issues by changing how you react, behave, and think.
CBT also teaches life skills so we can cope more effectively. Subsets of CBT include dialectical behavior therapy (DBT) and acceptance and commitment therapy (ACT). A typical CBT treatment plan involves limited and structured sessions with a mental health professional. CBT may be used by itself or in combination with other therapies or medications.
Additional Treatments
In addition to talk therapy and medications, both anxiety and depression can benefit from lifestyle changes and a willingness to get help. Some examples include:
• Get treatment for the medical condition causing the mood disorder.
• Exercise.
• Eat a healthy diet rich in vitamins and nutrients.
• Join a support group.
• Utilize meditation practice and relaxation techniques.
Still Not Sure if You Have Anxiety, Depression, or Both?
Because anxiety and depression have similar symptoms, causes, and treatments, knowing which common mental health disorder is the primary condition can be difficult. Remember that anxiety tends to be about fear, and depression tends to be about hopelessness.
While depression and anxiety exist separately from each other, there is a high probability that a person with a depressive order has an anxiety disorder as a secondary symptom and vice versa.
To know for sure and to get the proper treatment, you need to see a mental health professional like the experts at Goodman Psychologist Associates. Our therapists are trained in anxiety and depressive disorders and have extensive experience treating both. Make an appointment today or call 630-377-3535.
When those storm clouds surround us, it is hard to see our way out of them. It is even harder to ask for help. We encourage you to reach out to mental health specialists or to friends and family to talk. You don't have to tackle these issues alone.
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Dealing with Emotional Pain
How to Deal with Emotional Pain: 3 Ways to Feel Better Today
Emotional pain can stop us in our tracks. It can feel unbearable—almost physically painful at times—but unlike physical pain, taking a pain reliever and getting rest doesn’t make emotional pain go away. If you’re wondering how to deal with emotional pain, you aren’t alone.
Some emotional pain can stem from a major life change or disruption like a breakup, a divorce, the loss of a job, or the death of a loved one. When we can pinpoint the trigger of our emotional pain, it may help us to recognize that it’s part of the natural grieving process. Grief hurts.
Sometimes, though, the emotional pain can feel like it's too much to bear. It may last for months and may start to disrupt our day-to-day activities. When this happens, it's time to reach out for support. Whether the emotional pain comes from a life change or is more nebulous in nature, talking to a professional counselor can get you through. Reach out today to schedule an appointment with one of our therapists so that you can deal with emotional pain in a manageable way.
Why Emotional Pain Happens
Anyone who's experienced the deep emotional pain of a loss or trauma can attest that it hurts. Sometimes that hurt is so intense that it feels physical. In fact, it's not uncommon to experience physical manifestations of emotional pain.
When we're going through an emotional upset, we may have headaches, stomach pains, and digestive issues. Our sleep may be disrupted, and we may find that we're unable to focus on work or our usual activities. As a result, our performance can suffer in our jobs and personal lives.
We may also find that we don’t have much of an appetite, or some people may turn to comfort foods—feeling an almost insatiable desire to eat ice cream, cookies, chips, bread, and other carbs (they trigger "feel-good" serotonin in our brains and help us feel relaxed). Other people may turn to less healthy behaviors like smoking, drinking, or drugs in an attempt to numb and deal with emotional pain.
When we experience emotional pain, we can even experience real, physical symptoms. For example, as discussed in Scientific America's article, What Causes Chest Pains When Feelings Are Hurt?
“According to a 2009 study from the University of Arizona and the University of Maryland, activity in a brain region that regulates emotional reactions called the anterior cingulate cortex helps to explain how an emotional insult can trigger a biological cascade. During a particularly stressful experience, the anterior cingulate cortex may respond by increasing the activity of the vagus nerve—the nerve that starts in the brain stem and connects to the neck, chest, and abdomen. When the vagus nerve is overstimulated, it can cause pain and nausea.”
Those gut-wrenching, heart-achy feelings aren’t in our heads. They’re actual bodily reactions to the emotional discomfort. When we grieve or experience a loss, the physical sensations can be particularly strong and overwhelming.
At the same time, our brains are looking for patterns and reasons for the loss. We may find ourselves going through the stages of grief during a breakup or job loss, just like a death. We might experience "magical thinking” where we believe our thoughts, feelings, or actions might have inadvertently caused something to occur. We may try to rationalize and find a sense of control over the situation. Often, we may look for somewhere to put the blame or think, "If only I'd done something differently."
We may also experience guilt over what happened, or we may find ourselves feeling deeply sad, tired, and listless. It's not uncommon for those experiencing emotional pain to feel overcome with emotion suddenly. One minute we're standing in line at the grocery store listening to a song, and suddenly we're in tears.
During grief, sorrow, and emotional pain, we may also find that we feel anger. We might feel abandoned by our loved ones, unsupported in a situation at work, or enraged at our ex. All these complex emotions can come in waves—one moment we’re fine, and the next moment we’re ready to scream, cry, or both.
Emotional pain is challenging, but it doesn’t have to be permanent. It's essential that we feel grief and allow ourselves space to experience the emotions. However, when we don't know how to deal with emotional pain, or it becomes destructive and ever-present in our lives, it may be time to reach out. Whether our pain happens because of a loss or we're not sure what has caused our pain, a professional can provide the supportive space to talk through our problems.
Should we discover that our emotional pain is caused by depression, or if it’s a reaction to circumstances in our life, we can still find relief. While working with a therapist or counselor, it can also be helpful to try these three techniques to alleviate emotional pain.
3 Tips for Dealing with Emotional Pain
1. Practice Mindfulness
Mindfulness and meditation are helpful practices for addressing many different mental health concerns, including emotional pain and depression. When we're mindful, we bring our brains back "online" and help ourselves reorient to the moment. Instead of ruminating on the past source of our emotional pain (or worrying about the future), we look at the present. Even if these pockets of mindfulness are brief, they can help us find relief and deal with emotional pain.
Meditation and mindfulness are easy to learn. There are helpful apps out there like Headspace and Calm that can guide us through the process. There are also many resources online, including free videos on YouTube that can help you get the hang of mindfulness and meditation.
Practice mindfulness anywhere—at home, at the office, in the classroom. It doesn't require anything extra. To give it a shot, we can try to take several deep breaths, focusing on the air coming into our nose and out of our mouth. As we breathe, we can observe our thoughts and feelings. Rather than getting caught up in a thought, we allow the mind to acknowledge it and let it flow by.
Unlike depression and grief, which can trigger catastrophizing thoughts, mindfulness helps us feel calm and relaxed. We focus on the here and now rather than asking what if.
We can also try a mindful walk outside. During our walk, we can do a mental inventory. First, focus on what we see for one minute. Next, spend a minute focusing on the sounds we hear. For the next minute, focus on a physical sensation—like touching a tree, rubbing our fingers on a leaf, or taking off our shoes and walking through the grass. Then focus on the smells in the air, like the scent of flowers, trees, cars, even someone's cooking as we walk by. Repeat this sensory inventory for the duration of the walk.
2. Get Creative & Cerebral
Another way to deal with emotional pain is to focus on stimulating our brains in other ways. Therapy can often be part of the cerebral or cognitive approach (hence, Cognitive Behavioral Therapy). During CBT or talk therapy, we often identify negative thinking patterns and counter them with a more positive perspective.
But in addition to therapy, engaging our brains in other positive pursuits can help us deal with emotional pain in a positive, forward-focused way. When we're learning about a new subject, reading a book, or attempting something new, we use a different part of our brain. We do not forget the subject of our grief (which is often a fear during a loss—we don't want to "get over" someone we love). Instead, we're shifting our brains a little to allow ourselves a rest and to focus on other thoughts.
Journaling can be another technique to help us get our creative juices flowing and start to help us deal with emotional pain. Write out feelings, compose a letter to someone, or look for journal prompts that can help us explore some of the complicated emotions we’re experiencing.
Other outlets such as drawing and coloring, playing music, dancing, or photography can also be excellent ways to work through emotional pain and sadness. While something like dancing may feel challenging (or even impossible) at first, we can channel some of the frustrations and energy into our movement.
Exercise is a great coping tool and can have other benefits for our bodies as well. Again, the thought of going for a jog may seem absolutely out of our range at the moment. But slipping on comfortable shoes and taking a brisk walk around the block, or even doing some jumping jacks in our bedroom can help us start to see positive benefits and boost our mood.
3. Supplement Support
Grief, sorrow, depression, and emotional pain often feel very lonely. We may believe that no one will understand what we're going through; we may feel guilty like we can't offer emotional support back to our friends, or we may feel like we're worthless and people don't want to be around us.
When our brain is experiencing emotional pain, these irrational thoughts can feel very real and insurmountable. But it’s crucial that we find a support system. A therapist or counselor is an important part of the journey, but friends, family, and other people can help too.
We can look through the people in our lives and choose a few key people who might provide a sense of support and empathy. It's important to remind ourselves that we aren't a burden. Part of feeling better is asking for and accepting help to get us through this difficult time. Eventually, we can pay it forward when we're feeling more up to it.
If we can’t readily identify a friend who could support us, consider a family member, a teacher, a coworker, or someone from church or our religious practice. Emotional support can come from many different places, so explore social circles to find a connection.
Even talking to and hugging a pet can be therapeutic and helpful to get us through a difficult time. We can walk the dog or play with a cat and feel less alone. Animals can also remind us to be mindful—after all, they live in the moment, and it can be an excellent example of how we can shift our thinking too.
Most importantly, realize that if you aren’t sure how to deal with emotional pain, you don’t need to go it alone. There are ways to get the support you need to help you move forward to a brighter future. Reach out today to schedule with one of our practitioners. We're ready to listen and help you find ways to feel like yourself again.
Waiting
Don't Worry, Be Happy
Don't Worry, Be Happy: How to Cope with Life
As we all know, some people worry too much. Rather than solving a problem, too much worry becomes the problem. Not only does excessive worry create much personal suffering, but it also affects the people around the worrier. I wonder if a lot of our worrying in life is like this: constant, spontaneous and effortless focus that gets dislodged by distracting external events or our own change of perspective. Now, I think that anyone who does not worry is just living on a different planet; yet, as we know, just worrying about the weather does not make it rain.
9 Tips for Coping with Life, from a Psychologist
After 31 years of working in the field of psychology, I know a few things make a difference in coping with life.
1. Pay Attention to the Important Things, More than the Urgent. Sometimes the only way to get the important done is to stick it between the urgent things that drive our days. Worry is often related to disorganization. Make a list of things to do each day and cross off tasks once they are completed. Leave early enough to make appointments on time. Put your keys in the same place every time you come home. Keep your house straightened up. When things are under control, there is less to worry about.
2. Take Action on What You Want To Do And Figure Your Results As A “Prototype”. A handy friend of mine told me how he approaches building things. He considers the first version as his working model. Although I have two left hands with tools, I always thought I had to get it right the first time. My combination of ridiculously high expectations and little tolerance for error was a deeply frustrating workshop ethic to follow.
3. If You Do Not Know How To Do it, Ask For Help. Most of us just need a little guidance or a resource with whom to check out our experience. We all need support and positive feedback from time to time. Other people may have solutions to problems that we haven’t thought about. For reassurance, find people who know how to give it. Many of us spend a lifetime looking in all the wrong places for approval.
4. Try To Do The Right Thing. Maintain your sense of integrity whenever you do something. Tell the truth. Obey the law. Keep to your promises. Let your conscience be your guide. Granted, we might tell an occasional lie or break a promise, and this is fairly common – but it can also set the stage for worry. We may think sometimes that we can get ahead in the world the easy way – but the price we pay could be excessive worry, among other penalties.
5. Minimize Catastrophic Thinking. Some people find it difficult to keep perspective when faced with even a minor stressor. Not every mole means cancer and not every bill is going to lead to bankruptcy. Test out the reality of these situations by talking them over with a trust friend.
6. Limit Your Exposure to the News. Although there is value in keeping up with the latest news, understand that the media focus on bad news since this tends to sell best. We seldom hear about the good news in the world on TV or newspapers. Constant exposure to negative events increases our tendency to worry. Instead, look for what is good in life.
7. Sleep, Eat Properly, Exercise. Lack of sleep and a bad diet can make us irritable, distracted, and anxious – all condition which set the stage for worry. (Try to be mindful of the problem of overeating as a way of making our worries disappear.) Exercise helps us dissipate the anxiety that often accompanies worry.
8. Avoid Substance Abuse. Drugs and alcohol may give the illusion of comfort for the time being, but using them has negative long-term consequences. They increase depression, cloud judgment and may give you something to really worry about later.
9. Learn How to Let Go of Worries. This is a skill that might require some practice and each of us will have our way of doing it. Some people do this by allowing themselves perhaps half an hour a day of worry time – and at the end of the allotted time period, they will be free of worrying until the next day. Some people give up their worries by writing them down on a piece of paper and then tearing them up. Some people prefer to hand them over to a higher power.
The Serenity Prayer
God grant me the serenity to accept the things I cannot change, courage to change the things I can, and wisdom to know the difference. Living one day at a time, enjoying one moment at a time, accepting hardships as the pathway to peace, taking, as He did, this sinful world as it is, not as I would have it, trusting that He will make all things right if I surrender to His Will, that I may be reasonably happy in this life and supremely happy with Him forever in the next.
As this year continues, on behalf of the psychologists in the practice, I want to thank you for recommending us to others.
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-3,387,314,864,486,792,000 | Stress, its causes in a medical/dental facility and methods and techniques for its management
How to manage stress
in medical facilities-with special emphasis on dental-
using ergonomic design, relaxation techniques and patient education
# Chapter page
1 What is Stress
2 Consequences of Stress
3 Stress Management Interventions
4 Primary Stress Management Interventions
5 Secondary Stress Management Interventions
Chapter One:
What is stress?
The non-specific response of the human body to any demand made on it.
A person under stress chooses to either fight or attempt to escape which is termed fight-or-flight reaction.
There is a two types of stress:
1. Good stress (Eustress) which provides challenges to motivate individuals to work hard and meet their goals.
2. Bad stress (Distress) which results from stressful situations that persists over time and produces negative health outcomes.
Stress mechanism of action or progression: ( General Adaptation Syndrome or GAS)
It is divided into three stages:
1. Alarm reaction: the bod mobilizes resources to cope with the added stress by increasing stress hormones such as adrenalin, noradrenalin, epinephrine and cortisol.
2. Resistance stage: the body copes with the original source of stress but resistance to other sources is lowered.
3. Exhaustion stage: overall resistance drops and adverse consequences, including burnout,severe illness, and even death can result unless stress is reduced.
Fight-or-flight reaction comes in response to type of stress that comes suddenly and is likely to last only a short time -episodic, acute stress- whereas GAS tracks the bod response to stress over a longer period of time.
Coping with stress:
Individuals cope with stress in different ways but they are typically divided into:
1. Problem-focused coping: which is directed at managing and altering the problem that is causing the stress. Such type of coping may include defining the problem , generating different solutions and weighing their costs and benefits and acting to solve the problem.
2. Emotion-focused coping: which is directed at reducing the emotional response to the problem , which can mean avoiding, minimizing, and distancing oneself from the problem.
What is a Stressor:
Physical or psychological demand to which an individual responds whereas reactions and responses to these stressors are called strains.
Types of Stressors:
Work stressors fall into two major categories
1. Physical/Task Stressors: Physical such as noise, light, heat and cold. Cohen, Evans, Stokols & Krantz,1986; have showed that uncontrollable noise is particularly stressful and leads to lower task performance and diminished motivation. Evans & Johnson(2000) have shown that low-level noise is associated with elevated levels of stress hormones and lower task performance. The importance of the increased hormone levels is that stressors may exist even when the worker is not aware of the stressor.
Task stressors such as demands of a given job ( e.g., pace of work, workload, the number of hours worked) can also contribute to the experience of stress and to subsequent strains. For example, Hurrel (1985) studied several thousand postal workers and found that those working in machine-paced jobs experiences greater stress, anxiety, fatigue and tension than those working in jobs where the pace is set by employees(e.g., hand sorting, helping customers, delivering mail).
2. Psychological Stressors: Lack of control/predictability Control is a major theme in the literature on stress(Ganster & Murphy, 2000;Landy, Quick, & Kasl, 1994). Varying levels of personal control and predictability have clear effects on job performance and work stress (Rastegary & Landy, 1993; Spector, 1986). As with any stressor, the individual’s perception of control or predictability determines his or her response to the situation, and such perceptions are affected by characteristics of the job and work environment. The scheduling and pace of work can influence feelings of control. For example, flexible time schedules enhance feelings of control over one’s schedule, even though the average arrival and departure times may differ only by minutes after a flexible time schedule has been introduced (Baltes, Briggs, Huff, Wright, & Newman,1999). Flextime also increases perceptions of control by helping employees to balance work and family commitments (Ralston, 1989). Perceptions of control in the workplace are also related to autonomy, the extent which employees can control how and when they perform the tasks of their job (Hackman & Oldham,1980). Overall, interventions that enhance perceptions of control on the job ,such as participative decision making or flexible time schedules, are likely to reduce stress and subsequent strains.
Interpersonal conflict is the negative interactions with co-workers, supervisors, or clients. It can range from heated arguments to subtle incidents of unfriendly behavior (Jex,1998). It can occur when resources at wok are scarce, when employees have incompatible interests, or when employees feel they are not being treated fairly. It can distract workers from important job tasks, and it can have physical health consequences.
Role Stressors they are role ambiguity, role conflict, and role overload. Most jobs have multiple task requirements and responsibilities or roles (Rizzo, House, & Lirtzman, 1970), and that a job is likely to be particularly stressful if these roles conflict with one another or unclear. Role ambiguity occurs when employees lack clear knowledge of what behavior is expected in their job. In such cases, individuals experience uncertainty about which actions they should take in performing their job most effectively. Role conflict occurs when demands from different sources are incompatible.
A more specific form of conflict is role overload, a stressor that occurs when an individual is expected to fulfill too many roles at the same time. It can cause people to work very long hours, increasing stress and subsequent strains.
Work-Family conflict A different type of role stressor which occurs when workers experience conflict between the roles they fulfill at work and their roles in their personal lives. Because working women and dual-career families have become the norm rather than the exception , work-family conflict has become a common source of stress . In a study of men and women n high ranking positions, women were more stressed by their greater responsibility for household and family duties. In addition, women with children at home or any of the men in the study (Lundenberg & Frankenhaeuser, 1999). One study concluded that, compared to men , women appear to have better coping strategies to handle stress (Korbaik & McDonald, 1991). In particular, women are more likely than men to have access to social support which is a critical factor in reducing stress and it’s harmful effects.
Emotional Labor Interest in role of emotions in the workplace has increased rapidly over the past decade ( Fisher & Ashkanasy, 2000). Emotions are important to consider because stress is, first and foremost , an emotional reaction. Emotional labor is the regulation of one’s emotions to meet the job or organizational demands. The study of emotional labor addresses the stress of managing emotions when jobs require that workers display only certain expressions to clients or customers ( Adelmann, 1995). Workers can regulate their actions through surface acting and deep acting ( Morris & Feldman, 1996). Surface acting consists of managing or ‘faking’ one’s expressions or emotions. Deep acting consists of managing one’s feelings including trying to feel the emotions required by the job. Imagine a telemarketer who learns during lunch break a parent has been diagnosed with a life threatening disease. The struggle to maintain a cheery demeanor with customers would require considerable acting.
CHAPTER 2
Consequences of Stress
The link between occupational stress and adverse health outcomes among employees is clear ( Cooper et al., 2001). The negative consequences of chronic stress can be divided into three categories: behavioral, psychological, and physiological.
1) Behavioral consequences of Stress
Among the behavioral consequences of stress are absenteeism, accidents, alcohol and drug abuse, poor job performance, and counterproductive behaviors including workplace violence (Kahn & Boysiere, 1992). We will focus on the effects of stressors on two particularly important behavioral outcomes:
1. Information processing, which affects a variety of other critical work outcomes.
2. Job performance, which can include information processing, but often involves global measures of effectiveness.
1. Information processing The influence of stress has been widely investigated . Chronic stress has detrimental effects on memory, reaction times, accuracy, and performance of variety of tasks (Smith, 1990). In addition, individuals under stress often have difficulty focusing their attention. Stress leads to premature reactions to stimuli, restricted use of relevant cues, and increased errors on cognitive tasks (Svenson & Maule, 1993).
Because each of us has limited cognitive resources, stressful situations that restrict such resources will impair our ability to cope with the task at hand . Stress also correlates with lower creativity and poorer decision making , particularly under time pressure (Rastegary & Landy, 1993; Shanteau & Dino, 1993). For example, fast-food delivery drivers commonly have accidents during the rush period of deliveries (usually Thursday & Friday nights between 5:00 P.M. And 11:00 P.M.). They often report never seeing the object( e.g., car, truck, jogger, motorcycle) whose path they turned across. They simply did not ‘process’ that information when they turned left because they were looking for a street sign or a street number during the hectic evening hours
2. Job Performance For a century it has been investigated that arousal and performance have an inverted ‘U’ relationship. (Yerkes & Dodson, 1908). The hyposthesis is that as arousal increases, performance increases, but only up to a certain point, and then performance begins to decline. Thus, compared to situations with moderate arousal, both low levels of arousal (boredom) and high levels of arousal (extreme danger) result in lower performance. Alternatively, moderate arousal can lead to high motivation, energy, and attentiveness; this outcome is consistent with Selye’s concept of eustress. It is important to acknowledge that stress represents only one of many factors that may impact job performance (Jex, 1998).
2) Psychological Consequences of Stress
They include anxiety,depression, burnout, fatigue, job tension, and dissatisfaction with one’s job and life (Kahn & Byosiere, 1992). Burnout is a particularly important consequence of stress. It is an extreme state of psychological strain that results from a prolonged response to chronic job stressors that exceed an individual’s resources to cope with them ( Maslach, Schaufeli, & Leiter, 2001). Burnout was first observed in ‘caring professions’: dentists, doctors, nursing, social work, and teaching.
3) Physical Consequences of Stress:
Theories of Stress
Several theories have been developed to organize the relationships among stressors, strains and potential moderators of those relationships. Two theories that have received a great deal of attention are Karasek’s Demand-Control Model and French’s Person-Environment Fit Model. In addition, stress models have considered individual difference variables that influence the relationship between stressors and strain.
1. Karasek’s (1979) Demand-Control Model suggests that the two factors are prominent in producing job stress: job demands and control (also known as decision latitude). In this model, job demands are defined as the workload and intellectual requirements of the job. Job control is defined as a combination of autonomy in the job and discretion for using different skills. Karasek proposed that the combination of high work demands with low control results in ‘high strain’ jobs that result in a variety of health problems. Food services worker, waitperson , nurse’s aide, and assembly-line worker are considered high strain jobs. Machine-paced jobs, in particular, were highlighted as having high demands and low control. In contrast , jobs characterized by high demands also provide sufficient control create an ‘active’ job situation that is stimulating and health promoting. Active jobs include lawyer, engineer, manager, and physician. Jobs with low control and low demands (e.g., janitor, night watchmen) were labeled as ‘passive’ jobs. Finally, jobs with high control and low demands (e.g, architect, dentist) were considered as particularly low strain jobs.
Tests of the Demand-Control model are often conducted is using the Job Content Questionnaire (JCQ), designed to measure the ‘content’ of a respondent’s work (Karasek, 1985). The JCQ includes the following subscales:
‘ Role overload and role conflict (demands).
‘ Skill utilization and job decision latitude (control).
‘ Depression, job dissatisfaction, and sleep problems (health consequences).
The scales have been used extensively to investigate job-related stress and coronary heart disease in the United States and Sweden. For example, in a series of surveys involving U.S. and Swedish male workers, Karasek (1979) found that the combination of low control heavy job demands correlated positively with mental strain (i.e., depression and exhaustion) and job dissatisfaction.
Karasek and Theorell (1990) found an increased risk of illness(two to four more times more likely) for individuals whose lives or jobs make high demands on them but allow little control. Thus, an individual who has a demanding work schedule or environment and does not have have much decision latitude or control will have an increased risk of stress-related illnesses, both physiological and psychological. In contrast, individuals in active jobs that have high demands but high maintained good health and high job satisfaction. Karasek and Theorell (1990) noted that individuals in active jobs appear to participate actively in a variety of leisure activities as well, despite their high work demands. This finding is another example of the benefits of developing or designing jobs that allow workers to have control over decisions, resources, or skills that they can use.
Ganster, Fox, and Dwyer (2001) tested the Demand-Control model in a sample of 105 full-time nurses . They found that nurses with the lowest perceptions of personal control and highest workload demand were ill more often and incurred the highest cumulative healthcare costs over the ensuing five-year period. Thus, jobs that have high demands and low control are costly to both individuals and the organizations for which they work.
Person-Environment Fit Model
The Person-Environment (P-E) Fit Model (French, Caplan, Harrison, 1982) hypothesizes that the fit between a person and the environment determines the amount of stress that person perceives. A good person-environment fit occurs when a person’s skills and abilities match the requirements of the job and work environment. For example, an introvert with PhD in literature would be likely to have a good P-E fit with the job of university librarian, while an extraverted MBA have a good P-E fit with the job of sales manager. The amount of stress a worker feels is influenced by perceptions of the demands made by the environment, and by perceptions of his or her capability to deal with those demands. Using this model, French et al. found that a poor fit between a person and the environment was frequently associated with increased strains. Alternatively, employees whose skills and abilities fit well with the work environment reported less stress and fewer strains (Edwards, 1996; French et al., 1982).
Karasek (1979) did not formally emphasize perception in the Demand-Control model. In contrast, the P-E fit approach focuses explicitly on the perception of individuals concerning their skills and abilities relative to the demands of the work environment. In addition, unlike the Demand-Control model, the P-E fit approach considers external influences such as social support from family and work sources. For example, Edwards and Rothbard (1999) found that the well-being of the employees varied according to their perceptions of work and family experiences. The results of this study indicate that interventions to manage stress should consider the fit between employees and both their work and family environments, which is consistent with the research we discussed above on work-family conflict. In particular, if it is bad in both the family and the work environment, the cumulative stress is likely to lead to low job performance and high health problems.
Early work did not always specify what ‘environment’ was referred to in the P-E fit model. Recent work has more clearly differentiated between person-job fit and person-organization fit (Lauver & Kristof-Brown, 2001). Person-job fit refers to the extent to which the skills abilities and interests of an individual are compatible with the demands of the particular job. Alternatively, person-organization fit refers to whether the values of an employees are consistent with the values of held by most others in the organization. In a diverse sample of managers, Lovelace and Rosen (1996) found that perceptions of poor person-organization fit were associated with greater levels of stress, job dissatisfaction, and intentions to quit one’s job. Similarly, Saks and Ashforth (1997) found that favorable employee perception of person-job fit correlated positively with job satisfaction and organizational commitment, and negatively with stress.
It is clear that different types of fit have influence on a variety of problems, including stress, job dissatisfaction, and intentions to leave the organization. Organizations should strive to ensure that employees fit well in their jobs and have the skills necessary to complete their job tasks. In fact, fit is often increased through recruitment and selection processes that help applicants and those doing the hiring assess the likelihood that candidates will fit well in the job and in the organization (Schneider. 1987).
The P-E fit model suggests mechanisms by which individuals can protect themselves from the stress that accompanies the mismatch between the person and the environment. One of these protective mechanisms is social support. For example, employees who have seemingly impossible deadlines might seek informational and emotional support from co-workers. By reducing their experience of stress in this way, employees might be able to focus better and come closer to meeting their deadlines than if they were overwhelmed and suffering from strains. Overall, the P-E fit model allows us to examine work stress by looking at the interaction between the person and stressors in the work environment. This approach specifically acknowledges that stress can influence individuals differently depending on their preferences, values, and abilities (Edwards, 1996).
Individual Differences in resistance to stress
When you have been part of a group in a stressful situation, not everyone responds to stress in the same way. Several individual characteristics has been studied as the potential moderators of stressor-strain relationship. A moderator is a variable that affects the direction or strength of the association between two other variables. For example, if stressors led to strains for individuals with low self-esteem but not for those with high self-esteem, then self-esteem would be a moderator of the stress-strain relationship. If moderators reduce strains for only certain types of individuals, they are said to have an indirect effect on the reduction of strains. Individual difference characteristics that have received the most attention as moderators of the stressor-strain are locus of control, hardiness, self-esteem, and the Type A behavior pattern.
Locus of control (LOC) is a construct that refers to whether individuals believe that happens to them is under their control or beyond it (Rotter,1996). Individuals characterized as internals believe that outcomes are result of their own personal effort and ability, whereas persons classified as externals believes that outcomes are determined laregely by other people, luck, or fate. Many elite professional atheletes are confident-sometimes overconfident- that success lies completely in their hands (i.e., they have an internal LOC). In team sports, they like to be thought of as the ‘go to’ person. Several studies have indicated that internal experience lower strains than do externals. Researchers have proposed that because internals believe they can control a stressful situation to achieve their goals, they experience fewer strains than externals exposed to the same stressors. Overall, evidence indicates that having an internal locus of control moderates the relationship between stressors and strains (Horner,1996; Kahn & Byosiere,1992).
Hardiness is a set of personality characteristics that provide resistance to stress(Kobasa,1979). Specifically, individuals described as having a ‘hardy personality’ possess three characteristics:
1. They feel they are in control of their lives.
2. They feel a sense of commitment to their family and their work goals and values.
3. They see unexpected change as a challenge rather than an obstacle.
Cohen and Edwards (1989) observed that hardy individuals actively adopt problem-focused and support-seeking strategies. Kobasa, Maddi, and Kahn (1982) found that hardy individuals had fewer physiological reactions to stressors, reported fewer illnesses, and had higher levels of general well-being than those who were not hardy personalities were found to have significantly fewer strains than those who were not hardy. Among executives and lawyers who were under a great deal of stress, those who were hardy personalities were found to have significantly fewer strains than those who were not characterized as hardy (Maddi & Kobasa, 1984). Overall, evidence indicates that hardiness moderates the relationship between stressors and strains ( Cohen & Edwards, 1989). A key component of hardiness is transformational coping, which involves actively changing perceptions of a stressful event by viewing it as a challenge that can be overcome. For example, hardy students facing an important and stressful exam might cope by interpreting their exam as an opportunity to show their knowledge, thereby exerting control through preparation and good study habits (Quick et al.,1997).
Self-esteem, or positive self-worth or self-concept, is considered an important resource for coping. Individuals with high self-esteem are more likely to adopt more effective coping strategies in the face of stress than individuals with low self-esteem (Ganster & Schaubroeck,1995). Thus when faced with the same environmental stressors, individuals with low self-esteem will experience more strains compared to those with high self-esteem. Overall, research generally indicates that self-esteem is a moderator of the stress-strain relationship (Cooper et al., 2001). Although high self-esteem is clearly important in reducing the effects of stress at work, there is some evidence that the effects of high self-esteem are not always positive. Although many people assume that low self-esteem is related to work-place violence, Baumeister, Smart, and Boden (1996) conducted an extensive literature review that indicated that aggression and workplace violence were most characteristic of individuals with high self-esteem.
Type A Behavior Pattern
The potential moderator of stress-strain relationship that has been most intensively studied is the Type A behavior pattern (TABP), which was first identified in the late 1950s by two cardiologists, Meyer Friedman and Ray Rosenman (1959). Fifteen years later, Friedman and Roseman wrote Type A Behavior and Your Heart (1974), in which they described the Type A behavior pattern as a set of characteristics exhibited by ‘individuals who are engaged in a relatively chronic struggle to obtain an unlimited number of poorly defined things from their environment in the shortest period of time and, if necessary , against the opposing of other things or persons in the same environment’ (p.67).
The Type A behavior pattern is also known as the coronary-prone personality because of its proposed links to coronary heart disease and heart attacks. Individuals who exhibit this behavior pattern ( known as Type As) are characterized by ambitiousness, impatience, easily aroused hostility, and time urgency. Friedman & Roseman (1974) suggested that the core characteristic of TABO is an incessant struggle to achieve more and in less and less time. In fact, descriptions of Type As who are overly obsessed with saving time are common. For example, Typpe A men have been known to use two electric razors (one for each side of the face ) at the same time to shave more quickly as possible (Bluedorn,2002; Gilberth & Carey, 1948). Generally Type As seem to thrive on ‘life in the fast lane’ as they focus on quickly doing things that result in occupational and material success. In contrast, Type Bs are often described as relaxed patient, and easygoing.
Sapolsky (1998) described the history of how Friedman and Roseman missed an opportunity to identify some of the typical characteristics of Type As in the early 1950s. In the waiting room outside Friedman and Roseman’s Cardiology office, the lining of the chairs was worn down so much that the upholstery needed to be replaced frequently. Only years later that they began their formal work on Type A behavior pattern and thus realize that their heart patients had a consistent pattern of behavior , including nervous energy and fidgeting, that was related to heart disease. Research has indicated that Type As do tend to desire control and responsibility, and they prefer to work alone (Clark & Miller, 1990; Strube, Lott, Heilizer, & Gregg,1986). As for the outcomes compared to Type Bs, Type As are more punctual , work at faster rates, and are high achievers in college and in their professional careers (Gastorf, 1980; Taylor, Locke, Lee & gist,1984; Yarnold & Grimm,1982). So, although the Type A behavior pattern was initially because of its association with health problems, it also appears to be associated with positive outcome such as high work performance and career success.
It was important to have a clear evidence that these positive outcomes came at the cost of high stains and sucdequent health problems. Specifically, researchers were interested in whether Type As respond to stressful situations with greater physiological arousal and thus suffer greater strains than Type Bs. Accordingly, many studies have attempted to link TABP to increased physiological arousal and to the development of coronary heart disease. However these efforts were slowed by the use of imprecise, global TABP measures that attempted to assess several TABP subcomponents (Booth-Kewley & Friedman,1987). This led researchers to focus on identifying specific subcomponents of the TABP that were most predictive of coronary heart disease. Subsequent studies indicated that hostility is the primary TABP subcomponent associated with increased secretion of stress hormones as well as increased risk of coronary heart disease and other long-term, harmful health outcomes ( Krantz & McCeney, 2002; Miller,Smith, Turner, Guijarro, & Hallet, 1996). Thus, Type As who exhibit hostility pay a price for their accomplishments in terms of increasing their likelihood of suffering from a variety of long-term health problems.
They continued on examine other TABP subcomponents in their attempts to predict work and short-term health outcomes in Type As. Two TABP subcomponents that have received attention are achievement striving and impatience/irritability (Spence, Helmreich, & Pred, 1987). Achievement striving is the tendency to be active and to work hard in achieving one’s goals, whereas impatience/irritability reflects the intolerance and frustration that results from being slowed down.
The Achievement striving dimension is positively corelated with academic performance, sales performance, and job satisfaction (Bluen, Barling, & Burns, 1990; Spence et al., 1987). The impatience/irritability dimension is associated with health problems such as insomnia, headaches, poor digestion, and respiratory difficulties (Barling & Boswell,1995; Bluen et al.,1990). These studies indicate that achievement striving and impatience/irritability are independent from each other and that these TABP subcomponents can be used to differentially predict performance and health outcomes.
An additional TABP subcomponent that appears to be related to important work and health problems is time urgency, which refers to the feeling of being pressured by inadequate time. Time-urgent individuals check their watches repeatedly, even when they are not under the pressure of deadlines, and they are concerned with saving relatively small amounts of time (often measured in minutes or seconds). Time-urgent individuals seem to always know what time it is even when they are not wearing a watch. Increasing evidence indicates that individuals differ widely from one another in the degree to which they concern themselves with the passage of time and how to cope with it in accomplishing work-related and personal goals (Conte, Mathieu, & Landy, 1998). For example, some individuals are constantly making schedules, lists, and deadlines for themselves, whereas others do not pay attention to such temporal concerns.
Recent evidence suggests that time urgency has multiple dimensions including time awareness, eating behavior, nervous energy, list making, scheduling, speech patterns, and deadline control. Landy, Rastegary, Thayer, and Colcvin (1991) developed Behaviorally Anchored Rating Scales (BARS) for these dimensions of time urgency. Research indicates that these time urgency dimensions are relatively independent, which means that individuals can be high on some dimensions are relatively lower on others (Conte, Landy, & Mathieu, 1995; Landy et al.,1991). For exampple, workers may eat very quickly during a brief lunch break, but they may not focus much on making lists or following schedules very closely. Alternatively, some task-oriented individuals may work quickly and focus closely on schedules and deadlines, but they may not speak quickly or exhibit nervous energy.
Research also indicates that certain time urgency dimensions (e.g., list making, scheduling) are related to work outcomes, whereas other time urgency dimensions (e.g., eating behavior, nervous energy, speech patterns) are related to health outcomes. Menon, Narayanan, Spector (1996) related time urgency to occupational stress and health outcomes in a sample of nurses and physicians. They found that rapid talking and eating behaviors were positively correlated with arguments on the job and with lowered resistance to physical illness. In contrast, scheduling, list-making, and time-awareness behaviors were positively related to job satisfaction indicating that some time urgency dimensions can result in positive work outcomes.
Conte, Schenneker, Dew, and Romano (2001) found that the deadline control time urgency dimension was significantly related to work pace, that is, individuals who were focused on deadlines worked faster than those who were not controlled by them. This finding is likely to be usedful in organizations and industries in which a fast work pace is crucial. For example, there are immense pressures for efficient and timely development of new products in computer industry. Time-urgent individuals who have experience working under time constraints may be able to withstand a higher level of time pressure when the work situation requires it (Freedman & Edwards, 1998). However, difference in the way team members approach and utilize time may be a source of tension and may make it difficult for teams to function well under deadline pressures (Waller, Conte, Gibson, & Carpenter, 2001).
Overall, specific TABP subcomponents do a better job of predicting particular criteria than a global Type A measure that combines a variety of different subcomponents. Thus researchers and practitioners concerned about health and performance outcomes will have more success using TABP subcomponents to predict health and performance outcomes.
In summary, research on TABP subcomponents indicates that :
‘ Achievement striving is positively related to desirable work outcomes.
‘ Impatience/irritability is related to short-term health problems.
‘ Hostility is most predictive of long-term health outcomes ( e.g., coronary heart disease).
‘ The multiple dimensions of time urgency are related to a variety of work and health outcomes.
Reducing and managing stress
In 1990 stress was listed for the first time as one of the top 10 occupational health risks in the United States. As a result, concerns about stress at work became much more prominent in public and government discussions of health(Sauter, Murphy, & Hurrell, 1990). These concerns led to the development of the field of Occupational Health Psychology, which involves the application of psychology to improving the quality of work life, and to protecting and promoting the safety, health, and well-being of workers.
Occupational health psychologists often divide their approaches to stress reduction and management into three major categories: primary, secondary, and tertiary interventions (Cooper et al., 2001; Quick et al., 1997)
Primary Prevention Strategies
They are concerned with modifying or eliminating stressors in the work environment and therefore said to be ‘stressor-directed’ (Cooper & Cartwright, 2001). Primary interventions are the most proactive and preventative approaches to stress management (Cooper et al., 2001). Many primary intervention strategies give workers increased control over the job and work environment, which directly lowers stressors and increases employees satisfaction and well-being.
Primary prevention approaches include redesigning the task or work environment, encouraging participative management, developing clearer role descriptions, and modifying or changing Type A thought patterns. Another primary prevention strategy involves providing flexible work schedules which can be seen in recent trends toward flextime, shorter work weeks, and job sharing. Primary prevention approaches are aligned with problem-focused coping strategies, which are directed at managing or altering the source of stress (Lazarus, 2000).
Work and Job Design
Work and jobs can be designed or redesigned to reduce such stressors as noise, interruptions, time pressure, role ambiguity, and the number of hours worked (Sparks, Cooper, Fried, & Shirom, 1997). In addition, jobs can be redesigned to increase worker participation in decision making and to increase autonomy on the job. Decades ago, restaurant owners decided to reduce the stress on stress on short-order cooks by requiring waitpersons to clip their orders to a small, circular, revolving order stand. The cooks could then spin the stand around, see what orders were pending, and decided to pull off first. This principle was extended to auto manufacturing by Saab and Volvo. Automobile bodies circled work teams on oval track, and the teams decide which ones to pull off first for assembly and paint operations. Another example of redesigning of is the common ‘queuing’ process that is found at many service centers. Customers stand in one line and are not permitted to approach a service desk until their number is flashed or an available agent is identified by electronic screen. This process increases the customer service agent’s control over how quickly customers are served and thereby reduces the agent’s stress. Such changes can help workers feel that their work is more meaningful and that they have control over work outcomes. This in turn leads to a higher motivation and satisfaction as well as lower stress at work (Hackman & Oldham, 1980).
A study by Jackson (1983) provides a good example of the benefit of participative decision making. Jackson found out that nursing and clerical employees who participated in decision making at staff meetings had increased perceptions of control and reduced role ambiguity and role conflict. With stressors reduced by this relatively simple change in the way meeting were conducted, employees had higher job satisfaction and lower emotional strain at work, which over time led to fewer absences and lower intentions to leave the job.
Cognitive Re-structuring
Several of the approaches that we have discussed, including the Person-Environment Fit model and Type A behavioral pattern, highlight the role of perceptions in the stress process. Cognitive restructuring interventions focus on changing perceptions and thought process that lead to stress. These approaches reduce stress by changing an individual’s perception of the work environment or one’s capacities to meet the demands of the environment. Cognitive restructuring approaches encourage individuals to change negative thoughts to more positive ones (Quick et al., 1997). for example, a worker who thinks, ‘ I can’t handle this heavy workload’, might be encouraged to think instead: ‘This workload is a challenge that I can handle if I break it down into manageable parts’, or ‘ I won’t be considered a complete failure if I don’t push very hard to finish this task today’.
Secondary Prevention Strategies
It involves modifying responses to inevitable demands or stressors; thus, they are said to be ‘response-directed’. Because it addresses the experience of stress rather than the stress or stressors, it’s role is often one of damage control. Thus, this type of intervention is often described as the ‘Band-Aid’ approach (Cooper & Cartwright, 2001). They are aligned with emotion-focused coping strategies, which seek to reduce the emotional response to the stressor and can involve avoiding, minimizing, and distancing oneself from the stressor (Lazarus, 2000). For example, emotion-focused coping might be used to reduce the stress experienced in a job that requires emotional labor.
Secondary prevention strategies that require no special training (but might be formally encouraged through an employer-sponsored program) include lifestyle choices such as phyiscal fitness, healthy eating, and weight control, as well as a reduction in smoking and caffiene. Skills-training programs such as negotiation and conflict resolution are another form of secondary intervention. In addition, secondary stress management methods include relaxation techniques, biofeedback, and providing or encouraging social support at work. Many approaches use a combination of the above methods.
It is important to note that secondary prevention can be proactive or reactive. For example, Cooper et el. (2001) noted that training in conflict resolution skills can be used to reduce interpersonal conflict and its effects after it has occurred. Alternatively, such training can be used proactively to prevent interpersonal conflict from developing. Similarly, individuals can be proactive in exercising and maintaining a healthy diet, which can reduce or moderate future stress.
Stress Management Training
Programs involving stress management training are very popular with employers and employees. Cooper and Cartwright (2001) noted that the continued demand for stress management programs and the increasing stress levels reported in the literature are indicative of the acceptance by organizations that stress is an inherent and enduring feature of the work environment. Stress management training programs are useful for helping employees deal with those stressors that are difficult to remove or change. They often include a variety of secondary prevention techniques and may even include some primary techniques. For example , many stress management programs are described as cognitive behavioral skills training programs.
Cognitive-Behavioral Skills Training
It’s a variety of techniques designed to help workers modify the appraisal processes that determine how stressful they perceive a situation to be, and to develop behavioral skills for managing stressors (Murphy, 1996). The most common type of cognitive-behavioral skills-training is stress inoculation, which usually consists of an educational component ‘ learning about how a person has responded to past stressful experiences; rehearsal ‘ learning various coping skills such as problem solving, time management, relaxation, and cognitive coping; and application ‘ practicing those skills under simulated conditions (Murphhy, 1996). Thus, in many cases these approaches are a combination of primary (i.e., to reduce stressors by means of cognitive restructuring) and secondary (i.e., to manage or cope with symptoms of stress through behavioral skills training) prevention strategies.
Jones et al. (1998) developed an organization-wide stress management program that was used with employees of several hospitals. The program included video modules that enhanced understand of stress and provided information regarding how to develop and improve coping skills, health behaviors, and relaxation routines. In a longitudinal investigation that evaluated the impact of this stress management program, Jones et al., found that one result was a significant drop in the average number of monthly medication errors by doctors and nurses. In an additional two-year longitudinal investigation, they found that 22 hospitals that implemented the same organization-wide stress management program had significantly fewer medical malpractice claims compared with a similar, matched sample of 22 hospital that did not participate. This study showed that well-conducted , psychological research efforts can decrease malpractice claims through stress management interventions.
Relaxation and Biofeedback Techniques
Relaxation techniques include progressive muscle relaxation and deep breathing exercises. Progressive muscle relaxation involves starting at the top or bottom on one’s body, tightening one set of muscles at a time for five to seven seconds, and then letting those muscles relax. Individuals can work through each major muscle group and thus help to progressively relax the entire body. These relaxation techniques are effective in reducing arousal and anxiety (Murphy, 1996).
Biofeedback is a stress management technique that involves teaching individuals to control certain body functions such as heart rate, blood pressure, even skin temperature by responding to feedback about their body from an electronic instrument (Quick et al., 1997). One simple and inexpensive biofeedback device is a skin-sensitive ‘biodot’ that monitors stress levels and physiological changes according to color changes. The dot darkens after individuals discuss a stressful event and lightens when they feel more relaxed (Ulmer & Schwartzburd, 1996). Thus, this device shows individuals that stress ‘ and relaxation for that matter ‘ leads to measurable changes in the body and that careful monitoring of the body can reduce anxiety and arousal.
Social Support
Is the comfort , assistance, or information an individual receives through formal or informal contacts with individuals or groups. Social support has been widely investigated as a way to reduce stress and strain at work. House (1981) identified four different kinds of social support.
1. Instrumental support ‘ direct help, often of a practical nature; for example, a friend encourages a co-worker to slow down by suggesting joint walks during the lunch hour.
2. Emotional support ‘ interest in, understanding of, caring for, and sympathy with a person’s difficulties ; this type of support is often provided by a therapist or a family member.
3. Informational support ‘ information to help a person solve a problem; this type of support is often supplied by a health care professional. In addition, an increasing number of websites are popping up with useful information.
4. Appraisal support ‘ feedback about a person’s functioning that his or her self-esteem; this often comes from a close friend, a therapist, family members, or other members of a support group.
Researchers have given considerable attention to the possibility that social support moderates or reduces health problems by protecting individuals from the negative effects of work stressors. Studying such effects is called the buffer or moderator hypothesis because it seeks to determine whether the negative effects of work can be buffered or moderated by social support (Cohen & Wills, 1985). Evidence is mixed on the buffering hypothesis, which could be due to the failure of researchers to emphasize the match between stressors and support. That is , buffering should work when there is a reasonable match between the stressors and the available social support. A longitudinal study of 90 blue-collar metalworkers found evidence for the buffering hypothesis in reducing anxiety and other strains when social support was matched directly to a social stressor such as conflict with one’s supervisors (Frese, 1999). Social support at work may be particularly important as a moderator of stress-strain relationship in the present day when traditional societal structures such as the extended family are smaller than they once were (Quick et al., 1997). For example, in the 21st century American society, many adult children no longer live close to their parents or siblings. They may see family members infrequently, usually over holiday periods that carry their own stress and strain.
Employers can help build their own social support systems at work. For example, formal mentoring programs, reward and recognition system, and newcomer socialization programs can make work environments more supportive. Allen, McManus, and Russell (1999) found evidence for the important role that more experienced peers can serve in mentoring newcomers and in enhancing socialization. In turn they found a negative relationship between socialization and work stress, indicating that formal peer relationships can be critical in reducing stress and subsequent strains. Finally, the supportive relationships formed in team building have been shown to improve performance and reduce stress (Svyantek, Goodman, Benz, & Gard, 1999).
Tertiary Prevention Strategies
They are ‘symptom-directed’ and thus they are focused on healing the negative effects of stressors. Tertiary interventions include employee assistance programs and the use of medical care, individual psychotherapy, and career counseling (Quick et al., 1997).
Employee assistance program (EAPs) were originally developed by organizations to address alcohol and drug problems, and they were subsequently broadened to include stress management interventions. In most organizations, EAPs involve some form of counseling to deal with work stress, alcohol or drug difficulties, and problems outside the job (e.g., family problems, behavioral and emotional difficulties). Employee assistance programs can be provided by the human resources department within an organization, or they may be provided by an external consultants or vendors. If an organization is to have successful EAPs, its management must express support for th program, educate employees about it, provide the necessary training on its use, and make the program accessible to employees (Milne, Blum, & Roman, 1994). Organizations must ensure that confidentiality is maintained and that the use of an EAPs programs does not harm job security or advancement. These suggestions are particularly important because unhealthy work climates and distrust in EAPs often prevent employees from seeking help for alcohol or drug abuse problems. For example, police officers often avoid in-house EAPs because they are uncertain of confidentiality assurances and fear that will be stigmatized by commanding officers and colleagues. Even to be seen talking with an EAP coordinator is ‘dangerous’. Integrating positive messages about EAP into different types of training programs may be effective in improving the use of EAPs by skeptical employees (Bennet & Lehmann, 2001).
Although EAPs are not often systematically evaluated by the organizations using them, the few evaluations that have been done indicate that EAPs are successful. Cooper and Saderi (1991) found improvements in the mental health and self-esteem of employees participating in EAPs . In addition, Cooper and Cartwright (1994) found that EAP programs can be very cost effective for organizations in terms of reducing absences, accidents, and health care costs. Nevertheless, even though focusing on the treatment of strains may be an effective short-term strategy, the approach is essential reactive and reciprocative rather than proactive and preventative (Cooper et al., 2001). Because EAPs focus on dealing with the long-term outcomes of stress, they should certainly not be the only approach that organizations utilize in the stress prevention and management process.
Summary of Stress intervention strategies
Several recent studies have evaluated a variety of stress management interventions. In a study by Bellarosa and Chen (1997), 96 stress management experts evaluated occupational stress management interventions (e.g., relaxation, physical fitness, cognitive restructuring, stress inoculation, meditation, and assertiveness training) on the basis of practicality and effectiveness. Evaluations by stress management experts are useful, but psychologists are also interested in more quantitative assesments of stress management interventions (Murphy, 1996; van der Klink, Blonk, Schene, & van Dijk, 2001).
Murphy (1996) conducted a comprehensive review of effects of worksite stress management interventions on a variety of health work outcomes (e.g., blood pressure, anxiety, headaches, and job satisfaction). The stress management programs included in this review were progressive muscle relaxation, meditation, biofeedback, cognitive-behavioral skills, and combinations of these techniques. Meditation produced the most consistent results across outcome measures, but it was infrequently used in organizations. Relaxation and cognitive-behavioral techniques were found to be quite successful. Overall, the study indicated that using a combination of techniques (e.g., muscle relaxation and cognitive-behavioral skills) was more effective across outcome measures than using any single technique. In another review of stress management interventions, Bunce (1997) also concluded that combining various stress management interventions is more effective than using any single approach. A recent meta-analysis found general support for the benefits of interventions for work-related stress (van der Klink et al., 2001). This study found that cognitive-behavioral approaches worked best in reducing stress, but relaxation techniques were also successful. Overall, these studies show reason for optimism about stress management interventions, particularly when a combination of techniques is used. In addition, successful stress management interventions must accurately identify the stressors causing strains, and then actively determine ways to reduce those stressors (Briner & Reynolds, 1999). Employees should also participate in the process of identifying stressors and implementing the various interventions deigned to reduce stress ans strains.
Primary stress prevention strategies are generally preferred over the other interventions because they take an active approach to removing and reducing stressors (Quick et al., 1997). Secondary and tertiary interventions can play a useful role in stress management, but their effectiveness is limited because they fail to address the source of stress itself. Thus, identifying and recognizing the stressors and taking steps to remove or reduce them through job redesign, flexible work schedules, or other primary prevention strategies should receive the highest attention in organizations. Indeed, the limited research that has examined primary-level interventions has shown that they yield consistently positive and beneficial long-term effects (Cooper & Cartwright, 2001). Similarly, the National Institute for Occupational Safety and Health (NIOSH) urges occupational health psychology professionals to give special attention to the primary prevention of organizational risk factors for stress, illness, and injury at work.
Human Factors Engineering
The importance and meaning of human factors
Workers are exposed to a wide variety of work ‘conditions’. They included physical conditions such as heat, light, and noise. The individual worker was expected to either adapt, or at least put up with, these conditions.
The humman factors approach uses the ‘knowledge of human (Capabilities) to design systems, organizations, jobs, machines, tools, and consumer products for safe, efficient and comfortable human use’ (Helander,1997, p.4). The term ‘ human factors’ is synonymous to human factors engieering or human factors psychology. Human factors overlaps with related discilpines such as ergonomics, the study of the physical demands of work, such as reaching, streching, lifting, and carrying; applied experimental psychology; occupational medicine; and exercise physiology.
The human factors assumes that workers are constant , and that the work needs to adapt to the worker. Human capacities and limitations include physical and cognitive abilities, knowledge, presonality, and even physiology. The goal of the human factors is to develop a physical and psychological environment that is optimaly compatible with the capacities and limitations of humans. Rather than accepting the environment as a constant, and selecting those few individuals who may be most compatible with it, the human factors catalogs the human capacities and limitations and develops an environment that is ideally suited as possible to them.
This was not the case. In the early days of the factory system, machines were designed by mechanical engineers who had little concern for the capacities and limitations of humans. An exampke of that cab be seen in the design of a popular machine for working on metal parts called lathe. The purpose of a lathe is to create a shape in a piece of steel or aluminum by spining that piece at a high speed and applying a sharp bit to its surface while it is spinning. Before computers were introduced to the factory floor, lathes were operated by hand with lots of manual controls, usually in the form of wheels, levers, and buttons which were used to bring the bit into contact with the piece to be shaped.
Consider the two individuals depiceted in figure 16.1 The person in the top portion of the figure (A) represents a typical lathe designed by mechanical engineers in 1920s, as sketched in the lower portion (B), would look much different. The ideal operator would be slightly over 4.5 feet tall and 12 feet across the shoulder, and would have an 8-foot arm span. This ideal operator was determined by the way the mechanical engineers designed the lathe, and we can be fairly certain that few real-life lathe operaotrs resembeled the ideal. The engineers most likely began their design with standard measurements of the components from which the machine would be built. From the human perspective, this was foolish. The mechanical engineers should have begun their design with an appreciation of the range of likely characteristics, capacities, and the limitations of the operators of the lathe. The implications are clear. If the equipment and environment are not compatible with the human who will use that equipment and populate that enviroment, we also can expect problems in the form of lowered production, injuries, and accidents. We also expect to see unhappy workers who are continuallu ‘taxed’ by their work.
Figure 16.2 is a reminder of the fact that we often take human factors for granted. Imagine an elevator with such a control panel. Think of the extra time you might need to locate the button corresponding to the floor you wanted to visit. Worse than that, imagine the chaos of a telephone keypad with a rendomly arranged numbers. There are literally hundreds of devices you use every day that have been designed or modified by human factors specialits; the configuration of an automobile dashboard, the height and tilt of a chair; the keyboard and screen at a computer workstation, the arrangement of knobs and burners on the stove top, the positioning of the brakes on a mountain bike, even the way a radio dial or a TV remote control works. All of these are examples of products or objects desgined to acheive user friendliness – that is, to be comfortable, easy to use, and compatible with human capacities and limitations. In this chapter, we will consider the concept and discipline of human factors engineering as it applies to work.
Human Factors Models
Howel (1993) identified human factors as the dynamic force in both technology design ans society. We have adapted his view in Table 16.1. In the left-hand column is the ‘need’ or driving force. In the right-hand column is the himan factor, or applied, issue or area of concentration. this table provides a good overview of the substance of human factors. Two very simple models can be used to poosition human factors in the broader perspective of the study of work behavior. Consider figure 16.3. In a series of concentric circles, we see that the worker is embedded in a series of increasingly larger environments which include, respectively, equipment(e.g., computers), physical workplace (e.g., work cubicle or office), social work space(e.g., teams), and organizational work space (e.g., climate or culture). Each of these environmentshas an influence on the performance of of the individual. Traditionally, the human factors appoach has concentrated on the interface between the worker and the equipment – and in the very last several decades, the ‘equipment of choice’ has been the computer. Figure 16.4 illustrates a very basic model of the interactionof the worker and equipment.
There are several components of the model. There is a worker. the equipment, the way the worker receives information from the equipment, and the way the worker controls the equpment, the way that the worker receives information from the equipment, and the way the worker controls the equipment. Both the equipment and the worker have an input component and an output component. An everyday example of the this model is that you’re supposed to prepare a paper for one of your classes and you were preparing it on the computer. As you sit infront of the computer you see a screen and a keyboard. What appears on the screen is the output from computer ans input to you. what you type on the keyboard represents output from you, but input to the computer. You and the computer are connected through this information flow loop. You ask the computer to access information in a literature base related to industrial safety by first activating a search engine, then typing in a website, and finally inputting some key words for the search. With that instruction, the computer accompishes the search and provides you with the relevant journal articles. There have been a string of interactions between you and the computer. You truned it on, you activated its operating system, you started the search engine, you identified the website, and you listed the key words. At each point in this process, the computer asked you to make choices. You made these choices with the mouse or the keyboard, and when you made each choice, the computer ‘did its thing’. These was considerable input and output in both sides of the keyboard.
This simple example introduces two additional technical terms that are important in human factors; displays and controls. Displays (e.g., computer screen)provide an individual with information, while controls (e.g., keyboard or mouse) permit an individual to take actions. there is a rich history as well as an active current research interest in the design of the most effective methods of display and control (Salvendy,1997; Wickens, Gordon, & Liu, 1998). But displays and controls are only two components of a more elaborate model of work from the human factors approach perspective. Figure 16.5 presents a more complete systems view of the human factors approach to work.
Human factors is a global discipline. The same human factors issues affect virtually any industrialized country. Helander (1997) identified a number of human factors challenges characterise work in 25 different countries. These include the change of work organization and design, work-related musculoskeletal disorders, and human-computer interface. Muskuloskeletal disorders of the lower back and upper extremities are the most commonly studied injuries related to workspace safety. Human-computer interface (HCI) is the interaction between a human and a computer. Other factors that Helander identified are the change in social systems of work environments, high technology system design (particularly nuclear power plant control rooms), mental workload, and human reliability.
Work Schedules
The scheduling of work is under the control of the organization, and thus can be considered an issue of work design. Work schedules are playing an increasingly important role in managing work-life balance in two ways: Individuals desire the freedom to pursue leisure activities outside of work, and they often have obligations to fulfill multiple roles as spouse, caregiver, and the parent. This suggests that the scheduling of work can have substantial effects on worker well-being. There are three different scheduling formats that bear discussion: Shift work, flextime, and compressed workweeks.
Shift work
The scheduling of work according to a prticular time period is called shift work. The study of shift work and its effects on workeres has a long and rich research history. This history is well presented in a number of sources (e.g, Johnson, Tepas, Colquhoun, & Colligan, 1981; Landy, 1989; Tepas, Paley, & Popkin, 1997; Wedderburn, 1981). Much of this work has centered on the 24-hour a circadian cycle of humans, whose physiology tends to make them active during hours of light and inactive(e.g., sleeping or resting) during hours of darkness. Thus, workers assigned to shifts during daylight hours are following the circadian cycle, while those whose shift includes hours of darkness are working against the cycle. Psychologists found that, in general, the disturbance of thee circadian cycle has adverse effects on the health, performance, and general satisfaction. Shift work is categroized in to two different types: fixed shifts and rotating shifts. If workers are permenantly assigned to a particular shift, the shift is called fixed shift. Typical shifts inlude the day shift (e.g., 7:00 A.M. to 3:30 P.M.), the afternoon or evening shift – often called the ‘swing’ shift (e.g., 3:00 P.M. to 11:30 P.M.), and the night shift – often called the ‘ midnight’ or ‘graveyard’ shift (e.g., 11:00 P.M. to 7:00 A.M.). Workers who move from shift to shift are said to be working a rotating shift schedule. Shiftscan rotate rapidly (e.g., move to a different shift every week) or slowly (e.g., a worker may change shifts every three months). In union environments, worker can often bid on shifts based on seniority, resulting in more frequent shift changes for workers less seniority.
Generally speaking, rotating shifts are more likely to be associated with problems that fixed shifts (Parkes,1999). This is particularly true if the direction of the rotation is from day to night to evening (as opposed to day to evening to night). Rotating shifts and particularly rapidly rotating shifts, lead to sleep disturbances , which in turn are associated with medical (e.g., gastrointestinal) and psychological (e.g., anxiety and depression) difficulties. Rotating shifts also seem to be hard on older workers (Landy, 1989).
Shift work is more common in some occupational groups than others. Nurses, blue collar workers, and public safety personnel have higher concentrations of shift workers than professional, managerial, or white-collar groups ( Smith et al.,1999). The most frequently studied of those occupations is the nursing profession. Barton (1994) examined the nurses who take night shifts on permanent basis and nurses who where assigned to rotating night shifts. Permanent night shift nurses reported significantly fewer problems with health, sleep, and social or domestic activities. This was particularly true for individual nurse who chose to work on the permanent night shift compared with nurses who chose to work on permanent night shift compared with nurses who chose rotating shift schedule. The most important reasons the nurses in this study gave for choosing the permanent night shift were the night shift work permitted them to more easily fulfill domestic responsibilities, and it paid better. Thus, for those who chose permanent night work, it actually improved control and scheduling of work-nonwork roles. But the nurses on a rotating shift schedule felt that their lives were disrupted every time they had to work afternoon or night shifts (Barton, 1994). It appears that night shift work provides a significant opportunity for establishing a work-life balance that is not possible for rotating shifts or, in some circumstances, day or afternoon shifts. This seems to be a particularly true of dual wage earning families with young children. In another study of nurses, Bohle and Tilley (1998) found that work-nonwork conflict was one of the strongest predictors of satisfaction with shift work.
These balancing advantages notwithstanding, some research has shown that permanent day shift tends to be more intrinsically satisfying that afternoon, night, or rotating shift work. Blau and Lunz (1999) analyzed the effect of various shift schedules on 705 medical technicians (MTs) and found that MTs who worked a permanent day shift reported that their jobs were less routine than the jobs of MTs on any other shift. To some extent, this perception conforms with the reality of this job across shifts. Night shift MTs tend to perform standardized tests on samples gathered during the day. In addition, since many medical procedures are performed during the day. Since many medical procedures are performed during the day and vary substantially from patient to patient, it makes sense that the work of the day shift MT would be less routine. The day shift MTs were also more satisfied with supervision, mainly because supervisors were available on the day shift, as opposed to the night shift, which often functioned without any direct supervision.
Flexible and compressed workweek schedules
Shift work regardless of whether it is fixed or rotating, defines the work schedule rigidly. In general, shift workers are expected to work eight hours per day, five days per week. But there are other scheduling variations that are not so rigid.
Flextime Individual workers who are given discretion over the time they report to work and the time they leave work on a given day are working a flextime schedule. Such schedules are uncommon in manufacturing organizations, since the interdependence among workers in assembly-line and continuous process operations makes the absence of a particular worker particularly problematic (Baltes, Briggs, Huff, Wright, & Newuman, 1999). A survey of a diverse sample of more than 1000 organizations in 1995 revealed that 66% of them permitted some form of flexible workday (Hewitt Associates, 1995). That percentage has probably increased since 1995. In a typically flexible work schedule, every worker is expected to be at work during a ‘core’ period (e.g., 10:00 A.M. – 3:00 P.M.) but is permitted to arrive as early as 7:00 A.M. and leave as late as 9:00 P.M. (Baltes et al., 1999). Regardless of when they arrive and leave, they are expected to be at workplace for 40 hours a week. Ronen (1984) after the introduction of flextime the average arrival time of workers was 8 minutes later than it had been before, and that the average departure time was 22 minutes later after the introduction of flextime. The benefits of flextime to the individual worker are obvious. In addition to the psychological advantages of perceiving some control over the work schedule, there is the practical advantage of achieving a better balance between work and nonwork. Most workers express satisfaction with flexible schedules.
Compressed workweek Another nontraditional work schedule is the compressed workweek, which permits an employee to work for longer than eight hours a day and fewer than five days a week. A common plan is 4/10 plan, which permits a worker to accumulate the 40 hours of the workweek in four days. For some workers, this affords the opportunity to enjoy an ongoing series three-day weekends. For others it permits them to take another jobs or pursue further education on a more regular basis while still working. A 1995 survey of 1000 companies found that 21% offered workers the possibility of a compressed workweek. This type of schedule is found most commonly in the manufacturing organizations (Baltes et al., 1999). As with flextime, workers tend to express satisfaction with the compressed workweek (Landy,1989).
Consecuqeunces of Flextime and Compressed workweek Schedules Worker satisfaction with flextime and compressed workweek schedules is well documented (Baltes et al., 1999; Landy, 1989). But are these work schedules associated with organizational outcomes such as productivity, performance, and absenteeism? The activity of creating and maintaining nontraditional work schedules inevitably incurs some administrative costs, so organizations may well ask, What’s in it for us? Baltes et al., (1999) conducted a meta-analysis of 39 studies on the effects of flextime (27 studied) and compressed workweeks (12 studies). The results of analysis are useful and encouraging for both of these scheduling variations. They found that flextime was associated with higher productivity and lower absenteeism, although the impact on absenteeism was considerably greater than the effect on productivity. For the compressed workweek, they found that while absenteeism was unaffected, supervisors’ ratings of performance were higher (though productivity was not).
Baltes et al, (1999) did some further analyses of their data and found that flextime had little effect on productivity, performance ratings, or absenteeism for professionals and managers such as accountants or sales managers. In addition, they found that for non-professional, non-sales managerial workers =, programs with extremely flexible hours were less effective than more conservative programs. They concluded that this was probably the result of the inability of employees in the workplace to communicate with absent employees. This would be problematic in organizations that depend heavily on teams and groups as opposed to single contributors. They also found that the effects of flextime tended to diminish after the initial period of adjustment (typically a few months); as workers became accustomed to the new scheduling, it became the norm. Remember also that one study demonstrated that actual arrival and departure schedules remained very much the same (Ronen,1981).
Approaches to work design and redesign
With the study of different work design issues; which included technological variables (computers and automation) and social variables ( work scheduling). Campion and Thayer (1985, 1987; Campion, 1988, 1989) have proposed that one might take many different approaches to designing and redesigning work, and since each approach has different goals, we might expect different outcomes, Campion and Thayer (1985) examined 700 different ‘rules’ that have been suggested for designing work and reduced them to four different outcome. In table 16.3, you will see the specific questions that might be asked in designing or redesigning a job. Any given design change includes several different approaches, not just one, which includes elements of motivational, mechanistic, and perceptual-motor approaches. The motivational approach to work design and redesign is used to increase worker satisfaction and reduce turnover through modification of motivational levels. The mechanistic approach to work design and re-dseign is used to increase productive efficiency through the modification of tasks or equipment. The perceptual-motor approach is used to reduce errors or accidents through knowledge of perceptual-motor skills and abilities. Finally, the biological approach is used to reduce injuries and increase the physical comfort of workers thought the reduction of fatigue and discomfort. Automation included elements of the mechanistic, biological, and perceptual-motor approaches. Work scheduling is related to the motivational and biological approaches.
Campion’s (1988,1989) models have several implications. First, we need to be clear about what outcomes we expect or desire in the design or re-design of work. If we are designing work to increase worker satisfaction and reduce turnover, we may want to choose the motivational appoach. If , instead, we are trying to reduce injuries and increase the physical comfort of workers, we would rely on the biological model. A second implication is that conflict may occur between the approaches, resulting in both anticipated and unanticipated outcomes. If you were to use the mechanistic approach to increase productivity efficiency, you would simplify work. But by doing that, you would also make the work less interesting and motivating for the worker.
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Chinese Science Bulletin, Volume 64 , Issue 10 : 1027-1036(2019) https://doi.org/10.1360/N972018-00874
DNAzymes in biological detection and gene therapy
More info
• ReceivedAug 24, 2018
• AcceptedOct 9, 2018
• PublishedNov 23, 2018
Abstract
Funded by
国家自然科学基金优秀青年科学基金(81822024)
国家自然科学基金国际合作项目(11761141006)
国家自然科学基金(21605102)
国家重点研发计划生物安全专项(2017YFC1200904)
Supplement
补充材料
图S1 Pb2+ DNAzyme的二级结构
图S2 UO22+ DNAzyme
图S3 基于L-组氨酸依赖性的DNAzyme检测体系构建
本文以上补充材料见网络版csb.scichina.com. 补充材料为作者提供的原始数据, 作者对其学术质量和内容负责.
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Otomastoiditis
Otomastoiditis, or more simply inflammation of the mastoid air cells, can be divided into two distinct entities:
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Home > Services > Colour Vision Assessment
Colour Vision Assessment
Colour vision deficiency can be classified as acquired or inherited. Inherited colour vision deficiency is primarily genetic, characterised by red-green colour blindness or defects in most cases. Acquired colour vision deficiency is often associated with pathological changes of retina or optic nerve, which may be caused by glaucoma or side effects of drugs.
Cases of total colour blindness are rare, and people with colour deficiency may not find it too inconvenient coping with everyday life. They can tell the differences by other signals, such as the positions or icons of traffic lights. However, their choices on occupation may be limited, particularly in the fields requiring colour perception like fine art, medicine, chemical engineering, electrical engineering and telecommunications.
There are commercially available specialty contact lens tailored for people with red-green colour deficiency. This red contact lens may help them better differentiate the colour by comparing the different contrast between two eyes.
When conducting a colour vision assessment, optometrists will use Ishihara test to screen red–green colour blindness or defects. More accurate colour test such as a Farnsworth D-15 test is needed in order to ascertain the severity of colour deficiency. | {
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-520,775,862,581,782,300 | Terizidone
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{{Drugbox | Verifiedfields = changed | verifiedrevid = 470602455 | IUPAC_name = 4,4'-{1,4-phenylenebis[(E)methylylidenenitrilo]}diisoxazolidin-3-one | image = Terizidone.png | image2 = Terizidone_ball-and-stick.png
| tradename = | Drugs.com = International Drug Names | pregnancy_AU = | pregnancy_US = | pregnancy_category = C | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration =
| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =
| CAS_number_Ref = ☒N | CAS_number = 25683-71-0 | ATC_prefix = J04 | ATC_suffix = AK03 | PubChem = 65720 | DrugBank_Ref = ☑Y | DrugBank = | ChemSpiderID_Ref = ☑Y | ChemSpiderID = 59144 | UNII_Ref = ☑Y | UNII = 1199LEX5N8 | KEGG_Ref = ☑Y | KEGG = D07247
| C=14 | H=14 | N=4 | O=4 | molecular_weight = 302.286 g/mol | smiles = O=C3NOCC3/N=C/c2ccc(/C=N/C1C(=O)NOC1)cc2 | InChI = 1/C14H14N4O4/c19-13-11(7-21-17-13)15-5-9-1-2-10(4-3-9)6-16-12-8-22-18-14(12)20/h1-6,11-12H,7-8H2,(H,17,19)(H,18,20)/b15-5+,16-6+ | InChIKey = ODKYYBOHSVLGNU-IAGONARPBB | StdInChI_Ref = ☑Y | StdInChI = 1S/C14H14N4O4/c19-13-11(7-21-17-13)15-5-9-1-2-10(4-3-9)6-16-12-8-22-18-14(12)20/h1-6,11-12H,7-8H2,(H,17,19)(H,18,20)/b15-5+,16-6+ | StdInChIKey_Ref = ☑Y | StdInChIKey = ODKYYBOHSVLGNU-IAGONARPSA-N | synonyms = 4-[({4-[N-(3-oxo-1,2-oxazolidin-4-yl)carboximidoyl]phenyl}methylidene)amino]-1,2-oxazolidin-3-one }}
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Terizidone is a drug used in the treatment of tuberculosis.
References
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237,269,099,109,326,620 | muscle-icon
Knee pain..
Few days back I started to running coz of to lose weight and m 6feet n 86 kgs so it's started pain in my lower knee.. Please suggest me any home medicine..
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Doctor Answers (1) on Knee pain..
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Dr. Anil Kumar Jain Bangalore | General Physician
Answered
hello there.
the pain will reduce on its own.
just take rest and increase the intensity of the exercise gradually.
don't do intense exercise.
regards
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Kinematic analysis of impairments and compensatory motor behavior during prosthetic grasping in below-elbow amputees
• Amélie Touillet,
Roles Conceptualization, Investigation, Resources, Supervision, Validation, Writing – review & editing
Affiliation Louis Pierquin Centre of the Regional Institute of Rehabilitation, UGECAM Nord Est, Nancy, France
• Adrienne Gouzien,
Roles Conceptualization, Data curation, Funding acquisition, Investigation, Writing – review & editing
Affiliation Service de psychiatrie, Pôle Paris Centre, Hôpitaux de Saint-Maurice, Saint-Maurice, France
• Marina Badin,
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Affiliation Louis Pierquin Centre of the Regional Institute of Rehabilitation, UGECAM Nord Est, Nancy, France
• Pierrick Herbe,
Roles Methodology, Resources
Affiliation Louis Pierquin Centre of the Regional Institute of Rehabilitation, UGECAM Nord Est, Nancy, France
• Noël Martinet,
Roles Conceptualization, Investigation, Resources, Supervision, Writing – review & editing
Affiliation Louis Pierquin Centre of the Regional Institute of Rehabilitation, UGECAM Nord Est, Nancy, France
• Nathanaël Jarrassé,
Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Software, Supervision, Validation, Visualization, Writing – review & editing
Affiliation Institute of Intelligent Systems and Robotics (ISIR), UMR 7222, CNRS/INSERM, U1150 Agathe-ISIR, Sorbonne University, Paris, France
• Agnès Roby-Brami
Roles Conceptualization, Data curation, Methodology, Project administration, Software, Validation, Visualization, Writing – original draft
roby-brami@isir.upmc.fr
Affiliation Institute of Intelligent Systems and Robotics (ISIR), UMR 7222, CNRS/INSERM, U1150 Agathe-ISIR, Sorbonne University, Paris, France
Abstract
After a major upper limb amputation, the use of myoelectric prosthesis as assistive devices is possible. However, these prostheses remain quite difficult to control for grasping and manipulation of daily life objects. The aim of the present observational case study is to document the kinematics of grasping in a group of 10 below-elbow amputated patients fitted with a myoelectric prosthesis in order to describe and better understand their compensatory strategies. They performed a grasping to lift task toward 3 objects (a mug, a cylinder and a cone) placed at two distances within the reaching area in front of the patients. The kinematics of the trunk and upper-limb on the non-amputated and prosthetic sides were recorded with 3 electromagnetic Polhemus sensors placed on the hand, the forearm (or the corresponding site on the prosthesis) and the ipsilateral acromion. The 3D position of the elbow joint and the shoulder and elbow angles were calculated thanks to a preliminary calibration of the sensor position. We examined first the effect of side, distance and objects with non-parametric statistics. Prosthetic grasping was characterized by severe temporo-spatial impairments consistent with previous clinical or kinematic observations. The grasping phase was prolonged and the reaching and grasping components uncoupled. The 3D hand displacement was symmetrical in average, but with some differences according to the objects. Compensatory strategies involved the trunk and the proximal part of the upper-limb, as shown by a greater 3D displacement of the elbow for close target and a greater forward displacement of the acromion, particularly for far targets. The hand orientation at the time of grasping showed marked side differences with a more frontal azimuth, and a more “thumb-up” roll. The variation of hand orientation with the object on the prosthetic side, suggested that the lack of finger and wrist mobility imposed some adaptation of hand pose relative to the object. The detailed kinematic analysis allows more insight into the mechanisms of the compensatory strategies that could be due to both increased distal or proximal kinematic constraints. A better knowledge of those compensatory strategies is important for the prevention of musculoskeletal disorders and the development of innovative prosthetics.
Introduction
After a major upper-limb amputation, depending on the subject’s expectations and life project, various prosthetic solutions are available with different control systems and terminal effectors. The patient’s living conditions, leisure time and professional activity are considered to define the rehabilitation and fitting projects. The motor control of the prosthesis is not intuitive and requires learning. Body-powered prostheses are controlled through a harness connected by a cable that might provide for limited proprioceptive feedback [1]. Myoelectric control, which is the most common control mode, was invented in the fifties [2]. It associates the surface myoelectrical activities (EMG) from the residual limb to one or several prosthetic movements [3]. When several prosthetic joints have to be controlled, each of them is sequentially controlled by the same muscular contractions, with a switch between joint being activated by a co-contraction or specific contraction levels [4]. In addition, prosthetic users described that prosthetic use is complicated by the reduction of sensory information, particularly with current myoelectric prostheses which do not provide artificial sensory feedback [5, 6]. However, some limited perceptual information about the subject’s environmental context and the manipulated object can be collected through the prosthesis by dynamic touch, that remains possible even in case of sensory impairment [7]. Visual control is often required during using prosthesis [8]. So, despite the potential possibilities offered by advanced prostheses such as polydigital hands, and despite the progress allowed by pattern-recognition techniques (allowing a more precise decoding of myoelectric signals and thus more controllable prosthetic joints [9]), their control remains particularly non-physiological (sequential and delayed) and complex both to learn and to use [10, 11]. The importance of the cognitive load necessary to a task also influences the strategies used [12].
All this leads to altered or unusual movements with other joints and segments when manipulating an object with a prosthetic device [13, 14]. These multiple limitations have a direct functional impact and are responsible for a high attentional load [6]. Moreover, this leads some amputees to abandon the use of a prosthesis [15] and particularly of upper-limb myoelectric prostheses [5].
Further studies are needed to better understand the difficulties of the amputees using prostheses in order to improve prosthetic solution. Most clinical methods used for the evaluation of prosthetic devices use specific outcome measures, psychometric scales [16] or standardized tests consisting in the manipulation of a panel of objects (e.g. SHAP Southampton Hand Assessment Procedure [17]). Precise methods are important for the clinical monitoring of the patients, in particular for the evaluation of new clinical or technological solutions, as well as for the future development of innovative prosthetic progress [18]. Instrumented laboratory methods with kinematic and/or kinetic recordings allow a better quantification of the task performance (review in [15]). Kinematic assessments using motion capture technologies have proven to be valuable for identifying movement strategies and also for assessing compensatory movements in upper limb amputees [13, 19, 20], including in patients with targeted reinnervation [21, 22].
Kinematic studies are now largely used in clinical research, in particular for the analysis of gait in lower-limb amputees [23] (see a review in [24]) but remain relatively scarce in the domain of upper-limb prosthetics. The reason is probably linked to the greater complexity of upper-limb actions (non-automatic, asymmetric and open chain) relative to lower-limb and to a lesser standardization of kinematic methods.
In addition, some kinematic studies in the domain of upper-limb prosthetics have been carried out with prosthetic simulators on able-bodied volunteers [1, 2528].
The measurement of compensatory movements while moving objects with upper limb prostheses highlighted three categories of compensatory strategies following comparison of transradial myoelectric prosthesis users with able-bodied subjects during bimanual tasks: prepositioning of devices and objects in the workspace, posture compensations and a range of motion compensations [29].
The aim of the present study is to go further in the kinematic analysis of reaching and grasping by recording simultaneously the hand trajectory and joint rotations. Our perspective is to quantify both the alteration of movement quality during a simple goal-directed task and the amount of some proximal joints rotations in order to specify compensatory strategies. In particular we will study the impact on kinematic of the type of objects and of the distance between the subject and the object which have been mostly disregarded until now.
A better knowledge of compensatory strategies is important to understand how the motor system of amputees adapts to the loss of a part of a limb and its partial replacement with a prosthesis. From a clinical point of view, it is important to consider compensatory strategies and to differentiate between useful/unavoidable and harmful/avoidable ones. Indeed, certain compensations are inevitable when using prostheses. A better understanding of their mechanisms would help to manage compensatory strategies during rehabilitation for the prevention and treatment of musculoskeletal disorders. In addition, instrumented recordings may contribute to the evaluation of technical advances in prosthesis conception and control [30]. Additionally, a growing number of research projects in the development of advanced prosthetic control are being based on a better understanding of the compensatory movements and the pathological coordination strategies [31, 32].
Methods
Participants
A convenience sample of 10 participants with below-elbow amputation (9 males and 1 female aged from 22 to 61 years, mean 41.4 years, standard deviation 11.9) was included at the Regional Rehabilitation Institute (UGECAM Nord Est) in Nancy. The only inclusion criteria were amputation or congenital absence at the level of the forearm, in possession of a myoelectric prosthesis and normal, or corrected to normal, vision. Exclusion criteria were the presence of another neurological or orthopaedical pathology affecting the upper-limb. The protocol was approved by a local ethics committee (CER Paris Descartes) and all the subjects gave written informed consent prior to participating.
The main clinical data are indicated on Table 1. Nine right-handed participants were amputated after a traumatic injury, seven of their dominant right hand and two of their non-dominant left hand. The last patient suffered from right congenital upper-limb agenesis. The time elapsed since amputation as well as the cause and complexity of the prosthetic fitting varied greatly across participants (Table 1). The level of amputation also varied since four participants had a distal amputation level or radiocarpal disarticulation and six a middle or proximal forearm amputation. They were equipped with a myoelectric prothesis for 2.7 months to 27 years. The patients used their own prosthesis during the experiment. For all of them, prosthetic terminal effector was a tridigital prosthetic hand with one DOF (closing and opening tridigital pinch). Six of them, had a prosthesis with motorized wrist rotation, that they were free to use during the task. Only one participant with radiocarpal disarticulation (P8) keeps some physiological prono-supination.
In addition, the participants had a personal interview with AG, who is a psychiatrist, and responded to a questionnaire in order to evaluate the functional, aesthetic and psychological dimensions of the bodily integration of their prosthesis. The questionnaire and scale are fully described in [33]. Briefly, the scale included i) the time of wearing the prosthesis per day; ii) the evaluation of the compensation of the functional disability, based on the OPUS questionnaire [34]; iii) subjective evaluations of the aesthetic and social discomfort related to several contexts; iv) the feeling of body integrity (the prosthesis is a constitutive part of themselves) and of indispensability (without it, they feel that something is missing). The items were weighted and normalized as described in [33] so that the maximum embodiment score was 10.
Experimental set up and task
Participants were comfortably seated on a chair adjusted so that the table was approximately level with the navel, with the trunk free. The starting position was with the hand or prosthesis placed, with the fingers closed, on a mark on the table in the sagittal plane, the forearm was in mid-prone, the elbow flexed to ~90°. (Fig 1). The tasks were carried out with eyes open.
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Fig 1. Side view and horizontal view of the experimental set-up.
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The reference frame for the kinematic measures is indicated in red.
Reaching and grasping movements were evaluated with three different objects: a cylinder (height 0.15 m, diameter 0.04m, weight 0.3kg), a cardboard truncated cone (height 0.18 m, diameters 0.1m and 0.04m, weight 0.2kg) and a mug (height 0.10 m, diameters 0.9m, weight 0.32kg). These objects were chosen after discussion with occupational therapists examining the grasping affordances offered by various objects to anatomical or tridigital prosthetic hands. The easiest object to grasp by amputees is a cone, routinely used in rehabilitation. In contrast, amputees have difficulties to grasp a mug by the handle, the cylinder being intermediate. The objects were placed on the table in the midline at two distances close and far, adjusted for each subject at respectively to 60% and 80% of the maximal reachable distance (MRD) of the prosthetic side. MRD was measured before the session when the participant was comfortably sitting, between the patient belly and the most distant forward distance he/she is able to reach with the centre of the prosthetic hand. The handle of the mug was oriented 45° by reference to the sagittal plane.
After the installation of the set-up, participants practiced several grasping movements to each object before recording. They were instructed to reach the object at a comfortable speed after the verbal signal of the experimenter, to grasp it and to lift above the table, then to put it back in the same position. No instructions were given regarding the way the objects should be grasped, allowing different hand orientation and height for grasping the cylinder and cone; the mug was oriented in a way to favour grasping by the handle [35].
The participants performed the experiment first with the non-amputated limb then with the prosthetic one. Then participants had to perform the task in the different Object-Distance conditions in a pseudo-random presentation order. Three repetitions were successively recorded for each condition. The data collection for each trial began at the verbal signal and lasted for 5 s. The sitting posture was regularly visually checked by the experimenter.
Data collection
A 6-degree-of-freedom electromagnetic tracking device, the Polhemus Fastrak (SPACE FASTRAK, Colchester, VT, USA), was used to record the kinematic data at 30 Hz. This system gives position data and Euler angles (azimuth, elevation, roll) in a global coordinate system given by the Polhemus transmitter X rightward, Y forward, Z upward (The reported root mean square (RMS) accuracy of this system is 0.3–0.8mm for position and 0.15° for orientation when used within a 76-cm source to sensor separation, SPACE FASTRAK User’s Manuel, Revision F. Colchester, VT; Polhemus Inc.; 1993). The transmitter was fixed under the table. One Polhemus sensor was attached with tape on the dorsum of the hand with its main axis along the third metacarpal bone (or similarly on the prosthesis), another to the dorsum of the forearm (or prosthesis). A third sensor was attached to the ipsilateral acromion.
These sensors directly give their position and orientation by reference to the reference frame of the transmitter: X laterally, Y forward and Z upward (Fig 1B). The 3D position of the elbow PEL was calculated thanks to a preliminary calibration procedure of the forearm segment (individual measurements of hand and forearm sensor localization along the forearm and elbow axis position). The humerus segment (vector Xarm) was then reconstructed as the segment linking the shoulder acromion (PSH) and the centre of the elbow joint (PEL). and the centre of the elbow joint. The 3D positions and orientations obtained for the left arm were mirrored to the right side for statistic comparisons.
For the calculation of joint angles, we chose the rigorous formalism of the ISB shoulder group [36]. The analysis was focused on shoulder elevation α and elbow extension β, which were computed the following way (Fig 2).
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Fig 2. Schematic representation -projected in sagittal plane- of the shoulder elevation angle α and elbow flexion-extension β.
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Shoulder elevation angle α was defined as the angle between the arm/humerus vector and the vector representing the trunk. is the vector connecting the shoulder sensor (which centre is defined as PSH) to the reconstructed elbow point PEL (which position is reconstructed in the forearm sensor frame located in PFA thanks to initial measurement of length lfa). is the vector connecting the shoulder sensor centre PSH to the reconstructed centre of the hip PH (with norm being measured experimentally at the beginning of the experimental session, PH being the vertical projection of PSH(t0) on the horizontal plane to which the hip belong, and PH considered as fixed during the experiment). Thus,
Elbow extension angle β was defined as the angle between the previously defined arm/humerus vector and the vector which is one of the forearm sensor axis which was oriented specifically when placed on the participant limb so that it is aligned with forearm main axis. Thus:
The 3D positions and orientations obtained for the left arm were mirrored to the right side for ease of comparison.
Data analysis
The aim of the present study is to describe the kinematic behaviour of a case series of amputated patients wearing a prosthesis. To that end, we quantified a series of kinematic dependent variables in order i) to compare the prosthetic and non-amputated sides, so that each participant is his own control and ii) to examine the interactions of the Factor Side (Prosthetic, non-amputated), with the factors Distance (Close-Far) and Object (3 levels).
Dependent variables
The velocity profile of the hand (non-amputated or prosthetic) sensor was calculated by derivation of the displacement data and used to determine the timing of the tasks. The following times were automatically determined, checked and eventually corrected visually thanks to an interactive home-made computer routine presenting simultaneously the movement trajectory and velocity profile (programmed in Labview©).
• The onset of movement (t0) was the first sample above a threshold of 0.05 m/s.
• The time (tv) of the maximum tangential velocity (Vmax) delimits the acceleration phase (between, t0 and tv).
• The time of grasping (tg) was chosen as a local minimum of velocity between the reach and lift velocity peaks coinciding with a reversal point of the hand trajectory. The reaching phase (between t0 and tg) includes both reaching and grasping unto the time of lifting.
In order to quantify the smoothness of reaching movements, the number of velocity peaks was calculated during the reaching to grasp phase using a velocity threshold of 0.05 m/s and a duration threshold of 100 ms (Labview©).
The spatial organization of movement was quantified by the 3D displacement of the hand/prosthesis. The curvature of hand trajectory was calculated as the ratio between the cumulated distance of the trajectory for reaching and the direct 3D distance (it is 1 if the trajectory is linear). The trunk and upper-limb involvement in the task were measured by the 3D displacement of the elbow and acromion and by the range of rotation in shoulder elevation and elbow flexion-extension during the reaching phase respectively.
The orientation of the hand for grasping was quantified by the Euler angles recorded at time tg: hand azimuth is the orientation of the hand in the horizontal plane (0° is oriented forward, 90° internally); pitch is the angle within the vertical plane defined by the azimuth (positive upward) and roll is around the longitudinal axis of the hand (0° thumb-up, 90° palm-down).
Statistics
The independent factors were side (Prosthetic, non-amputated), distance (Close, Far) and Object (3 levels). Since the dependent variables were not normally distributed (Shapiro-Wills test, p<0.001 for most variables) we used non-parametric statistical analyses.
The analysis was performed according to the following steps.
First, we analysed the effect of Side and Distance on the values obtained by averaging the dependent variables over the three objects. Friedman analysis was used to test the effect of condition (4 conditions: Side x Distance). When Friedman analysis showed significant variations, Wilcoxon test was used for paired comparisons: separately the effect of Side (for both distances) and the effect of Distance (for both sides).
Secondly: the effects of object were investigated by Friedman performed for each of the four combined side-distance conditions and completed by paired comparisons between objects (Wilcoxon test).
Effect sizes of paired comparisons were measured by the Cohen’s d (difference between means divided by the standard error of the difference).
Correlation analysis was performed to test the relationship between clinical data (age, delay from amputation, duration of prosthetic use, embodiment score) and kinematic variables. Kinematic variables were expressed as a percent of variation of the prosthetic side (P) by reference to the non-amputated side (NA)
Results
Temporal organization of the hand movement. Effect of both side and distance
The kinematics of reaching and lifting are illustrated on Fig 3 in a representative participant amputated on the right side.
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Fig 3. Example of hand and acromion trajectories in a representative participant.
Horizontal (left) and sagittal (right) projections of the hand (black circles) and prosthesis (red circles) superimposed trajectories for the far (filled circles) and the close (open circles) targets, the object is a cylinder. The trajectories of the acromion sensor on the non-amputated (blue circles) and prosthetic (magenta circles) sides are also indicated. The corresponding velocity profiles are displayed on the right bottom corner for the close and the far targets. On the velocity profiles, black and red arrows indicate the times tr (onset of movements), tv (time of maximum velocity) and tg (time of grasping); the times tv and tg are also indicated by dotted and dashed lines respectively. The times tg are also indicated by arrows on the hand trajectories.
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All the kinematic variables describing the temporo-spatial organization of the hand reaching movement varied significantly with the side and distance conditions (Friedmann 4 levels, p<0.0001), excepted the duration of the acceleration (Friedmann ns).
The maximum velocity of reaching was similar on both sides: there was no significant differences for the close target and borderline difference (Wilcoxon p = 0.05, d = 0.7) for the far target. The maximum velocity increased with distance both on the non-amputated (mean ± sem: 0.67 ± 0.04 m/s and 0.86 ± 0.03 m/s for the close and far targets, d = 1.99, Wilcoxon p<0.005) and the prosthetic sides (0.66 ± 0.04 m/s and 0.79 ± 0.04 m/s, Wilcoxon p<0.005, d = 1.62) (Fig 4).
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Fig 4. Box plots comparing the temporal variables during reaching between the non-amputated (grey) and prosthetic (red) sides.
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The box limits indicate the 25/75 percentiles and the whiskers the confidence interval. The median is indicated by the thick line. Dots indicate outliers.
The duration of the reaching phase was significantly shorter on the non-amputated side (0.96 ± 0.04s and 1.11 ± 0.03s), than on the prosthetic side (1.58 ± 0.04s and 1.70 ± 0.06s) (Wilcoxon p<0.005, d = 2.59 and d = 2.21 for the close and far targets respectively). On the non-amputated side, the duration of reaching was longer for the far than the close target (Wilcoxon p<0.007, d = 1.87). This scaling was not observed on the prosthetic side (Wilcoxon non significant).
The duration of the acceleration phase was not significantly different in the non-amputated and prosthetic sides. It was longer for the far than the close target on the non-amputated side (Wilcoxon p = 0.007, d = 1.19) but not on the prosthetic side.
The number of velocity peaks during the reach to grasp phase was significantly smaller on the non-amputated side (Wilcoxon, p<0.005, d = 195 and d = 1.52 for the close and far targets) but did not vary significantly with distance on either side.
Shoulder and elbow range of rotation during reaching
The involvement of the upper-limb proximal joints was quantified by the range of rotation in the shoulder (alpha angle) and elbow (flexion-extension, FE). During reaching (Fig 5), both varied with the conditions (alpha: Friedman p = 0.002; elbow FE p = 0.00001).
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Fig 5. Amount of shoulder and elbow rotations during reaching phases, same legend as Fig 4.
The thick horizontal line indicates the median and the thin one the mean.
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The rotation in alpha angle increased with target distance without significant side difference. On the non-amputated side, it was 6.6 ± 2.2° and 19.5 ± 6° for the close and the far target (Wilcoxon p = 0.04, d = 0.76) and on the prosthetic side 8.7 ±1.0° and 20.9 ± 3.1° respectively (Wilcoxon p = 0.005, d = 1.33). The reaching movement was performed with elbow extension (positive values) which significantly increased with target distance. It was on the non-amputated side 26.0 ± 3.3° and 54.0 ± 3.3° for the close and the far targets (Wilcoxon p = 0.005, d = 2.97) and on the prosthetic side 36.0 ± 4.5° and 46.9 ± 5.3° respectively (Wilcoxon p = 0.005, d = 2.28). The effect of side was limited to a greater elbow extension on the prosthetic side for the close target (Wilcoxon p = 0.02, d = 1.18).
Comparison of hand, elbow and acromion displacement during reaching
The displacement of the hand in the forward, upward and lateral directions varied with the side-distance condition (Friedmann p = 0.00002, p = 0.0003, p = 0.002 respectively, Fig 6, upper panels).
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Fig 6. Comparison of the hand, elbow and acromion displacements in the three directions during reaching.
Same legend as Fig 4.
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As expected, the mean forward displacement of the hand during reaching depended on target distance without side difference (on the non-amputated side it was 20.45 ± 2.3 cm and 33.2 ± 1.7, for the close and far target, Wilcoxon p = 0.005, d = 2.57, and on the prosthetic side 21.6 ± 1.9 cm and 33.4 ± 1.6 cm respectively, Wilcoxon p = 0.005, d = 2.66). During reaching, the hand raised more above the table for the far than the close target (on the non-amputated side it was 3.7 ± 0.5 cm and 7.6 ± 1.2 cm for the close and far target, Wilcoxon p = 0.005, d = 1.39 and on the prosthetic side 3.9 ± 0.7 cm and 9.8 ± 1.6 cm respectively, Wilcoxon p = 0.005, d = 1.59). The side difference was limited to a higher displacement on the prosthetic side for the far target (Wilcoxon p = 0.03, d = 0.76). The hand moved internally during reaching from its lateral initial position towards the midline (negative values). On the non-amputated side, this internal displacement was larger for the close than the far target (-7 ± 1 cm and -6.2 ± 0.9, Wilcoxon p = 0.02, d = 1.02) in contrast, there was no differences between target distances on the prosthetic side (-4.1 ± 1.3 cm and -4.9 ± 1.4 respectively). The side difference was limited to a smaller internal displacement for the close target on the prosthetic side (Wilcoxon p = 0.05, d = 0.83).
The curvature of the trajectory varied with the condition (Friedmann p = 0.0008). The trajectory in the horizontal plane was almost rectilinear (i.e. its value was ~1) for the far target on the non-amputated side (1.08 ± 0.02) and slightly curved for the close target (1.22 ± 0.08, p = 0.005). On the prosthetic side, the trajectory was curved for the far target (1.22 ± 0.04) and even more for the close one (1.39 ± 0.08, p = 0.02). However, the greater curvature on the prosthetic side was only significant for the far distance (Wilcoxon, p = 0.02, d = 0.97).
The displacement of the elbow in the forward, upward and lateral directions during reaching varied with conditions (Friedmann p = 0.0002, p = 0.0005 and p = 0.0002 respectively, Fig 6, middle panels). The elbow displacement in those three directions was significantly greater for the far target for both sides (Wilcoxon p = 0.005). Significant side differences were observed for the close target: on the prosthetic side, the displacement of the elbow was higher (6.9 ± 1.0 cm versus 3.16 ± 1.1 cm, Wilcoxon p = 0.02) and more external than on the non-amputated side (8.9 ± 1.6 cm and 2.3 ± 1.0 cm respectively, Wilcoxon p = 0.01).
During reaching, the acromion moved mainly forward, with amounts which varied with side-distance conditions (Friedmann p<0.0002, Fig 6, lower panels). The forward displacement of the acromion increased with target distance on both sides (Wilcoxon, p = 0.005, d = 1.55 and d = 1.68 for the non-amputated and prosthetic sides and was larger on the prosthetic side for both targets. For the close target, the acromion remained stable on the non-amputated side (0.1 ± 1.0 cm) and moved forward (4.1 ± 1.7cm) on the prosthetic side (Wilcoxon p = 0.02, d = 0.98). For the far target, the forward displacement was smaller on the non-amputated (6.5 ± 2.1 cm) than on the prosthetic side (15.3 ± 3.2 cm, Wilcoxon, p = 0.005, d = 1.42).
Effect of object
Visual observation showed that the mug was always grasped by the handle.
The effects of object were investigated separately for each side-distance condition by Friedman analysis (3 levels) completed by two by two comparisons (Wilcoxon test and Cohen’s d).
The reach duration and maximum velocity of reaching varied with the object only on the non-amputated side for the close target (Friedman: p = 0.002 and p 0.007). In this later condition, the mug was reached with a significantly longer reach and slower velocity (0.61m/s ± 0.05) than the cylinder (0.70± 0.08 m/s, Wilcoxon p = 0.03, d = 0.73) and the cone (0.71 ± 0.08 m/s, Wilcoxon p = 0.005, d = 0.73).
The amount of hand displacement in the three directions during reach varied significantly with the objects in most side-distance conditions (Friedman ns to 0.0002). The statistical effects of object were similar in the non-amputated and prosthetic sides. The vertical displacement was higher for the cone (grand mean over conditions 8.1 ± 1.5 cm), than for the cylinder (6.3 ± 1.4 cm, d = 0.41 to d = 2.00) and the mug (4.3 ± 1.2 cm, d = 0.49 to d = 1.82). In most side/distance conditions the differences of forward and internal hand displacements were mainly observed between the mug and the two other objects (Wilcoxon p = ns to 0.005) the mug was grasped with a greater internal and shorter forward displacement than the cone or cylinder in all the side/distance conditions (Wilcoxon, p = 0.01 to p = 0.005, d = 0.88 to d = 2.23) there was no differences between the cone and cylinder.
Hand orientation at the time of grasping, effect of object
When considering the mean of the three objects, azimuth and roll varied with the side and distance (Friedman: azimuth p = 0.0002, roll d = 0.0002) but not the pitch (Fig 7).
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Fig 7. Euler angles describing hand orientation at the time of grasping for the three objects.
Same legend as Fig 4.
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On the non-amputated side, the hand azimuth was directed roughly forward (0°) for the far target (7.5 ± 3.0°) and was increased (more frontal) for the close target (17.7 ± 3.7°, Wilcoxon p = 0.005, d = 2.47). On the prosthetic side, the hand azimuth was also more frontal for the close relative to the far target (31.7 ± 3.9°, Wilcoxon p = 0.005, d = 2.38). It was more frontal than on the non-amputated side for the far target (19.9 ± 3.5°, Wilcoxon p = 0.005, d = 1.01) but there was no significant side difference for the close target. Concerning roll, on the non-amputated side the hand adopted an intermediate orientation between “thumb-up” (0°) and “palm down” (90°), which was slightly more rotated palm-down for the far target (32.7 ± 3.6° and 36.2 ± 3.6° for the close and the far targets, Wilcoxon p = 0.007, d = 1.69). On the prosthetic side, the roll was significantly less rotated than on the non-amputated side (9.5 ± 3.9° and 14.2 ± 2.9° for the close and far targets respectively; Wilkinson p = 0.007, d = 1.34 and Wilkinson p = 0.005, d = 1.70). On the prosthetic side, the roll did not vary significantly with target distance.
The hand orientation at the time of grasping depended on object shape differently according to the side. On the non-amputated side, it was quite independent of the object shape (Friedman analysis: significant difference only for pitch in the close target condition, p = 0.05). In contrast, on the prosthetic side there were significant differences for all the angles at both target distances: azimuth (Friedman p = 0.003 and p = 0.02 for close and far targets), pitch (Friedman p = 0.003 and p = 0.0001 respectively) and roll (Friedman p = 0.007 and p = 0.005 respectively). The mug was grasped more frontally than the cylinder (Wilkinson p = 0.05 and p = 0.04 for the close and far distances, d = 0.68 and d = 0.59) and the cone at close distance (Wilkinson p = 0.04, d = 0.77). The mug was grasped with a less “thumb-up” orientation than the cylinder (Wilkinson p = 0.02 and p = 0.05 for the close and far distances, d = 1.01 and d = 0.71) and the cone at close distance (Wilkinson p = 0.02, d = 1.22). On the prosthetic side, the pitch was larger for the cone and cylinder than for the mug for far targets (Wilcoxon p = 0.005, d = 2.03 and d = 1.76). On the non-amputated side, borderline differences were observed between the cone and cylinder (Wilcoxon p = 0.05, d = 0.66).
Analysis of individual factors
Correlation analysis was performed between the embodiment score and the main kinematic variables. It showed that when the prosthesis was acceptably embodied, the duration of the reaching to grasp phase expressed as a percent of variation relative to the non-amputated side was shorter (p = 0.03) (Fig 8).
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Fig 8. Relationship between the embodiment score and the duration of the reaching phase, expressed as a % of variation relative to the non-amputated side.
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There was no significant relationship between the embodiment score and other kinematic variables. We explored potential relationships between kinematic variables, motor strategies (trunk flexion for reaching, particularities of hand orientation) and clinical data, in particular the proximo/distal level of the amputation and experience duration with a prosthesis but we did not find any pertinent relation with clinical variables. The limited number of participants did not allow to make further statistics.
Discussion
To our knowledge, the present study is the first to analyse systematically the kinematics of grasping in order to compare the prosthetic and the non-amputated side with various objects placed at different distances. The kinematic analysis of hand trajectory during the reaching to grasp task demonstrates asymmetries between the non-amputated and prosthetic sides that affect both the temporal and spatial organization of the gesture. In addition, the trunk and upper-limb coordination differed between sides, showing that the use of a prosthesis impacts the proximal limb and the global body coordination. The proximal changes could be both direct consequences of the distal constraints brought by the prosthesis and/or motor strategies aiming at compensating these consequences. The extensive literature on the kinematics of reaching to grasp in healthy subjects contrasts with scarce observations in amputees using a prosthesis. We shall examine successively the temporal and spatial organization of the movement. Temporal organization.
The temporal organization of motion relies on the trajectory of the end-point of the limb during goal-directed movements. Physiological goal directed upper-limb movements are characterized by well-known characteristics. The trajectory of the end-point is roughly linear during pointing with a smooth bell-shaped velocity profile scaled to movement distance [37]. These features evidence some optimal anticipation of biomechanical constraints [38]. Prehension was particularly described in Jeannerod’s pioneering works on precision grip [39, 40], review in [41]. He distinguished the two components of prehension, reaching and grasping. Reaching is characterized by a smooth but asymmetric velocity profile, scaled to target distance. Preparation to grasp is performed in parallel with the fingers opening during reaching (preshaping) then closing at the termination of reach. Preshaping of fingers aperture is also observed during whole hand grasping [42]. The tight temporal coupling between reaching and grasping was confirmed by many experiments with perturbations [4347]. Kinematic studies in amputees showed that they were able to perform smooth horizontal pointing task, for example with a robotic manipulandum (InMotion2 Shoulder-Elbow Robot®) [48]. In contrast, prosthesis users perform movements with a degraded quality when it comes to grasp and manipulate objects.
The present study confirms and specifies previous observations since the delay before lifting was massively increased on the prosthetic side. In contrast, the initial reaching component was little affected: the duration of the acceleration phase and maximum velocity were similar on both sides. The maximum velocity (but not the acceleration duration) was scaled to target distance on both sides. This suggests that the reaching and grasping components were not performed in parallel but sequentially, consistently with [4951]. Certainly some authors describe that non-sequential prosthetic movement is possible with Wing and Fraser observing a child (13 years old) with a congenital absence of a fore-arm who used a mechanical prothesis since her early age; she could pre-shape her prosthesis during a slower reaching followed by a faster closure than on the non-amputated side [52, 53]. However, more recent studies in adults showed that the prosthetic reaching movements were generally slower, less rectilinear and less smooth than physiological movements [4951] with a temporal decoupling of the reaching and grasping components [49, 51]. Sequential control of prosthetic hand opening and prono-supination could participate in this phenomenon.
The increased number of velocity peaks on the prosthetic side suggests that grasping was prolonged with iterative small hand displacements related to difficulties for moulding the prosthesis around the object because of non-adaptative grip and smaller hand opening. The mechanical structure of the prosthetics (and its unbalanced weight repartition), obvious difficulties to operate the artificial control and impairment of direct somatosensory and proprioceptive feedback during interactions with the object, imposing permanent visual monitoring probably contribute to the slowing and irregularities of the grasping [54]. Moreover, the loss of mobility at wrist and finger levels probably participates to the impairment of grasping [28]. Kontson evaluated grasping simulating the limitations induced by conventional prostheses with bracing and strapping of able-bodied subjects performing Box and Block test. The simulation showed a decrease in performance [27, 55].
There are few kinematic studies of prosthetic reaching and grasping and most include a very small number of heterogeneous participants. The study by Martinet et al. [51] is a single case. Bouwsema et al. [49] included six participants three of them had upper arm amputation and used a combination of myoelectric hand and mechanical elbow (hybrid control), the three others had a transradial amputation and used myoelectric prosthesis. Engdahl et al. [50] included nine participants with transradial amputation using myoelectric or body-powered prostheses. So that, the mechanism of the decoupling between reaching and grasping remains unclear. The quality of prosthetic prehension movements depends on training as shown by studies in healthy subjects learning to use a prosthesis simulator with myoelectric [25] or body-powered control [1, 56]. In all cases, training reach to grasp tasks resulted in faster movements and shorter grasping delay.
Interestingly, the duration of the reach to grasp phase was correlated with a score evaluating the quality of embodiment [33] (see [57] for a similar evaluation of embodiment). However, the direction of the causal relationship is equivocal. Grasping and manipulation is at the basis of daily life activity. Is the feeling of embodiment determined by the duration of increased delays in performing daily activities? Or a lack of embodiment contributes to difficulties in motor control resulting in slower actions?
Spatial organization of hand trajectory and inter-joint configuration for grasping
The spatial trajectory of the hand during reaching to grasp has been largely documented in non-amputated subjects but has been little described before in participants wearing a prosthesis [13, 30]. In the present study, the trajectories of the prosthetic and non-amputated hands were globally similar, in particular the forward displacement of the hand was identical on both sides. However, on the prosthetic side the trajectory was more curved according to object distance as already observed [50]. The global hand displacement during reaching was slightly higher and less internally on the prosthetic side.
As largely observed in healthy subjects, the trajectory of the hand is due to some refined inter-joint coordination [58] involving most of the DoF of the upper-limb [59]. Coordination between the trunk, shoulder and elbow are particularly remarkable [60].
The use a prosthesis impedes or limits hand movement, wrist movement and prono-supination. Elbow movements can also be limited obviously if the amputation is transhumeral or for below elbow amputees because of the mechanical constraints of the socket. The present study allows to quantify the greater involvement of proximal limb and global body, confirming previous clinical and kinematic studies [13, 19, 30, 61, 62]. Amputees recruit additional DoF and/or increase the range of motion in the proximal joints and trunk (shoulder, torso) by reference to healthy subjects to compensate for the distal motor limitations [13, 61]. Those movements are specific and appropriate to the task, demonstrating that they are compensatory in nature as widely reported in clinical studies [63]. Montagnani evaluated compensation during grasping in able bodied subjects simulating the limitations induced by conventional prostheses with several orthosis. The compensations are more important with the orthesis which limits an higher number of DoF. He described that the presence of wrist flexion within the orthesis improves gesture efficiency and limits compensations [28].
The present study confirms that the involvement of the trunk and upper-limb joint rotations were quite different between sides. On the non-amputated side, the reaching movement was performed with a shoulder rotation (α angle bringing the arm away from the body) and an elbow extension β both scaled with target distance; the trunk contributed to hand movement only for far target. The trunk and upper-limb coordination were modified by the use of a prosthesis. For close targets, the movement was performed with a greater range of shoulder and elbow rotations (significant only for elbow extension). The shoulder range of motion was particularly variable, consistently with previous studies [13, 19, 30]. The increased contribution of shoulder joint is also supported by the greater upward and external displacements of the elbow on the prosthetic side. In addition, the far target was reached with a supplementary forward displacement of the acromion corresponding to an increased flexion and/or axial rotation of the trunk (including scapula) as previously clinically described [63] and quantified by kinematic analyses during goal directed activities [13, 19, 62].
The sitting position used in the present study is probably more constraining than the standing position. Indeed, in standing position, trunk inclination was favoured [27] while in sitting position, compensations via movable body parts (at the trunk-head-upper limb level, including shoulder abduction) are even more necessary.
The compensatory strategies impose increased workload on proximal joints, including trunk and neck, and on the non-amputated side. The repeated use of postures with trunk torsion, anteflexion and lateral inclination, and with abduction-internal rotation of the shoulder are known as risk factors for musculoskeletal disorders [64] which can contribute to the handicap [6569]. Indeed it is demonstrated that significant shoulder abduction is a source of major shoulder strain that can, in the long-term, cause pain [70] Similarly, prolonged arm elevation may result in shoulder pain and musculoskeletal disorders at various thresholds [71, 72].
Hand orientation for grasping to lift
The present study brings additional information on motor behaviour by quantifying the hand orientation at the time when the object is grasped stably so that the participant can possibly initiate a lifting action. The hand orientation for grasping was quite asymmetric. On the non-amputated side, it varied little with the condition: the hand was slightly elevated above the horizontal with an intermediate roll and its azimuth was scaled to target distance, consistently with [73].
On the prosthetic side, the azimuth at the time of reaching was more frontal and particularly sensitive to distance. The pitch was greater, particularly for the far target.
In addition, the orientation of the prosthetic hand at the time of grasping, as well as the upward and lateral displacement of the hand during reaching, were sensitive to the shape of the object. A stereotyped “thumb-up” orientation of the prosthesis (with roll tending to 90°) was preferred for the cone and the cylinder, the cone was grasped at the highest height with the greatest pitch. Despite the fact the mug could be grasped in a variety of ways [35] it was always grasped by the handle, probably due to implicit understanding of the task. The specific shape of the mug’s handle probably constrained the pose of the hand, which was grasped at the lowest height, with the most frontal azimuth, intermediate roll and without pitch. This suggest that on the non-amputated side, the different object shapes are taken over by the versatility of the fingers [74], so that they grasp objects with the same position and orientation of the hand relative to object position. In contrast, on the prosthetic side, the participants have to adapt their hand pose for grasping as a function of object shape.
Mechanisms of compensatory behavior
The influence of the distal impairment on the proximal coordination is quite complex and two mechanisms can be hypothesized.
On one side, the shape of the object relative to the configuration of the prosthesis itself, could influence the choice of a given orientation of the extremity (e.g. more frontal azimuth and/or “thumb-up” posture). Prosthetic hand opening is smaller than in a healthy hand and in our study, only one kind of grip is possible: tridigital. The lack of finger and wrist mobility and of prono-supination for prosthesis users impose increased constraints on the upper-limb [13, 19, 62]. Then the choice of a functional hand pose would determine the trajectory of the limb for reaching and the trunk and upper-limb rotations in order to remain in a comfortable configuration for lifting [13, 19, 62] Indeed, the choice of a more frontal hand orientation imposes an elbow flexion and thus some trunk flexion to preserve the reaching distance since the prosthesis has no wrist mobility.
On the other side, the amputation may directly affect the proximal shoulder/elbow coordination. The added distal weight of the prosthesis may incite the participants to decrease the length of the lever arm by bending the trunk in order to decrease the torque constraints on the shoulder. Indeed, the weight distribution of the prosthesis differs from that of the missing limb with a shift in weight towards the most distal part of the prosthesis. This is due to the prosthetic hand and the motor which are the heaviest parts of the prosthesis and are the most distal. This difference may contribute to the asymmetry observed between amputated and intact limb kinematics.
The possible limitation of elbow extension might be due to the structure of the socket that may encompass the elbow to maintain the prosthesis particularly when the amputation of the forearm is proximal. Some conflicts may also impede the flexion of the elbow to reach the close target. In addition, acquired musculo-skeletal disorders may complicate the clinical picture [67, 69]. The two most frequent musculo-skeletal disorders observed in case of unilateral upper limb amputation are contralateral carpal tunnel syndrome and homolateral shoulder pain, which affect about 40% of amputees [65]. Whatever its initial mechanism, the lessening of elbow extension compensated by the increased recruitment of trunk flexion can be compared to the motor condition in stroke patients [7578]. In both cases, trunk flexion is likely an exaggeration of the physiological coordination used to reach objects close to the maximum arm length [60].
Further studies are needed to determine, in each patient, the mechanisms of compensatory strategies since distal and proximal constraints may be combined [60]. Whatever their distal or proximal origin, kinematic modifications are probably learned skills, as suggested by Carey [19] who observed that compensations were greater in amputated prothetized participants than in non-amputated subjects braced. Accordingly, Major described that prosthesis experience had a strong positive relationship with average kinematic repeatability [13].
Limitations
Our preliminary observational study includes a small convenience sample of participants which does not allow to stratify the population in homogeneous sub-groups. It would have been interesting to measure the maximal extension and flexion of the elbow with the prosthesis and the posture of the elbow joint when measuring maximal reaching distance to quantify the limitation of elbow mobility by the socket.
The participants were their own controls. The recruitment of a control sample of non-amputated subjects (matched in age, gender and laterality) would increase the power of our study.
Moreover Metzger [48] found that reaching task in vision condition are modified for both arms of amputee subjects compared to healthy subjects.
The biomechanical methods were limited. The opening-closing of the non-amputated or prosthesis hand and the use or not of motorized pronosupination were not measured. The unique sensor placed at the level of the acromion does not allow to differentiate the movements of the trunk from those of the shoulder complex and external/internal rotation of the upper-arm could not be calculated. It would be interesting to add an axial sensor at the level of the spine in order to differentiate the compensations performed at the level of trunk (torsion and inclination) from those performed at the level of shoulder complex (elevation and protraction of the scapula) and to improve the biomechanical model in order to measure gleno-humeral rotation.
Perspectives
Precise kinematic analyses of the compensatory movements are important for the prevention and therapy of musculoskeletal disorders which are particularly frequent in amputated patients. The repeated use of postures with trunk torsion, anteflexion and lateral inclination of the trunk, and with abduction-internal rotation of the shoulder are known as risk factors for musculoskeletal disorders [79]. So, a better knowledge of these parameters is necessary.
A growing number of studies are now evaluating the quality and the performance of the motor assistance provided by technical devices such as prostheses through the quantification of compensatory strategies [80]. The amount of compensatory strategies can also be used to drive the adaptation of a control mode and personalize the behaviour of the prosthesis to the user [81]. More recently, some researches started to take even more advantage of those motor compensations by closing the prosthesis control loop on them (i.e. considering them as an «error»), to cancel them (by reconfiguring the kinematics of the prosthesis) while allowing user to perform a task in a more ergonomic way [31]. Those researches highlight the necessity of a better knowledge and understanding of patient’s particular kinematic strategies.
It would be important to have simplified recording devices usable in clinical routine to evaluate the compensations used by prosthetized patients in work or leisure situations. Further development are needed with inertial sensors in order to record longer activities in more ecological situations. Similarly, this method could be useful to evaluate other innovative medical devices such advanced polydigital hand [82], more flexible wrist prostheses, or the impact of artificial proprioceptive feedback. Kinematic analysis could be operational for the choice and prescription of prosthesis and in order to guide rehabilitation techniques while preventing musculoskeletal disorders. Indeed, the rehabilitation program focusing on compensatory movements of prosthetic users should be personalized. A better understanding of compensatory strategies that would help discriminate between useful/unavoidable and harmful/avoidable ones, would allow more efficient rehabilitation care in upper limb amputees and improve their autonomy with respect to prosthetic settings.
Acknowledgments
The authors thank all the participants to this study.
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-2,345,170,221,375,592,000 | Hepatitis A
PrintPrintSaveSave
Table of Contents
What Is Hepatitis A?
Hepatitis is an inflammation, or swelling, of the liver. Alcohol, drugs (including prescription medications), poisons, and some viruses can all cause hepatitis. Hepatitis A is a liver disease caused by the hepatitis A virus (HAV).
Worldwide, hepatitis A outbreaks tend to occur every now and then and are often related to contaminated food or water in a specific location. According to the World Health Organization (WHO), 1.4 million people acquire HAV each year.
According to the US Centers for Disease Control and Prevention (CDC), rates of hepatitis A in the US have dropped dramatically since the hepatitis A vaccine was introduced in 1995. However, there have been several hepatitis A outbreaks in the US in recent years. People at greater risk of severe disease from HAV include those with existing liver disease and people living with HIV.
Hepatitis A does not cause chronic (long-term) illness like hepatitis B and hepatitis C; and most people who get HAV can expect a full recovery.
How Is Hepatitis A Spread?
Hepatitis A is transmitted, or spread, when you take something into your mouth that has been contaminated by the feces or stool of a person with HAV. This could be by consuming contaminated water, food or drink prepared by a person living with HAV who did not wash their hands after using the bathroom, or through oral-anal (mouth-to-“butt”) sexual contact.
Prevention of Hepatitis A
Good personal hygiene and proper sanitation are key to preventing HAV. It is important to wash your hands with soap and water each time after using the bathroom, after changing a diaper, and before preparing and eating food. It is also important to thoroughly wash fresh fruits and vegetables with clean water before eating them.
If you are visiting a resource-limited country, it is especially important to follow these tips:
• Do not drink the water or eat the ice unless it has been boiled, or is commercially bottled. This applies to water you use to brush your teeth or any ice that may be in sodas, juices, or other beverages.
• Do not eat raw fruits and vegetables sold in the streets or at local markets without first cleaning them with clean (bottled or sterilized) water
Getting vaccinated for HAV is another way to protect against the virus. In the US, the HAV vaccine is approved for people 12 months old and older. The HAV vaccine is safe for people living with HIV (with CD4 >200), pregnant women, and women who are breastfeeding.
The HAV vaccine is given in two shots over six months. Some people living with HIV who have low CD4 counts may need either a higher dose of these two shots, or additional shots to complete their HAV vaccination. You can also get a combined hepatitis A and hepatitis B (HBV) vaccine. The combination (HAV + HBV) vaccine requires three shots over six months. It is important to get all your shots in order to be fully protected.
The vaccine is recommended for people living with HIV, as well as for those who live in or are traveling to areas with high rates of HAV. It is also recommended for gay and bisexual men, people who use drugs, people with blood clotting disorders (for example, hemophilia), and people with chronic liver disease (including hepatitis B or C). The CDC recommends that all children be immunized at age 1 year.
After a person has been exposed to HAV and has not received the hepatitis A vaccine, giving an injection of immune globulin can prevent infection. This is called post-exposure prophylaxis, or PEP. Immune globulin contains antibodies against HAV, which provide short-term protection against infection. Immune globulin can be given before and within two weeks after coming in contact with the virus. In 2007, the CDC changed the US guidelines to allow the use of not only immune globulin but also the hepatitis A vaccine to prevent infection after exposure in healthy persons aged one to 40 years.
Diagnosis and Treatment
A blood test for antibodies to HAV is the only way to be certain that someone has hepatitis A. The time between exposure to a virus and the development of symptoms is called the incubation period. For HAV, this period ranges from 15 to 50 days (average: 28 days). This means that people with HAV can spread the virus well before they know they have it. The incubation period becomes shorter as people get older.
Hepatitis A is an acute disease, which means that symptoms start suddenly and usually last no more than six months. Signs of HAV include:
• Jaundice (yellowing of the skin, eyes, and mucous membranes)
• Dark-colored urine
• Stool that appears pale and clay like
• Fatigue (extreme tiredness)
• Muscle and joint aches
• Loss of appetite
• Nausea
• Diarrhea
• Fever and chills
• Vomiting
• Pain in the right upper abdominal area
Some people who get hepatitis A have no symptoms at all, while others think they have the flu. There is currently no treatment for HAV, however rest and proper nutrition can relieve some of the symptoms. It usually takes about two months to recover, but one or two out of ten people may take up to six months.
Aside from supportive care and rest, it is important to stay away from alcohol and medications that are harmful to the liver. People living with HIV who aCquire HAV rarely need to interrupt their HIV treatment. If you have any questions, it is important to contact your health care provider.
Additional Resources
Select the links below for additional material related to hepatitis A.
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Red40something commented on 9 By 49
Wed, 9/15/2021 - 1:51am
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Red40something commented on 9 By 49
Wed, 9/15/2021 - 1:50am
Get basic information about a variety of approaches to treating the metabolic changes that may result from living with HIV or taking HIV drugs.
Lipodystrophy means abnormal fat changes. This article addresses treatments for fat loss, or lipoatrophy.
Get basic information about lipodystrophy: body shape changes, metabolic complications, and causes and treatment of fat loss and fat gain.
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6,897,326,428,434,366,000 | Menstrual cycles and ovulation
Your menstrual cycle
You probably already know quite a lot about your menstrual cycle – like how often you get your periods and how heavy they are. In this page we are going to take a more in-depth look at the female menstrual cycle, ovulation and periods. Obviously, no website can take the place of talking to a healthcare professional, but this should give you a good general understanding of how it all works.
Understanding your menstrual cycle
Women’s cycle lengths vary, and the most common cycle length is somewhere between 23 and 35 days. Any variation in menstrual cycle length that does occur is more likely to be during the part of the cycle before you ovulate (which is called the follicular phase). For most women, the length of time between ovulation (when an egg is released from the ovary) and their monthly period is between 12 to 16 days (this is called the luteal phase).
The menstrual cycle
Your period
The first day of your menstrual cycle is the first day of your period (day 1). The period usually then lasts anything from 3 to 7 days. You’ll probably find that if you get any period pains, they’ll be at their worst in the first few days of your period. This is because the hormones in your body are causing your womb to actively shed the lining that was built up in the previous menstrual cycle.
Preparing for ovulation
At the beginning of your cycle follicle-stimulating hormone (FSH) is produced by the pituitary gland in your brain. This is the main hormone involved in stimulating your ovaries to produce mature eggs. Follicles are the fluid-filled cavities in your ovaries. Each follicle contains one undeveloped egg. The FSH stimulates a number of follicles to develop and start to produce the hormone estrogen. Your level of estrogen is at its lowest on the first day of your period. From then on, it starts to increase as the follicles grow.
Now while a number of follicles initially begin to develop, normally one follicle becomes “dominant” and this egg matures within the enlarging follicle. At the same time, the increasing amount of estrogen in your body makes sure that the lining of your womb is thickening with nutrients and blood. This is so that if you do get pregnant, the fertilised egg will have all the nutrients and support it needs to grow. High estrogen levels are also associated with the appearance of ‘sperm-friendly’ mucus (or, to give it its technical name, fertile cervical mucus). You may notice this as a thin, slippery discharge that may be cloudy white. Sperm can swim more easily through this mucus and can survive in it for several days.
Preparing for Ovulation
Understanding the ovulation cycle
Ovulation
The level of estrogen in your body is still increasing and it eventually causes a rapid rise in luteinising hormone (the ‘LH surge’). This LH surge causes the dominant follicle to rupture and release the mature egg from the ovary, from where it enters the Fallopian tube. This process is known as ovulation.
Many women think that they ovulate on day 14, but 14 is an average, and most women will actually ovulate on a different day of the menstrual cycle. Your day of ovulation will vary from cycle to cycle.. Some women claim to feel a twinge of pain when they ovulate, but many feel no sensation at all and there’s no other sign that you are ovulating.
Ovulation
After ovulation
Once the egg (or ovum) has been released, it moves along the Fallopian tube towards your womb. The egg can live for up to 24 hours. Sperm survival is more variable, but typically 3-5 days, so the days leading up to ovulation and the day of ovulation itself are your most fertile – when you are most likely to get pregnant. As soon as you have ovulated, the follicle starts producing another hormone: progesterone.
Progesterone causes further build up the lining of your womb in preparation for a fertilised egg. Meanwhile, the empty follicle within the ovary starts to shrink, but carries on producing progesterone, and also starts to produce estrogen. You may get symptoms of pre-menstrual tension (PMS) such as breast tenderness, bloating, lethargy, depression and irritability at this stage.
After Ovulation
Preparing for the next period…
As the empty follicle shrinks, if the egg is not fertilised, levels of estrogen and progesterone decrease. Without the high levels of hormones to help maintain it, the thick womb lining that has been built up starts to break down, and your body sheds the lining. This is the start of your period and the beginning of your next menstrual cycle.
Preparing for the next period
Or for pregnancy
If the egg has been fertilised, it may successfully implant itself into the womb lining. This usually takes place about a week after fertilisation.
As soon as the fertilised egg has implanted, your body starts producing the pregnancy hormone, human Chorionic Gonadotrophin (hCG), which will keep the empty follicle active. It continues to produce the hormones estrogen and progesterone to prevent the lining of the womb from being shed, until the placenta (which contains all the nutrients the embryo needs) is mature enough to maintain the pregnancy.
All you need to know about your period
All you need to know about your period
Even if you get your period every month, how much do you really know about periods? | {
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128,204,703,190,500,860 | Hydrogen Peroxide
Intravenous Hydrogen Peroxide has the ability to help challenge cancer cells in a way they can’t respond to.
Intravenous hydrogen peroxide has the ability to oxidize most pathogens; increase tissue and cellular oxygen concentrations; which is involved in protein, carbohydrate, fat, vitamin and mineral metabolism, first line of defense in the immune response.
How does IV H2O2 therapy work? A hydrogen peroxide IV drip is put into a vein in the arm and enters the circulatory system. The IV drips over the course of ninety minutes. The hydrogen peroxide once in the bloodstream comes in contact with catalase and cytochrome-C which are two enzymes. Catalase turns the hydrogen peroxide into water and oxygen immediately.
The cytochrome-C enzyme, which binds to hydrogen peroxide, is not permitted to become water and oxygen for about forty minutes from first contact. Once cytochrome-C has been bound to it for the 40 minutes, the enzyme starts to behave just catalase and the hydrogen peroxide is broken down into water and oxygen.
The combination of hydrogen peroxide and the cytochrome-C enzyme has now been carried through the entire body. When this occurs all the benefits of hydrogen peroxide are now available to every cell.
The benefit to the body when having singlet oxygen spread throughout it is twofold.
First, it eliminates completely or dramatically prohibits anaerobic organisms from growing. The viruses and bacteria using carbon dioxide as fuel actually leave oxygen as just a by-product. When coming in contact with anaerobic organisms, the response is immediate. Pathogens which lead to disease are anaerobic bacteria and all viruses are indeed anaerobic.
Conversely, aerobic bacteria burns oxygen as fuel leaving carbon dioxide as a by-product. This is what humans do and it’s found in the intestine as friendly bacteria and is an aid in regards to digestion. These organisms do very well when coming in contact with hydrogen peroxide as it’s a natural part of the biological process.
Second, hydrogen peroxide through its natural process oxidizes environmental toxins and biological waste products which creates lifeless substances. The kidneys and liver can easily discard these substances.
What this does in the mitochondria is almost double the rate of metabolism with each cell! This enables the body to rid itself of poisons while having a surplus of energy to conduct the business of living every day life.
Hydrogen Peroxide For Cancer Treatments
This treatment is a vital part of the oxidative therapies used here at our healing center. Hydrogen peroxide therapy, ozone, and UVBI are all oxidative therapies and these treatments energize the oxidative pathways.
This is important because the way in which cancer is controlled and eliminated by our immune system is through oxidation. Life on earth would not exist without oxidation. The hydrogen peroxide therapy is used to naturally boost the immune system.
Oxidation is utilized to eliminate bacteria, viruses, cancer, and fungus. Hydrogen peroxide is used in such a way to naturally boost the ability of the body to kill off cancer cells or any other cells that are suspect.
Erica Johnson, RN In 2010, I received my RN from the University of Alaska, Anchorage. Throughout my career I have specialized in geriatric nursing with an emphasis on symptom management and chronic illness.
My personal interest in alternative medicine and nutrition inspired me to become a certified health coach through the Institute of Integrative Nutrition. I love working at An Oasis of Healing because my personal interests merge well with our program of working with our patients holistically.
An advocate of self- care, I believe that healing requires all aspects of the person – mind, body and spirit. In my free time, I enjoy creating art and spending time with my husband, 3 daughters and 4 dogs.
Would you like to speak with a caring member of our team to answer your specific questions? Call (480) 834-5414 | {
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-8,528,755,181,838,265,000 | Header Logo
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Synostosis
"Synostosis" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings). Descriptors are arranged in a hierarchical structure, which enables searching at various levels of specificity.
expand / collapse MeSH information
A union between adjacent bones or parts of a single bone formed by osseous material, such as ossified connecting cartilage or fibrous tissue. (Dorland, 27th ed)
expand / collapse publications
This graph shows the total number of publications written about "Synostosis" by people in UAMS Profiles by year, and whether "Synostosis" was a major or minor topic of these publications.
Bar chart showing 1 publications over 1 distinct years, with a maximum of 1 publications in 1992
To see the data from this visualization as text, click here.
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1,676,615,685,333,081,300 | AYAHAUSCA, Yage, Caapi, Soul Vine, Malpighiaceae (Banisteriopsis caapi)
AYAHAUSCA, Yage, Caapi, Soul Vine, Malpighiaceae (Banisteriopsis caapi)
Other Names: Ambihuasca, ambiwáska, ayawáska, biaxii, caji, caapi, calawaya, cipó, daime, daba, dapá, djungle tea, djunglehuasca, doctor, dschungel ambro- sia, el remdio, hoasca, honi, kaapi, kahi, hakpi, la purga, meti, mihi, natema, natemä, nepe, nepi, nixi honi, nixi paé, notema, ohoasca, pilde, pildé, pinde, pindé, remedio, sachahuasca, snato daime, tea, the brew, vegetal, yagé, yajé, yaxé
Identification: A shrub or climbing, twisting vine (or liana) with chocolate brown, smooth bark. Leaves are opposite, 6"–7" long, 3" wide, oval, double tapered, margins entire. Flowers are pink with 10 stamens. Fruit is a small nut. Seeds are fan-shaped; green when fresh, and brown when mature. Habitat: Tropical, Peru and other Amazonian regions. Toxins/Drugs: Beta-arboline alkaloids and monoamine oxidase (MAOI) inhibitors: harmine, harmaline—a subtle psychedelic, slightly hallucinogenic alkaloid.
Recipes: In former times the preparation of ayahuasca was a well-kept shamanic secret. Only the sha- man knew the sophisticated recipe: the necessary plants, where to find them, how the recipe was to be prepared, and which guarding spirits needed to be summoned. All recipes contain the stem of Banisteriopsis caapi as a base. All usable parts of the vine are decocted for the production of ayahuasca. Leaves of chacruna (Psychotria viridis) are then added. The mixture stays on the fire until a thick, black, dreadful-tasting liquid is produced. The drink should never be cooked in aluminum pots because ayahuasca interacts with the aluminum in such a way that it produces inedible aluminum salts. Very rarely, a pure cold water extract of Ban- isteriopsis caapi and Psychotria viridis is prepared, which is also effective (as Burroughs discovered in Pucallapa). Different ayahuasca preparations are com- bined with other ingredients. Many ayahuasca additions to the Banisteriopsis and Psychotria base are ethnomedically familiar healing plants, stimu- lants, aphrodisiacs, and entheogens. The plants of the paleros in the recipes of seven roots Amazonian elixirs are nearly all in use in ayahuasca concoctions.
Constituents and Effects: As far back as the nineteenth century, rumors and strange reports of the miraculous effects of aya- huasca reached the west. It was said that a person under its influence could walk through walls, find buried treasure, see through mountains, know the future, and influence events occurring in faraway places. Missionaries and doctors said the drink could activate and enhance telepathic abilities. The neurochemical secret behind the visionary effects of ayahuasca has only recently been clari- fied (River and Lindgren 1972). The two main components of ayahuasca are harmaline (also known as telepathine) and N, N-DMT. When taken orally, the drink can only unleash its consciousness- expanding effects when both substances are con- sumed together. By itself, orally ingested DMT cannot reach the brain because it is broken down by the enzyme monoaminooxide—MAO. Harma- line (as well as harmine and several other beta- carbolines) is an MAO inhibitor. MAO inhibitors block the release of MAO, making it possible for the DMT to pass through the blood-brain barrier and dock with the corresponding receptor sites, thereby inducing the nervous system to enter into an extraordinary state characterized by mag- nificent and overwhelming visions (McKenna et al. 1995; McKenna and Towers 1985B). Because of the powerful and often very vivid visions that result, ayahuasca is sometimes jokingly referred to as Amazonian TV (the “Nature Channel”) or the “cinema of the jungle.” It has recently been discovered that ayahuasca inhibits only MAO-A. The whole effect takes place over a period of four hours. First, the harmaline acts as a sedative, accompanied sometimes by immobility. During the early phase, harmaline causes overwhelming nausea that often leads to vomiting. Around forty-five minutes after ingesting the drink, the psychedelic action of the DMT begins, lasts about an hour, and then stops abruptly. When the DMT rush sets in, the nausea often dissipates. When ayahuasca is used on a regular basis, the body becomes accustomed to the pharmacological effect of the harmaline, so the nausea vanishes with chronic users. Because the body does not build up any intolerance to N, N-DMT, ayahuasca does not cause any physical or psychological addiction. In the West, scientists, entheogen enthusiasts, suburban shamans, and others have developed ayahuasca analogs that are the “Pan-Gæan” counterparts of Amazonian ayahuasca. As part of this work, both chemically pure tryptamines (DMT, 5-MeO-DMT) and harmaline alkaloids (harmin, harmaline) as well as plant extracts of each have been combined and successfully tested as bioassays.
First Aid: Because the drug has MAO inhibitors (MAOI), care must be taken with users who are on medicines that restrict the use of MAOI. In addition, MAO inactivates neurotransmitters, thus too much or too little is a problem. Low or high levels of MAO are associated with specific psychiatric disorders such as depression, schizophrenia, and attention deficit disorder. Irregular amounts of MAO leave a person susceptible to substance abuse. Because MAO levels affect epinephrine, dopamine, and norepinephrine levels, harmaline, a reversible monoamine inhibitor, can lead to extreme hypertension crisis, serotonin poisoning, and possibly death. Victim must discontinue use of drug, and in extreme cases, a serotonin antagonist is administered. Emotional support is helpful to control excessive agitation (which may require a sedative).
Note: According to Amazonian natives, the drug is a spiritual purgative, cleansing the body and opening the mind. | {
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2,948,789,524,246,374,000 | Stages in a Woman's Life According to Chinese Medicine
By Emma Suttie, D.Ac, AP
One of the reasons that I fell in love with Chinese Medicine was the beautiful way that it sees the body, health - and when expanded outwards - everything in existence. It is simply a way of looking at things that, to me, makes perfect sense and resonates deeply and profoundly.
Women's medicine is the way that I came to Chinese Medicine - I found it when Western medicine was not able to help me. Just one session with my wonderful acupuncturist and I was left with an overwhelming feeling that this system was what medicine was supposed to be. At its foundation was true healing, empowered by the individual and facilitated by the practitioner.
The Concept of Jing
Jing is a concept that is unique to Chinese Medicine and is sometimes difficult to explain. Jing is considered to be one of the three treasures in Chinese Medicine. Jing, Qi, and Shen comprise the three treasures. Jing is defined as the source of our life, health, and longevity. Qi is like our life force - and the force that animates all living things. Shen is the spirit and is closely associated with the heart and "the mind" in Chinese Medicine. All three treasures must be balanced for us to be functioning at an optimum state of health and wellbeing.
The Yellow Emperors Classic of Internal Medicine is one of the oldest medical textbooks on earth and was written around 240 BCE. It is in this text that the cycles of women and men are discussed. Women grow and mature in seven-year cycles and men in eight-year cycles.
Cycles for Women in Chinese Medicine
Women - 7 Year Cycles
7 years old
A woman’s kidney energy becomes abundant, teeth change and hair grows strong.
Kidney is a special term in Traditional Chinese Medicine. It not only has the function of controlling the urinary system, but also has a very important role – control the developing, growing, and reproduction. In terms of reproduction, you can think Kidney as a “Small Kidney”- the ovaries or testis.
At the age of 7, a woman’s reproductive system starts to develop.
14 years old
Her menstruation appears as the Ren meridian (the sea of Yin) flows and the Qi and blood in the Chong meridian (the sea of blood) becomes abundant, she can have children.
At the age of 14, her menstruation appears and she is able to have a child. In Traditional Chinese Medicine, the age of menarche is one important factor to help make a diagnosis. If menarche is later than 14 years old, it often indicates lower fertility energy.
21 years old
Her kidney energy is balanced, her adult teeth become completely developed and her body grows to full height.
A woman’s energy, especially fertility energy is full at the age of 21.
28 years old
Vital energy and blood are abundant, her bones and muscles are strong, her hair grows to full length and her body is in optimal condition.
At the age of 28, a women’s fertile energy reaches its peak. This is considered the best age for her to have children.
35 years old
Her peak condition declines gradually. Her energy in the yang ming meridian declines. Her face starts to wither and her hair starts to fall out.
From 35 year old, she starts to have wrinkles on her face, and her overall energy and fertility start to decline. She is still however, able to have children.
42 year old
The three Yang channels - Tai Yang, Yang Mind, Shao Yang - energy begins to decline. Her face wanes and her hair begins to turn white.
From the age of 42, her physical energy and fertility energy declines and it becomes more difficult to conceive.
49 years old
The Ren meridian (Conception Vessel) and Chong meridian vital energy declines, her menstruation dries up, her physique turns old and feeble and she is no longer able to conceive.
From the 7-year-life cycle, we can see that, according to Chinese Medicine, a good age for a woman to have children is from 21 to 35, and the best age is around 28 years old when her energies are at their "peak".
These cycles are still relevant in diagnosing and treating women's health issues in the context of Chinese Medicine. These stages are of course just a guideline, but they are immensely helpful in understanding - in a general way - how men and women move through their lives and what strengths, needs and imbalances they may face in different stages. Chinese Medicine is incredibly complex and has a vast body of knowledge that has been collected over thousands of years, and this is why it is still able to treat the health problems that people in our modern world face.
Beautiful featured image photo by Thomas Hafeneth on Unsplash
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Menopause - A Chinese Medicine Perspective
By Emma Suttie, D.Ac
Menopause is a time when a woman’s life transitions from one stage into another. Ideally, this is done gracefully, and without any problems or health concerns.
In reality, I see women entering menopause with dread and fear. They have been taught that menopause is a disease and that it will be a time for unpleasant symptoms and hormone therapy. Much of our culture supports this, and it is no wonder women feel this way. So why is it that women in the West react this way to a natural life process while their contemporaries in the East do not? In an interesting bit of trivia, the Western thinking on the subject it seems, was fuelled by a physician and a book he wrote on the subject in the 1960’s...
“The current medical wisdom is the product of an industrially manufactured consciousness. In 1966 Searle, Upjohn, and Wyeth-Ayerst pathologized the perception of menopause, transforming it from a transitional life stage into a chronic disease process by hiring a Brooklyn physician named Robert A. Wilson to write a book called Feminine Forever, proclaiming that estrogen would protect a woman's youth and save her from "living decay." The book injected fear by insisting that without estrogen replacement therapy (ERT), bones would dissolve, hearts clog, vaginas shrivel, breasts sag, skin crinkle, and minds deteriorate.”
By Harriet Beinfield, L.Ac. and Efram Korngold, L.Ac., OMD from their article Recognition and Prevention of Herb-Drug Interaction for Menopause
In China, women do not fear this natural stage of life. It is not part of their culture, or their experience. Menopause is not something that should cause anxiety, as it is seen as a completely natural process and not an illness that needs medicating. It is a time that a woman moves out of the reproductive part of her life and enters deeply inwards, bringing the focus to herself, often after many years of focussing on others. It is a time that is welcomed and honoured.
We are a culture that reveres youth and beauty. The transition into menopause is seen as a permanent loss of both. In China, one’s elders have great importance in both the family and social structure. As we move through life, we are seen to be accumulating something very valuable - WISDOM.
As we age, both our yin and yang energy are seen to be in a gradual state of decline. This is a natural part of life, and we are certainly able to supplement them by eating well, getting enough sleep, exercising and taking care of our bodies, minds and spirits.
Jing - The Essence of Your Being
To understand menopause, we must first understand what is called Jing, or essence - which is stored in and regulated by the Kidneys. Jing can be loosely compared to our genes or DNA. Jing is like our life force, and we are all born with a finite amount. This is supplemented throughout our lives by the food we eat and nutrition derived from the external environment, so the better we eat and take care of ourselves, the less we are drawing on our Jing or essence. A good way to illustrate how Jing works, is to think about it as a savings account. The better your health in your adult life, the less you will have to draw from your Jing account, and the more you will have when you get older (which is when you really need it).
How difficult menopause will be for a woman is largely dependent on the physical, spiritual and emotional health she has maintained throughout her adult life. At the first signs of menopause, or perimenopause, a woman will often seek out her doctor or gynaecologist and the recommendation is often Hormone Replacement Therapy, or HRT. While this is an option for some women, there are certainly alternatives, and Chinese medicine has been treating gynaecological issues for more than 2000 years. In Chinese medicine, menopause is not seen as a disease, but merely a stage of life where the needs of the body change. If a woman has led a relatively balanced life, then she will go through menopause without incident, and yes this does happen! This is largely the experience in China. If a woman has had a lot of stress, emotional upheaval, poor nutrition and insufficient exercise, the effects will be felt when she enters menopause. When we are young our bodies are able to handle a lot more abuse and bounce back - living an unhealthy lifestyle would be constantly drawing on the Jing in our savings account, and it is when we are older, when we continue the behaviours of the past, that we notice that our bodies don’t respond as quickly or as well to our demands. In a bank account that was overflowing in our youth, we are now functioning at a deficit.
The Jing, or essence is stored in the Kidney and is the source of all our body’s vital energies. When the Jing becomes deficient we lose our capacity to remember, have vision and hearing problems, our libido is compromised, stamina decreases, bones become thin and brittle, our minds become dull, teeth and gums deteriorate, we experience vaginal dryness, have sore lower back, hips and knees and emotionally we become apathetic and prone to despair. These are symptoms of a deficiency of Jing in Chinese medicine, but, as you can see, they are also in our experience, signs of aging.
A deficiency of Jing, as it is at the core of our health, has huge consequences as everything else draws from it, leading to deficiencies of yin and yang, qi and blood. Deficiency of qi presents as symptoms of fatigue, feeling unmotivated, unable to think and concentrate, an overwhelming desire to sleep and feeling sad and melancholy. A deficiency of blood manifests as dizziness, memory problems, numbness and vision problems. Insufficient blood is unable to nourish the body’s tissues, causing it to stiffen up, losing its suppleness and flexibility, not only physically, but there is a lack of emotional flexibility as well. Yang deficiency is literally a lack of the warming energies of the body manifesting as chills, cold limbs, loose stools, and spontaneous sweating. Hot flashes are a symptom of yin deficiency, as yin is not able to anchor yang fire, causing it to rise up uncontrollably. Yin deficiency also causes anxiety, and night sweats which are so often associated with menopause.
Diet & Nutrition
Menopausal women often notice a change in the way they process food, therefore, dietary changes can be hugely helpful for dealing with symptoms. Women going through menopause often become lactose intolerant, so eliminating dairy products will help eliminate bloating and gas. Supporting the beneficial bacteria in the body like probiotics will help to normalize the functions of the digestive system.
Another dietary consideration is that of carbohydrates and insulin. Carbohydrates (bread/grains/cereal/pasta/potatoes) are broken down into sugar or glucose which causes the body to release insulin. The role of insulin in the body is to break down glucose. Increased consumption of carbohydrates leads to increased insulin levels which interfere with the cells ability to respond to hormone stimulation. Women with symptoms of liver qi and blood stagnation (sx: anger, irritability, frustration, depression, feeling emotionally ‘stuck’, lump in the throat, anxious and easily stressed, severe pain that is fixed, stabbing severe, fixed masses, dark complexion, bleeding with clots, purple lips and nails), are likely estrogen dominant and would most benefit from a limited carbohydrate intake, preferably one meal a day.
Dietary Recommendations for Menopause
Smoking - smoking is extremely drying to yin fluids which are needed to combat common menopausal symptoms like night sweats and hot flashes, so either quit or cut down and try to stay away from secondhand smoke.
Avoid foods like sugar, dairy, alcohol, spicy foods, caffeine and red meat as they aggravate symptoms like hot flashes and decrease emotional stability causing mood swings.
Beneficial Foods
Include foods rich in phytoestrogens like soy (from non processed or GMO soybeans) including tofu, tempeh and miso pastes, flaxseed, sesame seeds, hummus, dried apricots and dates, alfalfa and mung bean sprouts and pistachios. Soy is not a popular food choice in North America, but it is a staple of the Chinese diet and the highest source of phytoestrogens known.
estrogenfoods
Also including foods that are a source of progesterone is important in menopause. Those foods include yams (not to be confused with sweet potatoes), turkey, walnuts and fortified cereals. Eggs, dairy products and chicken are good sources of progesterone, but it can be difficult to find sources that have not been given antibiotics or hormones which you want to avoid.
Other Things You Can Do To Ease Menopause Symptoms
You may be wondering if you have lived a less than healthy lifestyle up until now, if your menopausal symptoms can still be treated - and the answer is definitely yes. Women with menopausal symptoms, sometimes very severe or debilitating ones, are often seen in clinical practice. Even though the basis of Chinese medicine is on prevention, it still offers us an incredible array of tools that can be used to help reduce the symptoms of menopause.
Get some acupuncture. A practitioner of Chinese medicine with their robust skills of interrogation and diagnosis will ferret out the source of the imbalance and has many tools at her disposal with which to correct it. Acupuncture and Chinese herbs have been used for thousands of years to treat gynaecological disorders and work very well to combat menopausal symptoms. As I often tell people, there is no miracle formula or acupuncture point for night sweats or hot flashes. Chinese medicine is a holistic system, and the reason that you are having the symptoms is because the body is simply out of balance. It is the job of the acupuncturist to discover the root of the imbalance and correct it, while educating their patient on things like nutrition, lifestyle, exercise and meditation so that the body will remain in balance and the symptoms will never reappear.
Menopause should never be a time for worry and fear, it should be a time for inner reflection, and many women find it is an incredibly powerful and edifying part of their lives. All stages of life are important, so if you are experiencing problems, just know that you are not alone and that Chinese medicine can offer relief. | {
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Algae, The Ultimate Biohack
The ultimate goal of biohacking is optimal health, well-being and longevity. Put simply, it is the desire to function effortlessly at your peak level. Optimal health is not just about living as long as possible; it’s about living the healthiest you can for the longest.
Biohacking is a DIY biology. There are lots of cool but pricey biohacking technologies you can purchase but frankly biohacking doesn’t have to be complicated or expensive when you realize algae is the ultimate hack.
Algae is not just a one-stop-shop for optimizing health, longevity, and performance, it also up-levels your results when you add it to any of the buzzy bio-hack technologies like cryotherapy or red- light therapy. How? By improving your body’s chemistry, physiology and cellular communication and decreasing inflammation and pathogens with its dense nutrition.
Hey, we know that algae nutrition doesn’t sound as sexy as the other bio-hacks like cryotherapy but it works and its results are proven in tens of thousands of scientific papers. And you’ll feel pretty sexy when you take it because algae light up your life, brain and body – all naturally. It is, afterall, it’s the most nutrient-dense superfood in the world!
Read on to see how algae is not just the easiest bio-hack, it will boost your results when paired with any other biohacking methods…
Algae Hack Improves Your Longevity
Your organs and body is constantly trying to keep your cell’s pH within a specific range for optimal function.
When your body runs more acidic, it pulls alkaline nutrients, like calcium, out of your bones to try and balance the pH [1]. And when your cells are too acidic, toxins can’t be removed, mitochondria get damaged and cellular communication and health deteriorates.
The famous German scientist Otto Warburg won a Nobel Prize for discovering that no disease, including cancer can exist in an alkaline environment. So, for optimal health, you want to keep your cell pH as alkaline/neutral as possible and algae helps you do that.
Want to stay in the know and up to date with all things algae? Sign-up here for free!
Dr. Otto Warburg
Unfortunately, the typical American Diet is full of acidic foods like meat, processed foods, fried foods, dairy, eggs, refined grains, and alcohol. Acidity contributes to the development of heart disease, dementia, inflammation, osteoporosis, cancer, high blood pressure, obesity, diabetes, and autoimmune diseases [1].
Algae, on the contrary, is the most alkaline food in the world and can help to neutralize this acidity. Algae also has the highest concentration of chlorophyll in the world. Chlorophyll builds your hemoglobin (red blood cells) because it virtually identical in composition. And then you have healthy blood, your brain, organs, gut and body are healthy too and this makes it easier to achieve optimal levels of wellness and performance.
With ENERGYbits® I am assured that it is not only pure and has the highest nutrient density, but is also a powerful immune builder that optimized my cellular health, energy and metabolism.
Dr. Lori Shemek, PhD, CNC and Best Selling Author How to Fight Fatflammation
To improve your longevity, include ENERGYbits® algae in your diet to restore cellular health, balance your blood pH, reduce inflammation, improve your mitochondria health, slow aging, and help prevent metabolic disorders like heart disease and diabetes [2].
Algae Hack Improves Your Brain Health
Research has confirmed there is in fact a link between brain health and longevity [3].
Your brain needs things like glucose, amino acids, fat-soluble nutrients, and ketones to function properly, and all these essential nutrients get to your brain through semi-permeable blood vessels [4].
When you nourish your brain with complete proteins like those found in ENERGYbits® algae, you feel your best. Spirulina algae has the highest concentration of protein in the world and the protein is already in amino acid form, so you absorb it instantly.
woman and brain
Both spirulina and chlorella algae have many nutrients to boost brain health!
Algae is the original source of Omega-3, DHA and GLA to improve brain health. It’s where the fish get it! So, skip the fish oil and go straight to algae like ENERGYbits® spirulina. And when you do, you won’t have to worry about any fishy taste or it ever going rancid. And you’ll protect the oceans too.
Spirulina and chlorella both have many nutrients to boost brain health:
• High Vitamin K2 reduces calcification in the brain [5]
• High boron increases cognitive function and protection [6]
• High chlorophyll removes toxins and metals [7]
• High antioxidants & EFA’s reduce inflammation/free radicles [8]
• High RNA/DNA improve telomeres/brain health
• High plant-protein improves longevity/brain repair
• High B vitamins Increase mental energy and focus [9]
• High ribose in spirulina increases ATP energy & focus
• Prevents loss of memory and oxidative damage in the brain.
• Improves quality of life, mood, anxiety, and depressive attitude [10].
Algae Hack Improves Your Cellular Health
When your RNA/DNA is damaged, your cells and mitochondria fill up with toxins which leads to aging and disease [11].
Things like intense exercise, aging, stress, pollution, and poor diet can also deplete RNA/DNA causing inflammation, toxins and weakened immune systems. But with the right protein and nutrients, like those found in chlorella algae you can increase cellular healing, combat illness, generate cell recovery, reduce inflammation and more [12].
man and woman holding algae
Algae helps to heal cells and generate cell recovery to reduce inflammation and boost recovery.
Chlorella algae (RECOVERYbits®) also contains a unique nutrient called Chlorella Growth Factor (CGF) which has been shown to reverse cellular damage and help speed healing:
• CGF facilitates chlorella to multiply its cells by 4 every 20-24 hours.
• RNA/DNA is responsible for directing cellular renewal, growth, and repair [11].
• Chlorella has the highest RNA/DNA in the world (17x more than sardines). [13]
• Regular use of chlorella prevents the heart disease, and reduces high blood pressure and serum cholesterol levels [14].
• CGF improved the resistance to abdominal tumors and increased the number of immune cells [15]
• Eliminates mercury from the gastrointestinal tract, muscles, ligaments, connective tissue, and bone, as well as our skin [16].
Taking chlorella algae every day is like giving your body a shower from the inside!
Taking chlorella algae every day is like giving your body a shower from the inside!
Taking chlorella algae every day is like giving your body a shower from the inside!
Omega-3 and other fatty acids like GLA that are found in spirulina algae also help repair cellular walls, reduce inflammation and improve all cellular health [17]. High antioxidants found in algae reduce free radicles and oxidative damage keeping your body functioning optimally [18].
Want to learn more? Sign-up here for free!
Algae Hack Improves Your Physical Health
Combining ENERGYbits® spirulina algae with exercise will control glycemic levels [19], and provide you with steady energy. Algae has zero carbs, so it is also ketogenic unlike sugary drinks or snacks that shoot your insulin levels up and not just cause metabolic havoc but result in an energy crash later.
man working out with algae
Have a longer, stronger better workout with algae!
In fact, spirulina algae is composed of 64% protein [20], and projections indicate that within 30 years, over 50% of the world’s protein market will be plant-based. Algae is expected to be one of these main protein sources so now is a good time to learn about it and start enjoying it![21]
Algae is also a fantastic source of all your daily iron needs–up to 48% more iron than a serving of spinach [22]. Iron keeps your red blood count high, which means maximum oxygen absorption. Without oxygen absorption, your major organs and tissues cannot perform adequately during exercise, leading to burnout, injury, and fatigue.
• High plant-based protein (3 x steak) builds muscle and energy
• High Nitric Oxide vasodilator improves oxygen & blood flow [23]
• High Chlorophyll improves ATP and improves mitochondria
• High B Vitamins improve energy and methylation [24]
• High Bioavailability & rapid absorption results in immediate energy
• High iron (non-heme) increases oxygenation of blood and energy without stimulating mTOR pathway [25]
• High Antioxidants remove free radicals to improve longevity [8]
• Reduces Muscle Soreness & DOMS from removal of lactic acid
• Enhances endurance, reducing time to fatigue [26]
Algae Hack Improves Your Sleep
We all know that sleep is essential to our mental and physiological health. When we think about sleeping, we often think about things to avoid before bed like sugar, caffeine etc. However, there are foods that can help you fall asleep, and get a good night’s rest- like chlorella algae!
Chlorella algae (RECOVERYbits®) helps you recover your sleep time because it has the highest concentration of tryptophan in the world [27]. The body uses tryptophan to help make serotonin and melatonin, the neurotransmitters that produces healthy sleep and a stable mood.
man and woman dreaming about algae
Chlorella algae has the highest concentration of tryptophan in the world to ensure better sleep.
Bonus; during sleep, the space between cells increases, creating room for toxins to be flushed out [28].This system “opens” allowing more rapid flow of fluid throughout the brain and detox [28].
To make the most out of your sleep we recommend taking RECOVERYbits® chlorella before bed. This is because chlorella algae has been shown to bind to toxins and heavy metals so it facilitates and enhances your detox and repair while you sleep. You’ll awake refreshed, renewed and ready to go!
Algae Hack Improves Cold Therapy Results (Cryotherapy)
Cold therapy (also known as Cryotherapy) helps to increase cell longevity, induce rapid fast loss (increases metabolism by 16%) [29], lower your appetite, and strengthen the Vagus nerve connection between your gut and brain [30].
When your body is exposed to cold for a short period of time as it is in cryotherapy, your blood is pulled from your extremities (hands, feet etc.) and moves into your core where your organs are. This process brings oxygen and rich nutrients to your organs which help them heal and it facilitates cellular apoptosis (cell death) for the cells that are unhealthy. After the cryotherapy session is over your blood rushes back out to your extremities which provides you with a boost in physical energy and mental alertness and entire process boosts your metabolism which improve weight loss and appetite control.
When you have algae in your blood stream prior to your cryotherapy, your blood oxygen, chlorophyll and nutrient levels will be significantly higher which will up level the healing during your cold exposure. And since algae is a vasodilator (it expands your blood vessels) when your cold/cryotherapy session is over, your blood will rush out even faster and since algae’s nitric oxide will have helped dilate your blood vessels. Even better, the rich nutrition in the algae will rush out to your extremities so full of nutrients, your energy, mitochondria and metabolism will be dramatically enhanced, and your benefits will be deeper and last longer.
woman going into cryotherapy chamber
Take algae to enhance cryotherapy benefits and boost recovery!
That’s why we recommend taking both ENERGYbits® Spirulina and RECOVERYbits chlorella before any cryotherapy treatments. Chlorella algae has the highest concentration of chlorophyll and RNA/DNA in the world so it will significantly boost your organ and blood health while you are in the cold chamber. Spirulina algae is a vasodilator and has the highest concentration of protein in the world so after your cold treatment, it will help your blood out even faster to saturate your body and brain with the protein and nutrients it needs. Spirulina has also been shown to help you withstand the cold. Bonus points for algae!
Algae Hack Improves Light Therapy
Scientists have recently discovered that when you have chlorophyll (the fat-based pigment that makes plants green) in your blood stream and you are exposed to sunlight or red-light therapy, it recycles your CoQ10 in the “Mitochondria Electron Transport Chain” which generates ATP in the mitochondria [31]. In other words, your body creates its own energy through light with the help of chlorophyll. No food required! Woo hoo!
man using red light therapy
Chlorella algae helps to generate ATP at the cellular level, improving your energy without food!
But before you do your happy dance and have a salad in the sun, be aware that vegetables these days do not contain the same amount of chlorophyll as they did fifty years ago (because our soils are so damaged).
That’s whys the only reliable source of concentrated chlorophyll comes from algae especially chlorella algae (RECOVERYbits®). Chlorella algae contains the highest concentration of chlorophyll in the world (400 x more chlorophyll than arugula and 25 x more chlorophyll than liquid chlorophyll) which why it can also replace your need for greens!
That’s why we recommend you take RECOVERYbits® chlorella algae before your red-light therapy or before going out in the sun. You’ll get more out of your treatment and you’ll get a bonus boost in energy!
Conclusion
Biohacking in still in its infancy and every day we learn more about how to hack, protect and optimize our health and wellbeing. But the good news is that algae optimizes your body, health and brain all by itself or in conjunction with other bio-hacks.
Only you know what’s best for your body but we invite you to try the simplest. easiest, scientifically backed hack of them all. Algae. It’s the oldest hack in the world and has been waiting billions of years for you to enjoy its benefits.
Honor your body and algae and will do all the rest! ENERGYbits® algae!
To learn more and stay up to date with algae, sign-up for our newsletter here!
Sources
1. https://academic.oup.com/jn/article/128/6/1051/4722393?login=true
2. https://pubmed.ncbi.nlm.nih.gov/7797810/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465694/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508927/
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566462/
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1566632/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523211/
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982418/
9. https://www.sciencedirect.com/science/article/abs/pii/S0304394009011367
10. https://www.ncbi.nlm.nih.gov/pubmed/20938423
11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978769/
12. https://www.ncbi.nlm.nih.gov/books/NBK224629/
13. http://www.juergenmaimann.ca/articles/chlorella.php.
14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551956/
15. https://www.sciencedirect.com/science/article/pii/S0753332218370318
16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055906/
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404917/
18. https://pubmed.ncbi.nlm.nih.gov/23865357/
19. https://pubmed.ncbi.nlm.nih.gov/30928787/?from_term=exercise+algae&from_pos=2
20. https://www.health.harvard.edu/staying-healthy/by_the_way_doctor_is_spirulina_good_for_you
21. https://www.researchgate.net/publication/6605171_Micro-algae_as_a_source_of_protein
22. https://www.algaeindustrymagazine.com/special-report-spirulina-part-3-an-impressive-nutritional-profile/
23. https://pubmed.ncbi.nlm.nih.gov/19298191/
24. hhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/
25. https://pubmed.ncbi.nlm.nih.gov/30664135/
26. https://pubmed.ncbi.nlm.nih.gov/16944194/
27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1197660/
28. https://www.nih.gov/news-events/news-releases/brain-may-flush-out-toxins-during-sleep
29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064898/
30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049052/
31. https://jcs.biologists.org/content/127/2/388
ENERGYbits Team
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Single-cell sequencing and tumorigenesis: improved understanding of tumor evolution and metastasis
Abstract
Extensive genomic and transcriptomic heterogeneity in human cancer often negatively impacts treatment efficacy and survival, thus posing a significant ongoing challenge for modern treatment regimens. State-of-the-art DNA- and RNA-sequencing methods now provide high-resolution genomic and gene expression portraits of individual cells, facilitating the study of complex molecular heterogeneity in cancer. Important developments in single-cell sequencing (SCS) technologies over the past 5 years provide numerous advantages over traditional sequencing methods for understanding the complexity of carcinogenesis, but significant hurdles must be overcome before SCS can be clinically useful. In this review, we: (1) highlight current methodologies and recent technological advances for isolating single cells, single-cell whole-genome and whole-transcriptome amplification using minute amounts of nucleic acids, and SCS, (2) summarize research investigating molecular heterogeneity at the genomic and transcriptomic levels and how this heterogeneity affects clonal evolution and metastasis, and (3) discuss the promise for integrating SCS in the clinical care arena for improved patient care.
Introduction
The human body is composed of an estimated forty trillion cells [1]. Cellular diversity is controlled by specific RNAs and proteins, whose expression is influenced by exogenous and endogenous signals. While DNA was traditionally thought to be stable, with individual genomes set at the time of fertilization, recent evidence demonstrates that humans are genomic mosaics, comprised of cells that are genetically distinct even though they were derived from a single zygote [2]. Cancer is one of the most common forms of mosaicism in humans, where genetic changes occur in the cancer genome during tumorigenesis. Genomic heterogeneity in cancer is further complicated by the polyclonal nature of most carcinomas, with populations of tumor cells harboring genetic alterations that differ from the host genome and from other cells within the tumor. Intratumor heterogeneity can affect all stages of cancer care from diagnosis through treatment of metastatic disease. Diagnoses based on a single biopsy will likely underestimate the extent of heterogeneity within the tumor and fail to completely detect all clinically-actionable variants, leading to the emergence of drug-resistant populations of cancer cells. Designing therapeutic regimens based solely on characteristics of the primary tumor often fails to effectively treat metastases, which may be descended from minor sub-clones within the primary tumor and/or have acquired new mutations [3]. Therefore, the ability to optimize patient care will depend on a thorough characterization of genomic and transcriptional heterogeneity in cancer at the single-cell level.
Evaluating genomic heterogeneity at the single-cell level requires overcoming a number of challenges including isolation of individual cells, effective amplification of a single-cell genome to allow for targeted, exome- or genome-wide sequencing, and bioinformatics approaches to discriminate technical artifact from biological differences [4]. The advent of next-generation sequencing (NGS) methods enables researchers to generate genomic, transcriptomic and/or epigenetic data from a single cell (Fig. 1). In this review, we describe (1) current single-cell sequencing (SCS) methodologies and their applications for investigating the important role of genomic and transcriptomic heterogeneity in cancer and (2) how SCS approaches may be incorporated into the clinical arena for improved patient care.
Fig. 1
figure1
Applications of single-cell sequencing in cancer research. a Resolving intratumor heterogeneity; b investigating clonal evolution in primary tumors; c studying invasion in early stage cancers; d tracing metastatic dissemination; e genomic profiling of circulating tumor cells; f investigating mutation rates and mutator phenotypes; g understanding evolution of resistance to therapy; h defining cancer stem cells and cell hierarchies; and i studying cell plasticity and the epithelial-to-mesenchymal transition [86]
Single-cell sequencing technologies
SCS is a relatively new technology. The first single-cell RNA sequencing (RNA-seq) data, generated from a single mouse blastomere, were published in 2009 [5], and the first protocol to sequence DNA from single cells was published in 2011 [6]. Generation of whole-genome sequence (WGS), whole-exome sequence (WES), or RNA-seq from single cells requires isolation of individual viable cells or intact nuclei, amplification of minute amounts of DNA or RNA from the cell, sequencing, and analysis of the ensuing data. Continuous advancements in technology over the past 5 years have led to significant improvements in genome coverage and sequence quality, as well as drastic reductions in overall costs.
Isolation of single cells
A summary of methods for isolating single cells is presented in Fig. 2. Serial dilution provides a simple, low-cost method for isolating individual cells from abundant cell populations but is time consuming and requires expertise [7]. Micromanipulation and laser capture microdissection (LCM) both rely on visualization of the cells using a microscope. While LCM has the advantage of preserving spatial relationships within a tissue specimen, the tissue must be sectioned, often at thicknesses smaller than the diameter of single cell, leading to loss of chromosomal material [8]. Flow-assisted cell sorting and microfluidic platforms represent high throughput approaches that utilize specific properties of the cells, such as size or expression of biomarkers, for isolating individual cells from cellular suspensions of fresh tissue [9]. The approaches outlined above are sufficient for isolating single cells from tissue sections or large populations of cells in culture, but are not effective for isolating rare cells such as circulating tumor cells (CTCs) in peripheral blood or disseminated tumor cells (DTCs) in bone marrow.
Fig. 2
figure2
Single-cell isolation methods. a Methods for isolating single cells from abundant cell populations include: robotic or manual micromanipulation, serial dilution, flow-sorting, microfluidic methods, and laser-capture microdissection; b methods for isolating single cells from rare cell populations include: CellSearch™, DEP-Array™, CellCelector™, MagSweeper™, and nanofilters [16]
In contrast to the relatively non-specific methods mentioned above, numerous techniques have been developed for targeting and isolating single rare cancer cells from large populations of histologically diverse cells such as peripheral blood (Fig. 2). The CellSearch™ system is the only FDA-approved cell isolation and enumeration system currently available. An important component of the system is the CellSearch® Epithelial Cell Kit, which contains magnetic capture particles with a surface layer coated with antibodies targeting epithelial markers including leukocyte common antigen (CD45−), epithelial cell adhesion molecule (EpCAM+), and cytokeratins 8, 18+, and 19+. Rare CTCs are isolated from whole blood and enriched by exposing the buffy layer to the capture particles. During incubation, CTCs bind to the capture particles, are magnetically separated from unbound cells, and are then enumerated by fluorescence staining [10].
MagSweeper™ is an automated system that also uses immunomagnetic separation to purify rare cells in circulation. A magnetic rod is robotically swept through a sample containing labeled cells from peripheral blood to specifically capture circulating epithelial cells. Sequential rounds of cell capture-wash-release-recapture result in an enrichment of epithelial cells by 108-fold. Purified cells can be individually selected for subsequent biochemical analysis [11].
The DEP-Array™ system combines size and cell-surface expression properties for cell isolation. DEP-Array™ achieves CTC enrichment by density gradient centrifugation followed by staining with antibodies directed against CD45− and various cytokeratins. CTCs with the appropriate epithelial cell morphology and staining patterns are then recovered for molecular assessment [12].
CellCelector™ is a technique that uses automated micromanipulation for isolating individual cells from dense, single-cell microarrays. A suspension of cells from culture (or peripheral blood) is deposited on custom-made arrays containing micro-wells, controlling distribution and density to deposit one cell in each well. The array is then screened by a process known as micro-engraving—the array is covered with a glass slide coated with mono-clonal antibodies (goat anti-mouse IgA and IgG) and incubated. Using a microarray scanner, the glass slide can be interrogated for antibodies of interest that were secreted by the cells in the corresponding wells. Areas on the glass slide serve as a guide to locate matching micro-wells and individual cells in the wells can be selected by micromanipulation for subsequent analysis [13].
Because some of these isolation methods rely on cell-surface markers such as EpCAM and other epithelial proteins, these systems may not detect all rare cancer cells, including those that have undergone epithelial-to-mesenchymal transition (EMT). The CellSieve™ technique uses size discrimination to separate and isolate cells, and thus may be useful for capturing CTCs that are frequently larger than white blood cells [14].
Whole-genome amplification
The minute amount of DNA (~6 pg) and RNA (~10 pg) isolated from a single diploid cell requires whole-genome amplification (WGA) or whole-transcriptome amplification (WTA) to generate sufficient material for NGS. In recent years, numerous methods have been developed to amplify the DNA or RNA in a single cell with a focus on minimizing technical artifacts, such as preferential amplification of certain regions and/or allelic loss, and providing complete coverage of the genome [8, 1517].
Currently, three main approaches are used for WGA (Table 1). In the degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR) method, amplification is initiated with primers that share defined sequences at the 5′- and 3′-ends but contain six variable nucleotides (all possible combinations of A, C, G, and T) near the 3′-end to allow dense, even hybridization to the template DNA [18]. During the initial five to eight cycles of amplification, the defined and variable nucleotides at the 3′-end of the primers bind to the DNA template at many sites throughout the genome, followed by strand extension. In the second stage of amplification, the previously generated amplicons are amplified using primers that target the common sequence at the 5′-end of the primers [15] (Fig. 3a). High amplification bias, in which only certain regions of the genome are preferentially amplified and thus amenable to large-scale sequencing, results in relatively low coverage of the genome (~10%), making DOP-PCR useful for copy-number assessment in single cells but undesirable for single nucleotide variant (SNV) detection [16].
Table 1 Comparison of whole-genome amplification methods for single-cell DNA sequencing.
Fig. 3
figure3
Main approaches used for whole-genome amplification of single cells. a Degenerate Oligonucleotide-primed polymerase chain reaction (DOP-PCR) uses primers with common sequences at the 5′- and 3′-ends, but six random nucleotides near the 3′-end to allow hybridization at many sites throughout the genome; b multiple displacement amplification (MDA) uses φ29 DNA polymerase and random primers in a non-PCR based amplification reaction in which newly-synthesized strands are displaced from the original DNA molecule and serve as templates for additional DNA synthesis, resulting in a hyper-branched network; c multiple annealing and looping based amplification cycles (MALBAC) uses random primers with a common sequence at the 5′-end to amplify only the original template DNA and semi-amplicons. Full amplicons have complementary ends that allow the formation of closed-loop structures that prevent further amplification [15]
Multiple-displacement amplification (MDA) is a non-PCR based amplification technique that does not require thermal cycling, in which random hexamer primers are annealed to denatured DNA from a single cell to synthesize new DNA strands [19]. As the polymerase advances, newly-synthesized strands are displaced from the original DNA molecule and serve as templates for further primer annealing and additional DNA synthesis, resulting in a hyper-branched network and exponential amplification (Fig. 3b). DNA synthesis is normally catalyzed by φ29 DNA polymerase, an isothermal enzyme capable of generating quality DNA with high coverage of the genome for use in SCS. MDA works best for mutation detection but is not sufficient for copy number analysis due to moderate amplification bias and non-uniform genome coverage.
The multiple annealing and looping based amplification cycles (MALBAC) method utilizes a quasi-linear pre-amplification step to decrease amplification bias [20]. An important strategy of the MALBAC method involves amplification using only the original template DNA, rather than exponential amplification, by protecting the amplification products (Fig. 3c). Amplification using Bst (Bacillus stearothermophilus) polymerase is initiated with primers that share a common 27-nucleotide sequence at the 5′-end but contain eight variable nucleotides at the 3′-end to allow random hybridization to the template DNA. A polymerase with strand displacement activity first synthesizes semi-amplicons of variable length, which dissociate from the template at high temperature. Amplification of the semi-amplicons generates full amplicons with complementary ends that allow the formation of closed-loop structures, which prevent the full amplicons from being used as template. The full amplicons can then be exponentially amplified by PCR to generate microgram quantities of DNA for NGS. MALBAC provides high uniformity in coverage across the genome (93% coverage of at least 1X at a mean sequencing depth of 25× for a single human cell) and is useful for detecting copy number variants (CNVs) in single cells; however, MALBAC has a high false positive error rate and is not appropriate for detecting point mutations [8].
Whole-transcriptome amplification
A number of approaches have been developed for WTA of single cells (Fig. 4; Table 2; reviewed in [8]). The basic steps include reverse transcription of messenger RNA (mRNA) to complimentary DNA (cDNA) followed by cDNA amplification via PCR [9]. Tang and colleagues [5] first described a method for single-cell RNA-seq in which reverse transcription was performed using an oligo-dT primer with an anchor sequence, then a poly-A tail was added to the 3′-end of the first cDNA. The second strand was synthesized using a different oligo-dT primer with a different anchor sequence, and the cDNA was amplified by PCR.
Fig. 4
figure4
Main approaches used for whole-transcriptome amplification of single cells. a The Tang method performs reverse transcription of mRNA for single-cell RNA-seq using an oligo-dT primer with an anchor sequence, then a poly-A tail is added to the 3′-end of the first cDNA and the second strand is synthesized using a different oligo-dT primer with a different anchor sequence; b Smart-seq and Smart-seq2 implement a template-switching step to increase the number of full-length cDNA transcripts with an intact 5′-end; c quartz-seq limits amplification of unwanted byproducts by removing excess primer with exonuclease I before second-strand synthesis and using suppression PCR to form hairpin structures that cannot be amplified; d cell expression by linear amplification and sequencing (CEL-Seq) includes a template-switching step and uses molecular barcodes and pooling of samples from multiple single cells prior to linear amplification; e single-cell tagged reverse transcription (STRT) permits multiplex sequencing of multiple cells in the same reaction using a template-switching mechanism to simultaneously introduce a molecular barcode and an upstream primer-binding sequence during reverse transcription; f quantitative single-cell RNA-seq generates full-length transcripts using template switching and incorporating random UMI (unique molecular identifier) sequences to label individual cDNA molecules and eliminate amplification bias [8]
Table 2 Comparison of single-cell transcriptome sequencing methods.
Smart-seq and Smart-seq2 (switching mechanism at the 5′-end of the RNA transcript) represent variations of this approach designed to reduce 3′-bias, increase cDNA yields and the number of full-length transcripts, and detect alternative splice sites, novel exons, and genetic variants [21, 22]. These techniques implement a template-switching step, which increases the number of transcripts with an intact 5′-end. During first-strand synthesis, the reverse-transcriptase enzyme, isolated from the Moloney murine leukemia virus, adds extra cytosine (C) nucleotides to the 5′-end of the cDNA. By adding a primer containing guanine (G) nucleotides, the enzyme will switch templates and reverse-transcribe to the end of the primer, resulting in a full-length cDNA molecule that contains the complete 5′-end of the mRNA and an anchor sequence that will serve as a universal priming site for second-strand synthesis. Smart-seq2 contains technological improvements to increase sensitivity, accuracy, and the number of full-length transcripts.
Quartz-seq was developed to improve reproducibility and sensitivity of SCS methods to quantify the heterogeneity of gene expression between cells. Quartz-seq focuses on limiting the amplification of unwanted byproducts by removing excess primer with exonuclease I before second-strand synthesis, restricting poly-A tailing, and using suppression PCR, which permits short DNA fragments to form a hairpin structure that cannot be amplified [23]. Similar to other poly-A tailing methods for WTA of single cells, Quartz-seq shows a weak 3′-bias but is capable of detecting differentially expressed genes between different cell types.
The cell expression by linear amplification and sequencing (CEL-Seq) method overcomes challenges posed by the minute amount of RNA in a single cell by including a template-switching step and using molecular barcoding (attaching a short unique sequence to template DNA or RNA molecules to uniquely identify each molecule) and pooling of samples prior to linear amplification of mRNA in one round of in vitro transcription [24]. Subsequent modifications (CEL-Seq2), including shortening the CEL-Seq primer, optimizing the conversion of RNA to dsDNA, and ligation-free library preparation, have increased the efficiency, sensitivity, and cost-effectiveness of the method [25]. Despite recent improvements, these approaches still suffer from 3′-amplification bias, and therefore may not detect variable transcripts.
Unlike other whole-transcriptome amplification methods, single-cell tagged reverse transcription (STRT) is a highly multiplexed method for single-cell RNA-seq that quantifies gene expression in single cells by sequencing the 5′-ends of mRNA. STRT uses a template-switching mechanism to simultaneously introduce a molecular barcode and an upstream primer-binding sequence during reverse transcription, which permits multiplex sequencing of multiple cells simultaneously. STRT provides the ability to identify the transcription start site, locate promotor and enhancer elements, and conduct large-scale quantitative analysis but is not suitable for detecting alternatively-spliced transcripts [26].
Sequencing considerations
Despite recent progress, SCS techniques currently being used in research have technological limitations. Amplified DNA from single cells may be subjected to targeted sequencing, WES, or WGS. Targeted sequencing is associated with a lower false positive rate, with more uniform coverage of the targeted areas. In contrast, WES and WGS provide greater coverage of the genome and an increased ability to discover mutations; however, as genome coverage increases so does the false positive rate. WGS of single cells provides the greatest opportunity to detect genetic alterations across the genome but at significantly increased cost [4].
Data analysis
Single-cell isolation techniques and WGA/WTA may introduce artifacts that must be considered when analyzing sequencing data. Based on the cell selection approach utilized, cells may be biased in size, rates of cell division, or cellular properties. WGA techniques result in low physical coverage of the genome, allelic dropout (where one or both alleles at a heterozygous locus fail to amplify and therefore are not detected), uneven genome coverage, and false-positive and false-negative errors. For RNA-seq, reverse transcription of mRNA to cDNA followed by cDNA amplification via PCR introduces technical artifact and amplification bias, particularly for lower-abundance transcripts. In fact, only ~10–20% of transcripts are reverse transcribed with current methods and many transcripts are not full-length [9]. Comparing SCS results to bulk tumor sequence can be used to estimate technical errors; however, this approach may decrease the ability to detect variants specific to the single cells. Incorporating molecular barcodes, also known as unique molecular indices or UMIs, may prove useful for improving efficiency and distinguishing true mutations from PCR or sequencing errors [27]. New algorithms and computational methods to address these limitations are currently being developed and may provide the necessary informatics infrastructure to accurately and reliably analyze SCS data.
Single-cell sequencing of tumor cells
Cancer stem cells
Normal stem cells are rare, quiescent cells that survive in an undifferentiated state for extended periods of time and have the capacity for unlimited self-renewal and the ability to generate morphologically diverse progeny cells [28]. Tissue-specific stem cells that reside in differentiated tissues are important in growth and development because they also have the capacity for self-renewal and the ability to differentiate into a variety of specific cell types. Tissue-specific stem cells may accumulate certain mutations over time that initiate carcinogenesis, causing them to become cancer stem cells. Additional mutations in cancer stem cells that alter molecular pathways influencing genome stability, resistance to apoptosis, and normal growth and differentiation, may occur during tumorigenesis, leading to substantial genetic and functional diversity among clonal populations of cells within a primary carcinoma [29, 30]. Although the development of genetic diversity in cancer stem cells has not been well defined, SCS is now being used to study cancer stem cells to identify mutations in key functional pathways promoting tumorigenesis [31]. Because cancer stem cells are believed to be responsible for many aspects of cancer biology such as tumorigenesis, metastasis, and drug resistance, eradication of these stem cells has become a prime objective of modern anti-cancer therapeutics.
The ability to quantify cell-to-cell variation in gene expression using single-cell RNA-seq is important to understanding clinical parameters such as a patient’s response to treatment and the potential for disease recurrence. As a result, research on cancer stem cells at the individual cell level has accelerated in recent years, focusing on unique functional properties, including extensive cell-to-cell heterogeneity in gene expression and plasticity in the degree of “stemness” [32]. Single-cell transcriptome analysis of cancer stem cells has been difficult due to their rarity and the small amount of total RNA in a single cell; however, recent developments in single-cell isolation, WGA, and RNA-seq discussed above [33] provide an opportunity to study the transcriptomes of these rare stem cells and provide insight into the complex nature of functional heterogeneity at the individual cell level [34].
In breast cancer, single-cell gene expression profiling has been used to identify regulatory networks influencing differentiation, stemness, pluripotency, EMT, and proliferation, which are important for the identification of rare cell types such as stem cells [35]. Investigating the potential role of stem cells in the initiation and progression of breast cancer metastases, Lawson and colleagues [36] developed a fluorescence-activated cell sorting assay to identify human metastatic cells from a patient-derived xenograft (PDX) mouse model. Multiplex analysis detected heterogeneity in gene expression and revealed a distinct stem-cell-like gene expression signature in early stage metastatic breast cancer cells, suggesting that breast cancer metastases may be initiated by stem-like cells. Paired-end transcriptome sequencing identified unique patterns of gene expression in breast cancer stem cells compared to other breast cancer cell types that may regulate the effects of oncogenes and tumor suppressor genes [37].
Using single-cell RNA-seq to profile 430 cells from five primary glioblastomas, Patel et al. [38] found variability among cells in patterns of gene expression in pathways such as oncogenic signaling, proliferation, and immune response. Importantly, an examination of “stemness” genes identified a continuous, rather than discrete, stemness-related gene expression signature among individual glioblastoma cells, which suggests that glioblastomas contain primitive populations of stem-like cells with variable degrees of differentiation and proliferative capacity.
Primary tumors
Breast cancer
A summary of SCS studies on primary tumors from a variety of human cancers is presented in Table 3. The first report of SCS in cancer published in 2011 [6] performed copy number evaluation on flow-sorted nuclei from two triple-negative breast carcinomas. One tumor was found to be highly mono-genomic and was composed of cells representing a single clonal expansion, but the other carcinoma was genetically heterogeneous, containing distinct clonal subpopulations of cells that were hypothesized to have originated early in tumor development. Further single-cell studies supported this concept that CNV tends to occur early in the development of breast cancer. Wang and colleagues [39] evaluated nuclei from cells undergoing cell division (G2/M nuclei) to examine clonal diversity and mutational evolution in two breast cancer patients. No two single cells from a luminal A or triple negative breast tumor exhibited identical genomic profiles even though the mutation rate was significantly higher in the triple negative carcinoma (>13-fold). Alterations in copy number were widely shared, suggesting they occurred early in carcinogenesis, while point mutations appeared to evolve gradually over a longer period of time. A follow-up study using single-nucleus sequencing of 1000 single cells from 12 patients with triple-negative breast cancer identified one to three major clonal subpopulations in each tumor that shared a common evolutionary lineage and were unlikely to result from gradual accumulation of CNVs over time [40]. Similarly, in two patients with estrogen receptor (ER)-positive breast cancer, chromosomal alterations characteristic of ER+ tumors including duplications of 1q and 8q and deletion of 11q were shared across most single cells from both patients, indicating that these events occurred early in the development of these tumors [41]. Together, the SCS data suggest that the earliest steps of tumor development involve copy number changes that occur in punctuated bursts, but point mutations evolve gradually, driving clonal expansions and generating extensive clonal diversity within a primary carcinoma.
Table 3 Summary of single-cell sequencing studies on primary tumors from a variety of human cancers
NGS technology is being used extensively to identify genetic variability associated with acquired resistance to chemotherapy, which has become a major barrier to successful cancer treatment. Large-scale RNA-seq on single cells from breast cancer cell lines has shown that cells exhibiting high variability in RNA transcripts, which was also evident at the protein level, possess increased metastatic capacity and survival following chemotherapeutic treatment [42]. Whole-transcriptome sequencing detected high heterogeneity in gene expression among individual cells from the MDA-MB-231 metastatic breast cancer cell line following exposure to paclitaxel (100 nM) for five days. Although most cells were killed, a small number of drug-tolerant cells survived, which expressed unique RNA variants influencing cell adhesion, cell surface signaling, and microtubule organization/stabilization [43]. These studies demonstrate that molecular heterogeneity at the single-cell level may have a significant impact on patient outcomes and that quantification of this heterogeneity will be vitally important to successful cancer treatment.
Adenocarcinoma of the lung
Adenocarcinoma of the lung is the most common histologic subtype of lung cancer, accounting for more than 40% of lung cancer incidence. Several studies have performed single-cell RNA-seq on lung cancer patients to investigate molecular heterogeneity at the single-cell level. Min et al. [44] examined 34 single cells from a lung adenocarcinoma PDX model, and after filtering out differentially expressed genes associated with xenografting and cell culture, identified a set of 64 genes associated with poor prognosis that stratified the adenocarcinoma cells into two groups. In a separate study, single lung adenocarcinoma cells from this same PDX were evaluated by RNA-seq and expressed mutation profiling to study how heterogeneous cell populations respond to anti-cancer treatments [45]. Combining the status of the Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D (35G>A) mutation with the expression profiles of 69 genes associated with clinical prognosis classified the adenocarcinoma cells into four groups with different gene expression patterns. One group of cells that appeared cell-cycle quiescent and exhibited upregulation of ion channel transport genes survived exposure to chemotherapeutic agents and thus may be responsible for treatment failure. This study suggests that the actual cells responsible for drug resistance may be masked when analyzing large sections of the primary carcinoma, but single-cell RNA-seq data may be useful for detecting rare potentially drug-resistant sub-clones. Suzuki and colleagues conducted single-cell RNA-seq on 336 cells from seven lung adenocarcinoma cell lines to investigate how cellular heterogeneity influences drug response [46]. Focusing on the LC2/ad cell line and a derivative cell line (LC2/ad-R), which has acquired resistance to the multi-tyrosine kinase inhibitor drug vandetanib, showed that average gene expression levels changed more in LC2/ad-R cells than in LC2/ad cells in response to vandetanib treatment, potentially reflecting an acquired plasticity in the ability to respond to vandetanib. As seen in other single-cell studies, the great diversity in gene expression at the single-cell level, which may serve as a reservoir for cells to acquire drug resistance, cannot be detected with bulk tissue sequencing.
Glioblastoma
Glioblastoma multiforme is the most common brain and central nervous system malignancy, characterized by a poor prognosis with exceptionally low overall survival. Glioblastomas are biologically aggressive carcinomas that present unique clinical challenges due to rapid growth rates with widespread invasion throughout the brain and inherent resistance to traditional as well as targeted therapies [47]. Extensive cellular and molecular heterogeneity is a common feature of glioblastomas, including multiple alterations in the epidermal growth factor receptor (EGFR) gene that may affect treatment response. To characterize genomic heterogeneity in EGFR-amplified glioblastomas, Francis et al. conducted single-nucleus WGS on two glioblastomas with focal amplification of EGFR [48]. EGFR copy number was observed to be highly variable between single cells due to varying levels of EGFR amplification (5–200 copies), EGFRvII truncation (deletion of exons 14–15), and EGFRvIII deletion (deletion of exons 2–7). These data suggest that heterogeneity in the expression of oncogenic EGFR mutations may contribute to therapy resistance and combining multiple EGFR inhibitors that act through different mechanisms may be required in glioblastoma patients who carry multiple EGFR variants.
Patel and colleagues used single-cell RNA-seq on 430 cells from five primary glioblastoma neoplasms to systematically interrogate intratumor heterogeneity [38]. In agreement with the study described above by Francis et al. [48], several oncogenic variants of EGFR were detected within a single glioblastoma. Based on patterns of gene expression, all five tumors were found to consist of heterogeneous mixtures of individual cells corresponding to different glioblastoma subtypes defined by The Cancer Genome Atlas. Importantly, cell-to-cell variability was also detected in the expression of various signaling molecules and cell-surface receptors comprising pathways that may contribute to targeted-therapy resistance in glioblastoma. As higher levels of cell-to-cell subtype heterogeneity were associated with decreased patient survival, previously unrecognized heterogeneity may be an important factor contributing to the high mortality rates associated with glioblastoma.
Colon cancer
Unlike many types of human cancer, linear models of evolution have been developed for colon cancer, with mutations in genes such as adenomatous polyposis coli (APC) and tumor protein p53 (TP53) playing critical roles in tumor progression. WES performed on 63 single colon adenocarcinoma cells revealed two groups of tumor cells with distinct genetic profiles [49]. The major subgroup of tumor cells was characterized by a high frequency of APC and TP53 mutations while in the minor subgroup, mutations in the cell division cycle 27 (CDC27) and polyadenylate-binding protein, cytoplasmic, 1 (PABPC1) genes were predominant. The authors concluded that this tumor was bi-clonal in origin, with each subpopulation deriving from separate ancestors; however, this conclusion has been questioned as not all cells in the major population had mutations in APC and TP53 and mutations in CDC27 and PABPC1 were present in both groups, suggesting possible technical difficulties associated with WGA [16]. In a separate study, RNA-seq data generated on 96 single cells from the HCT116 colon cancer cell line were used to assess patterns of gene expression and detect enrichment of DNA variants in colon cancer-related pathways [50]. SNV data from the single isolated cells were mostly consistent with results obtained when the cell line was sequenced en masse, but single cells displayed an array of variants that were masked when many cells from the cell line were sequenced together (bulk sequencing). This study showed that single-cell RNA-seq of colon cancers may reveal cryptic genetic alterations in cancer-related genes, enrichment of certain functional pathways, and presence of fusion proteins that may play important roles in the development of colon cancer.
Urinary system cancers
Bladder cancer accounts for nearly 5% of all new cancer cases in the United States and is responsible for approximately 3% of all cancer deaths. Bladder cancer is marked by heterogeneity in the types of carcinomas observed in patients and the presence of infiltrating normal cells. Single-cell exome sequencing of 66 individual tumor cells from a muscle-invasive bladder transitional-cell carcinoma revealed that all cells were descended from a common ancestral cell, but subsequent genomic evolution created variability that could partition the cells into two distinct groups [51]. The authors hypothesized that the bladder cancer cells were subjected to selective pressure and accumulated mutually-exclusive driver mutations within these cell lineages during development. The projected timing of key mutations during cancer growth suggests that mutations in cancer-associated genes may initiate carcinogenesis and lead to genetically-distinct cell lineages that influence resistance to treatment.
To evaluate cellular heterogeneity in gene expression within a squamous cell carcinoma of the urinary bladder, Zhang et al. subjected 75 individual cancer cells to RNA-seq [52]. Cell-to-cell heterogeneity was detected for multiple genes in important cancer-related pathways, including the mitogen-activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK-STAT), Notch, phosphoinositide 3-kinase (PI3K), and vascular endothelial growth factor (VEGF) pathways. Because these pathways represent important targets for anti-cancer therapeutics, heterogeneity in expression may affect tumor response to therapy and patient survival.
Renal cell carcinoma accounts for more than 200,000 new cancer cases and over 100,000 deaths worldwide each year. Clear cell renal cell carcinoma (ccRCC), the most common form of renal cell carcinoma, is characterized by a relatively low mutation rate with few mutations shared among patients. To investigate intratumor heterogeneity at the individual cell level in ccRCC, WES was conducted on 20 single ccRCC cells from a 59-year-old male patient [53]. Phylogenetic analysis suggested that progression from normal to cancer cells occurred quickly. Although no significant sub-clonal populations of cells were detected within the tumor, there were many rare mutations, each present in only a few cancer cells. These mutations would not have been detected using whole-tumor sequencing. This study provided an important view of the intratumor genetic landscape of a ccRCC carcinoma at the single-cell level and revealed that renal carcinomas may be more genetically complex than previously thought.
To examine transcriptional heterogeneity during metastatic progression and the activation of signaling pathways influencing drug responsiveness, single-cell RNA-seq was performed on a primary ccRCC carcinoma and a paired lung metastasis following propagation in a PDX model [54]. This patient was not responsive to sequential therapies, including pazopanib, everolimus, and high-dose interleukin-2. The RNA-seq results revealed significant variability in expression and activation of pathways targeted by therapy, such as the EGFR and c-Src proto-oncogene pathways, between the primary carcinoma and the metastasis, and among individual cancer cells within both tumors. Heterogeneity in the activation status of the EGFR and Src pathways corresponded to variability in drug sensitivity at the individual cell level. High-resolution transcription profiling of single cells established the molecular basis for treatment resistance and led the authors to propose that combination therapy with afatinib and dasatinib may be a more effective treatment option than monotherapy for metastatic renal cell carcinoma.
Hematopoietic tumors
Hematopoietic and lymphoid tissue malignancies affect the blood, bone marrow, and lymphatic system. To further examine genomic complexity in hematopoietic cancers previously studied by WGS of bulk tumor samples, Hughes and colleagues performed targeted sequencing to genotype more than 1900 SNVs in single cancer cells from three patients initially diagnosed with myelodysplastic syndrome who progressed to secondary acute myeloid leukemia, the most common form of acute leukemia in adults [55]. SCS identified genomic complexity not evident in the whole-tumor analysis and improved the ability to resolve clonal relationships compared to sequence generated from unfractionated tumor samples. To delineate the clonal structure and evolutionary history of acute lymphoblastic leukemia (ALL), targeted sequencing of a panel of SNVs, deletions, and immunoglobulin heavy chain sequences was performed on 1479 single cells from six children with pediatric ALL [56]. As seen with other types of cancer, ALL carcinomas were characterized by distinct clonal populations of cells where alterations in copy number preceded the occurrence of SNVs. Phylogenetic analysis revealed that KRAS-associated driver mutations occurred late in tumor development and facilitated the expansion of certain clones, which became dominant but did not completely outcompete all of the other clones in each patient. Separately, Bakker et al. used single-cell WGS to examine karyotype dynamics in three children with chromosomally-unstable B cell ALL [57]. Traditional cytogenetics conducted at the time of diagnosis characterized the ALL carcinomas as displaying different levels (low, intermediate, and high) of aneuploidy. SCS identified subpopulations of cells within each tumor that harbored copy number alterations not detected in whole-tumor analysis. When cells from the ALL tumor with intermediate levels of aneuploidy were engrafted into immunodeficient mice, changes in copy number were observed, suggesting that copy number heterogeneity in individual cells may evolve in response to stressors, such as a new microenvironment or exposure to therapy.
Essential thrombocythemia (ET) is one of several myeloproliferative neoplasms in which sustained proliferation of megakaryocytes leads to an excess of circulating thrombocytes (platelets). Although more than half of all ET patients carry mutations in the Janus kinase 2 (JAK2) gene, mutations in other genes are known to affect disease phenotype and clinical outcome. WES of 58 single cancer cells from a JAK2-negative ET patient was used to examine clonal composition of the neoplasm and identify genes involved in disease progression [58]. The authors identified 18 genes hypothesized to play a role in tumor development and concluded that the disease was monoclonal in origin. However, these conclusions were contradicted by phylogenetic analyses, which showed large genetic distances between cells, and therefore it is unclear if these differences reflect real genomic diversity or technical artifact.
SCS has been useful for revealing molecular heterogeneity among individual cells of primary carcinomas from a variety of human cancers that would not be detectable with bulk tumor sequencing. At the single-cell level, most primary tumors are polyclonal due to punctuated clonal evolution where copy number alterations serve as founder mutations and additional CNVs and/or point mutations occur later in tumor development. These subsequent mutations are restricted to subpopulations of cells where they contribute to clonal fitness and thus influence resistance to treatment and patient survival.
Circulating and disseminated tumor cells
A summary of SCS studies on CTCs and DTCs from a variety of human cancers is presented in Table 4. Substantial evidence suggests that distinct subpopulations of stem-like cells mediate many aspects of cancer biology, including metastasis and therapeutic resistance [59]. CTCs are viable cells that are shed from a primary carcinoma and circulate throughout the bloodstream, carrying genetic alterations found in the primary tumor [60]. The presence and/or abundance of CTCs in whole blood has been shown to be an independent predictor of poor survival and an unfavorable response to treatment in numerous cancer types [61], and the persistence of disseminated cells in bone marrow after adjuvant therapy is significantly associated with increased risk for recurrence and mortality [62].
Table 4 Summary of single-cell sequencing studies of CTCs and DTCs
Only certain CTCs are believed to be capable of forming successful metastases. Recent evidence suggests that some CTCs, referred to as circulating cancer stem cells, exhibit a stem-cell-like phenotype and may possess metastasis-initiating capabilities associated with resistance to therapy [63, 64]. Because CTCs that display stem cell characteristics may initiate successful metastases, it is important to characterize these cells, which are easily accessible in peripheral blood, for their usefulness in predicting cancer progression, metastasis, and treatment response.
Circulating tumor cells
SCS is a useful technique for improving our understanding of clonal evolution in human cancers, as well as molecular changes that occur in disseminated cancer cells, which may drive metastasis and lead to development of therapeutic resistance. Numerous studies have shown that mutational profiles identified by NGS may be similar in primary carcinomas, metastases, and CTCs in patients with a variety of cancer types, but important molecular heterogeneity has been detected, suggesting potential utility of CTCs in patient care (reviewed in [65, 66]).
NGS of 68 cancer-associated genes in individual CTCs from patients with stage IV colorectal cancer found that most mutations, particularly those in driver genes, observed in the primary tumor and metastatic deposits were also present in CTCs, suggesting that the mutational spectrum of complex tumor genomes can be inferred from CTCs [67]. Similarly, WES of single CTCs in lung cancer patients detected reproducible CNVs that were similar to those in metastatic deposits of the same patient [68]. In patients with prostate cancer, 70% (51/73) to 86% (197/229) of all mutations observed in individual CTCs were also found in the primary tumor and metastasis [69, 70].
SCS has been used to identify within-patient genomic heterogeneity among single CTCs isolated from blood of breast cancer patients. For example, mutational heterogeneity in the TP53 gene, platelet-derived growth factor receptor, alpha (PDGFRA), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and other genes has been observed among individual CTCs from women with metastatic breast cancer [71, 72]. Similarly, the mutational status of TP53 has been shown to vary among CTCs in breast cancer patients, with some CTCs carrying the same mutation(s) as the corresponding primary carcinoma, while other CTCs carry different mutations [73].
Mutational heterogeneity present in a primary carcinoma is often reflected in the genomes of CTCs; however, further genomic changes that promote successful metastasis may occur exclusively in CTCs and DTCs [74]. Such heterogeneity at the single-cell level likely reflects dynamic and ongoing mutational changes that occur during disease progression in a constantly evolving cancer genome. Therefore, the genomic signatures of many individual CTCs from a cancer patient may be more informative than traditional biopsies of the primary tumor for designing targeted therapies and monitoring therapeutic response.
Optimal therapeutic strategies in breast cancer patients are highly dependent on the behavior and resilience of CTCs, which may be influenced by patterns of gene expression. Similar to genomic heterogeneity, cell-to-cell variability in patterns of gene expression has been identified among individual CTCs. In women initially diagnosed with human epidermal growth factor receptor 2 (HER2)-negative breast cancer, RNA-seq of individual CTCs documented the emergence of HER2 + CTCs [75]. The persistence of discrete populations of HER2+ and HER2 − CTCs, which have the capacity to interconvert spontaneously, may contribute to progression of breast cancer and acquisition of drug resistance. Similarly, single-cell transcriptome analysis of CTCs revealed heterogeneity in the expression of genes associated with metastasis and induction of the EMT, where epithelial cells transition to a more mesenchymal phenotype, which increases invasiveness and resistance to apoptosis [76].
Men with prostate cancer may be initially responsive to androgen receptor (AR) inhibitors, but in some patients, single-cell RNA-seq of individual CTCs detected heterogeneity in the expression of AR gene mutations and activation of non-canonical (β-catenin-independent) Wnt signaling, which may promote invasiveness and malignant progression, thereby contributing to treatment failure [77]. In pancreatic ductal adenocarcinoma, RNA-seq has been used to compare genome-wide expression profiles of single cells disaggregated from the primary carcinoma with corresponding CTCs in a mouse model of pancreatic cancer [78]. Compared with cells from the primary tumor, CTCs showed enrichment of some genes associated with stem cells and reduced expression of epithelial markers (E-cadherin and Mucin 1). Within CTCs, a high degree of heterogeneity was evident in the expression of mesenchymal transcripts, platelet-derived markers, and proliferative gene signatures.
Disseminated tumor cells
Research on the role of DTCs in bone marrow of cancer patients has increased in recent years because the dissemination of cells from a primary carcinoma is believed to be a critical step in the process of disease progression and formation of distant metastases. The presence of single DTCs in bone marrow has been established as a strong predictor of distant disease-free survival and breast cancer-specific survival in breast cancer patients [79]. Patients with non-metastatic breast cancer remain at significant risk of relapse, even after complete surgical excision of the primary carcinoma, likely due to the persistence of disseminated cancer cells [80].
Disseminated cancer cells detected in bone marrow of patients with breast cancer have been found to express proteins characteristic of cancer stem cells [81]. DTCs are similar to CTCs in that they arise from sub-clonal populations of cells in the primary carcinoma and undergo further molecular changes after dissemination [82]. Cancer biomarkers and genetic variation in both CTCs and DTCs may evolve during disease progression, and significant molecular discordance with important therapeutic implications may develop between the primary tumor and disseminated cells [83].
SCS studies of DTCs have been limited, presumably because of the invasive surgical procedures needed to collect these cells. In one study, Carpenter and colleagues isolated 144 disseminated cells from bone marrow of patients affected with neuroblastoma [84]. In patients carrying a mutation in the anaplastic lymphoma kinase (ALK) gene in their primary tumor, single-cell WGA and sequencing detected the same mutation in single DTCs from bone marrow. Demeulemeester and colleagues used SCS to trace the origin of 63 single disseminated cells from six non-metastatic breast cancer patients [85]. Approximately one-half of the DTCs which morphologically resembled cancer cells were found to be disseminated from the primary tumor; however, some of the remaining cells displayed normal copy-number profiles, while other cells had CNVs that were genetically different from the primary tumor. Reconstructing evolutionary relationships between the primary tumor and DTC genomes showed that some DTCs originated from the predominant clone in the primary carcinoma, other DTCs arose from less prevalent lineages in the primary tumor, and a few DTCs descended from minor clones observed in the axillary lymph node metastases.
Single-cell sequencing in clinical practice
Targeted therapeutics are designed to focus on actionable mutations detected in a biopsy of the primary tumor, but these “actionable” mutations may no longer drive disease progression once tumor cells disseminate from the primary carcinoma and undergo unique genomic changes. The ability of single-cell sequencing to delineate the genomics and transcriptomics of circulating and disseminated cancer cells holds great promise for making meaningful improvements in personalized oncology over the next several years. To date, SCS has been used primarily in the research setting; however, there may be a number of clinical applications, including diagnosis, prognosis, treatment decisions, and monitoring [86]. An intriguing use of SCS would be early disease diagnosis through the analysis of bodily fluids such as blood or urine. Through regular noninvasive monitoring of high-risk patients, single disseminated cancer cells may be detectable at an early stage of disease before a cancerous lesion could be visualized with current imaging technologies. Identification of clinically-actionable mutations at an early stage could lead to targeted treatment before tumor heterogeneity and multiple genomically-distinct clones that are resistant to therapy can evolve. Additionally, improvements in SCS technologies will enable analyses of small tumors which previously were too small to analyze using bulk sequencing approaches. As demonstrated by SCS of primary carcinomas, single biopsies may fail to adequately account for intratumor heterogeneity. Assessing genomic heterogeneity within the primary tumor or among disseminated cells would allow for the calculation of diversity scores which may be used prognostically, with higher intratumor heterogeneity associated with less favorable outcomes [65, 87].
SCS may also be used to optimize treatment. The ability to identify common mutations throughout a carcinoma could permit use of single agents that target the bulk of the tumor, while assaying heterogeneous actionable mutations could lead to implementing combinatorial approaches that target sub-clonal populations of cells [86]. For cancer treatment, the most promising clinical use of SCS is the analysis of CTCs, which may provide a non-invasive method for clinicians to monitor response to therapy before tumors become symptomatic or detectable through traditional approaches. Serial analysis of individual CTCs isolated from blood samples taken over the course of treatment may be used to identify new mutations that emerge in response to therapy which influence disease progression or therapeutic resistance [88], enabling oncologists to alter treatment accordingly. Targeted elimination of circulating tumor cells with stem-cell-like expression profiles could prevent the colonization of secondary sites and formation of metastases.
Despite the potential utility of SCS in clinical cancer care, several current limitations need to be addressed before SCS can be used routinely in clinical practice. In the clinical environment, cancerous tissues excised from the body have traditionally been prepared for pathological examination by fixing the tissue in formalin and embedding in paraffin. However, most single-cell isolation and sequencing methods have been designed for use with suspensions of live cells acquired from fresh tissues [86]. Although the nuclear membrane is resistant to freezing and thawing, allowing individual nuclei to be isolated from nuclear suspensions derived from frozen tissues for DNA sequencing [89], fresh tissue is currently needed for single-cell RNA-seq. To implement SCS in the clinic, new tissue collection and handling protocols will have to be established and validated at medical centers and treatment facilities. Single-cell WGA and WTA techniques currently being used in the research setting have technological limitations, and an important challenge to implementing SCS in the clinic is overcoming errors that may be introduced by amplifying the minute amount of DNA or RNA in a single cell and properly validating the sequencing results. Improved technologies as well as new computational methods will be needed before SCS can reliably distinguish technical errors from true biological variability and generate valid results for informing patient care [7, 90].
Currently, the cost of SCS prohibits large-scale implementation in the clinical setting, particularly because added costs for computational analysis will be incurred and assessment of numerous individual cells is often necessary. Hundreds of single cells may need to be sequenced, depending on a variety of factors, including the state of disease progression, tumor heterogeneity, and rarity of clinically important clones. Few insurance companies provide coverage for SCS, particularly for cancer patients, and until the clinical validity and clinical utility of SCS are unequivocally demonstrated, patients will have to pay out of pocket for these services. Large studies assessing clinical validity and robust decision models regarding patient outcomes are needed to influence payer coverage decisions regarding SCS [91].
A major obstacle complicating the introduction of SCS into the clinical environment is the lack of onsite oncologists or physicians who sufficiently understand the sequencing results and are able to translate those results into clinical action. Questions being asked by clinicians include: (1) how to interpret and apply SCS results to individual patients, (2) how to translate DNA or RNA variation within single cells into definable clinical phenotypes, and (3) how to use SCS results to predict patient response to treatment [92]. Despite the growing availability of clinically-useful DNA- and RNA-based tests, ethical issues of sharing with the patient secondary (incidental) findings—genetic alterations associated with conditions or diseases unrelated to the patient’s present condition—remain unresolved [93]. In addition, although the cost of SCS continues to decrease, the time required for completing the isolation of single cells, DNA amplification, NGS, and data interpretation remains a significant obstacle. One recent study examining the integration of WGS analysis into cancer care found that results were clinically actionable in ~55 days, considerably longer than the 10- to 14-day time frame that most patients and physicians would find acceptable for diseases such as cancer where rapid treatment decisions are highly desirable [94].
The Individualized Molecular Pancreatic cancer Therapy (IMPaCT) trial, designed to improve outcomes using genomic information to guide treatment decisions for patients with advanced pancreatic cancer, found that a complex infrastructure and multidisciplinary team consisting of a genetic pathologist, oncologist, genetic counselor, research coordinator, and project manager were necessary to collect and process biospecimens, conduct genomic analyses, and return results in a clinically relevant timeframe [95]. The median time from consent to return of validated results was 21.5 days (range 7–82 days). The trial concluded that current barriers to implementing NGS technology in the clinic are surmountable with the appropriate personnel and sufficient resources.
Conclusions
Over the next several years, advancements in the isolation of single viable cells, as well as WGA, NGS, and computation methods will be needed to improve the clinical utility of SCS [4]. The ability to amplify and sequence RNA molecules other than polyadenylated mRNAs, such as long non-coding RNAs and micro RNAs, will provide valuable information on gene regulation. New methods to simultaneously amplify and sequence genomic DNA and full-length mRNA from the same cell may provide powerful tools for assessing the effects of genomic variation on gene expression profiles [96, 97]. Likewise, the ability to couple genome-wide methylation [98] and/or proteomic [99] analysis with single-cell DNA- and RNA-sequencing from individual cells may reveal mechanisms by which genetic and epigenetic modifications regulate transcriptional heterogeneity in cancer. Fluidic systems to simultaneously isolate and analyze millions of cells in parallel may provide a comprehensive view of cancer development and response to therapy within each patient. Finally, localizing the spatial organization of gene and protein expression within a single cell may be key to determining the behavior and survival of individual cancer cells during therapy [100].
SCS is providing new insight into the biological and molecular complexity of cancer, yet despite major recent advancements, the extent of genomic and transcriptomic heterogeneity at the individual cell level in human cancer remains largely uncharacterized. Heterogeneity in cancer patients is known to be dynamic and to evolve unpredictably during disease progression, which creates a significant challenge for modern cancer treatments. SCS has the potential to create a paradigm shift in cancer care to precision (personalized) treatment where heterogeneity is thoroughly characterized prior to and during treatment. Cancer immunotherapy, in particular, may benefit from single-cell methods that define the role of innate heterogeneity in the development of immune resistance and monitor the response of individual cancer cells to immune-regulatory agents. Integrated SCS approaches may provide important new insights into cancer evolution and unveil new avenues for dissecting the complex activation of signaling pathways that cause heterogeneous cellular responses during treatment.
Abbreviations
ALK :
anaplastic lymphoma kinase
ALL:
acute lymphoblastic leukemia
APC:
adenomatous polyposis coli
AR :
androgen receptor
ccRCC:
clear cell renal cell carcinoma
CD45−:
leukocyte common antigen 45−
CDC27 :
cell division cycle 27
cDNA:
complimentary DNA
CEL-seq:
cell expression by linear amplification and sequencing
CNV:
copy number variant
CTC:
circulating tumor cell
DOP-PCR:
degenerate oligonucleotide-primed polymerase chain reaction
DTC:
disseminated tumor cell
EGFR :
epidermal growth factor receptor
EMT:
epithelial-to-mesenchymal transition
EpCAM+:
epithelial cell adhesion molecule
ER:
estrogen receptor
ET:
essential thrombocythemia
HER2 :
human epidermal growth factor receptor 2
JAK2 :
Janus kinase 2
JAK-STAT:
Janus kinase/signal transducers and activators of transcription
KRAS :
Kirsten rat sarcoma viral oncogene homolog
LCM:
laser capture microdissection
MALBAC:
multiple annealing and looping based amplification cycles
MAPK :
mitogen-activated protein kinase
MDA:
multiple-displacement amplification
mRNA:
messenger RNA
NGS:
next-generation sequencing
PABPC1 :
polyadenylate-binding protein, cytoplasmic, 1
PDGFRA :
platelet-derived growth factor receptor, alpha
PDX:
patient-derived xenograft
PI3K :
phosphoinositide 3-kinase
PIK3CA :
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
RNA-seq:
RNA sequencing
SCS:
single-cell sequencing
SMART-seq:
switching mechanism at the 5′-end of the RNA transcript
SNV:
single nucleotide variant
STRT:
single-cell tagged reverse transcription
TP53 :
tumor protein p53
UMI:
unique molecular identifier
VEGF :
vascular endothelial growth factor
WES:
whole-exome sequencing
WGA:
whole-genome amplification
WGS:
whole-genome sequencing
WTA:
whole-transcriptome amplification
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Authors’ contributions
REE, HLB, and DLE contributed equally to the writing of this paper. All authors read and approved the final manuscript.
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This research was supported by a grant from the Office of Congressionally Directed Medical Research Programs (Department of Defense Breast Cancer Research Program, W81XWH-11-2-0135). The authors confirm that the funding agency had no influence over the study design, content of the article, or selection of this journal.
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Ellsworth, D.L., Blackburn, H.L., Shriver, C.D. et al. Single-cell sequencing and tumorigenesis: improved understanding of tumor evolution and metastasis. Clin Trans Med 6, 15 (2017). https://doi.org/10.1186/s40169-017-0145-6
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Keywords
• Single-cell sequencing
• Whole-genome amplification
• Cancer
• Tumor heterogeneity
• Cancer stem cells
• Circulating tumor cells | {
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280,359,064,358,027,460 | Shoulder Injuries
shoulderFor additional questions click here.
What is the shoulder joint?
The shoulder joint is made of three bones which come together at one place. The arm bone (humerus), the shoulder blade (scapula), and the collarbone (clavicle) all meet up at the top of the shoulder. The joint between the humerus and scapula, the glenohumeral joint, is a ball-and-socket joint--the ball is on the top of the humerus, and this fits into a socket of the shoulder blade called the glenoid. This joint allows us to move our shoulder though an amazing arc of motion--no joint in the body allows more motion than the glenohumeral joint. Unfortunately, by allowing this wide range of motion, the shoulder is not as stable as other joints. Because of this, shoulder dislocations are not uncommon injuries.
The rotator cuff muscles control rotation of the shoulder. They consist of the infraspinatus, teres minor and supraspinatus which rotate the shoulder outwards and the subscapularis which is one of the muscles which rotate the shoulder inwards.
These muscles are put under a great deal of strain especially in throwing events and racket sports where your arm is above your head a lot. A sudden sharp pain in the shoulder would indicate a possible rupture of a tendon, while a gradual onset is more likely to be inflammation.
What is a SLAP lesion?
A SLAP Lesion, or Superior Labral tear from Anterior to Posterior is a specific injury / tear to the labrum of the shoulder joint.The shoulder joint is a ball and socket joint with a cuff of cartilage called a labrum that holds the humeral head. The SLAP lesion occurs at the point where the tendon of the biceps muscle inserts on the labrum. The mechanism of this injury is usually a fall onto an outstretched arm.
What are the symptoms of a SLAP lesion?
Typical symptoms of a SLAP lesion include a catching sensation and pain with movement, most typically overhead activities such as throwing.
How is a SLAP lesion diagnosed?
Diagnosis can be quite difficult, as these injuries do not show up well on MRI scans. Usually, the diagnosis is made at the time of surgery. A typical course of action when there is suspicion for a SLAP lesion is to try physical therapy, rest, and anti-inflammatory medication.If these treatments do not help the problem, shoulder arthroscopy can be performed, and the injury can be definitively diagnosed and treated.
Surgery for SLAP lesions:
SLAP lesions are usually repaired by keyhole surgery (arthroscopically) through 2 or 3 small incisions. Some SLAP lesions can be simply debrided and cleaned, while most need repairing depending on the severity of the lesion.
What is a Bankart lesion?
When the labrum of the shoulder joint is torn, the stability of the shoulder joint is compromised.A Bankart lesion is due to dislocation of the shoulder, causing a tear in the labrum. A procedure called a Bankart repair can be performed to fix this ligament. A Bankart repair can a be done either through an incision or an arthroscopically.
What is a Shoulder Dislocation?
A shoulder dislocation occurs when there is an injury to the joint between the humerus and scapula, generally after an injury such as a fall or a sports-related injury. About 95% of the time, when the shoulder dislocates, the top of the humerus is sitting in front of the shoulder blade--an anterior dislocation. In less than 5% of cases, the top of the humerus is behind the shoulder blade--a posterior dislocation. Posterior dislocations are unusual, and seen after injuries such as electrocution or after a seizure.
What is the treatment of shoulder instability?
Treatment of shoulder instability depends on several factors, and almost always begins with physical therapy and rehab. Physical therapy with specific strengthening exercises will help maintain the shoulder in proper position, and will most likely help athletes with multi-directional shoulder instability.
What is a Rotator Cuff injury?
Signs and symptoms
• Recurrent, constant pain, particularly with overhead activities.
• Pain at night that prevents you from sleeping on the affected side.
• Muscle weakness, especially when attempting to lift the arm.
• Catching and grating or cracking sounds when the arm is moved.
• Limited motion.
• Usually occurs in the dominant arm (right shoulder for right-handed people; left shoulder for
left-handed people).
• May be triggered by a specific incident.
Risk factors
• Repetitive overhead motion, such as pitching or painting a ceiling.
• Heavy lifting.
• Excessive force, such as a fall.
• Degeneration due to aging, including a reduction in the blood supply to the tendon.
• Narrowing of the space (acromioclavicular arch) between the collarbone (clavicle) and the
top portion (acromion) of the shoulder bone (scapula).
• Abrasion (rubbing) of the cuff surface by the top portion of the shoulder bone.
Diagnosing a tear
Rotator cuff tears may be partial- or full-thickness. Partial-thickness tears do not completely sever the tendon and may respond well to nonoperative treatments. Full-thickness tears require surgery to correct. Surgery may also be used to treat partial-thickness tears that do not respond to nonoperative treatment.
Treatment options
In most cases, the initial treatment is nonsurgical and involves several modalities.
• Rest. If the tear is due in part to overuse, resting the shoulder may help.
• Nonsteroidal anti-inflammatory medications will help control pain.
• Strengthening and stretching exercises, as part of a physical therapy program.
• Corticosteroid injections can help reduce pain but cannot be repeated frequently because
they can also weaken the tendon.
There are several surgical options to treat rotator cuff tears, depending on the size, depth, and location of the tear. If other problems with the shoulder are discovered during the surgery, they will be corrected as well.
• Arthroscopy, in which miniature instruments are inserted into small incisions, can be used to
remove bone spurs or inflammatory portions of muscle and to repair lesser tears.
• A mini-open repair that combines arthroscopy and a small incision can be used to treat full-
thickness tears.
• In more severe cases, open surgery is required to repair the injured tendon. Sometimes a
tissue transfer or a tendon graft is used. Joint replacement is also an option.
For additional questions click here. | {
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29,012,299,736,465,576 | PT - JOURNAL ARTICLE AU - Schmidt, Fabian AU - Keele, Brandon F. AU - Del Prete, Gregory Q. AU - Voronin, Dennis AU - Fennessey, Christine M. AU - Soll, Steven AU - Kane, Melissa AU - Raymond, Alice AU - Gifford, Robert J. AU - KewalRamani, Vineet AU - Lifson, Jeffrey D. AU - Bieniasz, Paul D. AU - Hatziioannou, Theodora TI - Derivation of simian tropic HIV-1 infectious clone reveals virus adaptation to a new host AID - 10.1073/pnas.1818059116 DP - 2019 May 21 TA - Proceedings of the National Academy of Sciences PG - 10504--10509 VI - 116 IP - 21 4099 - http://www.pnas.org/content/116/21/10504.short 4100 - http://www.pnas.org/content/116/21/10504.full SO - Proc Natl Acad Sci USA2019 May 21; 116 AB - HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species. We derived an HIV-1–based molecular clone that can cause AIDS in monkeys after transient CD8+ cell depletion during acute infection, and have used this clone to identify the role of species-specific adaptations. In addition to illuminating how viruses colonize new host species, the availability of a cloned, pathogenic simian tropic HIV-1 strain could provide a more relevant animal model for the development and testing of drug and vaccine interventions against HIV-1.To replicate in a new host, lentiviruses must adapt to exploit required host factors and evade species-specific antiviral proteins. Understanding how host protein variation drives lentivirus adaptation allowed us to expand the host range of HIV-1 to pigtail macaques. We have previously derived a viral swarm (in the blood of infected animals) that can cause AIDS in this new host. To further exploit this reagent, we generated infectious molecular clones (IMCs) from the viral swarm. We identified clones with high replicative capacity in pigtail peripheral blood mononuclear cells (PBMC) in vitro and used in vivo replication to select an individual IMC, named stHIV-A19 (for simian tropic HIV-1 clone A19), which recapitulated the phenotype obtained with the viral swarm. Adaptation of HIV-1 in macaques led to the acquisition of amino acid changes in viral proteins, such as capsid (CA), that are rarely seen in HIV-1–infected humans. Using stHIV-A19, we show that these CA changes confer a partial resistance to the host cell inhibitor Mx2 from pigtail macaques, but that complete resistance is associated with a fitness defect. Adaptation of HIV-1 to a new host will lead to a more accurate animal model and a better understanding of virus–host interactions. | {
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478,517,578,835,736,900 | Nefrología Vol. 37 Issue 3 Year 2017
Nefrologia (Madr.) 2017;37:350-1 | doi: 10.1016/j.nefro.2016.11.009
Serratia marcescens, Morganella morganii, Klebsiella oxytoca related peritonitis attacks in a patient on automated peritoneal dialysis: A case report
Serratia marcescens, Morganella morganii, Klebsiella oxytoca relacionados con ataques de peritonitis en un paciente en diálisis peritoneal automatizada: Un caso
a Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
b Department of Infectious Diseases and Clinical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
Bacterial peritonitis is a common complication of peritoneal dialysis.1 We report here a case presented with peritonitis attacks caused by rarely reported unusual pathogens, probably related with poor home environment and hygienic conditions.
A 57-year-old female patient had a history of end-stage renal disease secondary to hypertensive nephrosclerosis and undergone dialysis for 4 years. She was sharing a small house in poor hygienic conditions with eleven other family members with low socioeconomic status. Five months after the initiation of automated peritoneal dialysis (APD), the patient presented with abdominal pain and nausea to our PD clinic. She was febrile (38°C), had involuntary abdominal guarding and rebound tenderness on physical examination. Dialysate white blood cell count was 1100/mm3 (79% neutrophils). Empiric antibiotherapy was initiated with intraperitoneal cefazolin (1g/day) and oral ciprofloxacin (250mg every 12h).
A pure growth of Serratia marcescens was obtained in both different culture media. The organism was resistant to cefazolin, ceftriaxone, piperacillin/tazobactam, but sensitive to cefepime. Cefazolin was stopped; cefepime could not be used due to a drug shortage; instead, intraperitoneal gentamicin (0.6mg/kg/day). Oral ciprofloxacin was also continued based upon the susceptibility results. Following the treatment modification, high-sensitivity CRP level decreased from 240mg/L to 9mg/L. Peritoneal effluent became clear and drainage fluid leukocyte count was 100/mm3 (10% neutrophils) on the third week of admission.
The patient was readmitted to the hospital with similar complaints 7 months after the first peritonitis attack. Peritoneal fluid leukocyte count was found to be 17000/mm3 and empiric antibiotherapy was initiated with intraperitoneal cefazolin (1g/day) and gentamicin (0.6mg/kg/day). Dialysate cultures showed the growth of Morganella morganii, resistant to cefazolin, cefuroxime but sensitive to cefepime, gentamicin. Cefazolin was stopped and gentamicin was continued for 21 days. The clinical findings and laboratory results were improved during the follow-up.
The patient also had two more peritonitis attacks after this episode, both caused by Klebsiella oxytoca 4 and 8 months later, respectively. These attacks were treated successfully with cefazolin and gentamicin, as isolated pathogen was susceptible to both.
Enterobacteriaceae accounts for over 10% of cases of peritoneal dialysis associated peritonitis. Among all the gram-negative infections, S. marcescens peritonitis has the worst outcome. Serratia is an opportunistic pathogen causing nosocomial infections and is one of gram-negative organisms which have inducible beta-lactamase genes known as AmpC and summarized by the acronym SPICE (Serratia, Providencia/Pseudomonas, indole-positive Proteus species, Citrobacter, Enterobacter). Peritonitis by S. marcescens is not common and there are only few case reports in the literature, usually in diabetic patients.1
Isolated organism during the first peritonitis attack of our patient had multiple drug resistance. In this case, adequate clinical response was only achieved with combination of gentamicin and ciprofloxacin, as reported in a previous report.2
M. morganii is a Gram-negative bacteria, also a rare cause of peritonitis. It has been reported as an opportunistic pathogen and associated mainly with urinary tract infections, bacteremia and sepsis. M. morganii is naturally sensitive to aminoglycosides as in our case. However, the widespread use led to increasing resistance to third-generation cephalosporins.3K. oxytoca peritonitis has been reported in a patient with cardiac ascites and another patient on continuous ambulatory PD (CAPD).4 Both M. morganii and K. oxytoca tend to cause peritonitis in a polymicrobial fashion.5 However in our case, they were both isolated as a single pathogen.
In summary, we present a rare case of peritonitis attacks caused by S. marcescens, M. morganii and K. oxytoca. Antibiotic options should be chosen carefully for peritonitis with these pathogens due to their ability to produce beta lactamase, which often complicates the therapy. We think that low socioeconomic status, poor home environment and hygienic conditions increase the peritonitis rates. Although modification of these factors may not be possible, we believe that more frequent and careful education of the patient and the family members under such conditions can improve patient care.
Bibliography
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H. Nakamoto,Y. Hashikita,A. Itabashi,T. Kobayashi,T. Suzuki
Changes in the organisms of resistant peritonitis in patients on continuous ambulatory peritoneal dialysis
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Peritoneal fluid neutrophil counts and cultures after intraperitoneal infusion of urokinase for relapsing Serratia peritonitis
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M.T. Tsai,J.T. Yeh,W.C. Yang,T.H. Wu
CAPD-related peritonitis caused by Morganella morganii
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J. Pascual,A. Sureda,F. Garcia-Hóz,J.C. Erdozain,F. Perez-Hernandez,D. Boixeda
Spontaneous peritonitis due to Klebsiella oxytoca in a patient with cardiac ascites
.Am J Gastroenterol, 83 (1988), pp. 1313-1314
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M. Windpessl,W. Prammer,R. Asböck,M. Wallner
More on peritonitis by Morganella morganii
.Perit Dial Int, 33 (2013), pp. 467-468 http://dx.doi.org/10.3747/pdi.2013.00104
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Chung, Lee, Choi, Ha, Suh, Choi, Baek, Na, Korean Society of Thyroid Radiology (KSThR), and Korean Society of Radiology: Clinical applications of Doppler ultrasonography for thyroid disease: consensus statement by the Korean Society of Thyroid Radiology
Abstract
Doppler ultrasonography (US) is widely used for the differential diagnosis of thyroid nodules, metastatic cervical lymph nodes in patients with thyroid cancer, and diffuse parenchymal disease, as well as for guidance in various US-guided procedures, including biopsy and ablation. However, controversies remain regarding the appropriate use and interpretation of Doppler US. Therefore, the Korean Society of Thyroid Radiology organized a taskforce to develop a consensus statement on the clinical use of Doppler US for thyroid disease. The review and recommendations in this article are based on a comprehensive analysis of the current literature and the consensus of experts.
Introduction
Doppler ultrasound (US) is an imaging technique that exploits the shift in the frequency of US waves when they are reflected by moving blood (the Doppler effect) [1]. Doppler US can provide information on perithyroidal vessels and the vascularity of thyroid lesions and is widely used in daily practice for the evaluation of thyroid disease alongside gray-scale US. There are several types of Doppler US techniques, including spectral Doppler US (SDUS), color Doppler US (CDUS), power Doppler US (PDUS), and superb microvascular imaging (SMI). Many studies have used these techniques and reported different results regarding focal thyroid nodules and diffuse parenchymal disease [2-11]. Doppler US is also widely used for US-guided procedures, such as biopsy and ablation of thyroid nodules [3-7,12,13]. With the increasing use of these procedures, there is a need for a consensus statement on the clinical applications of Doppler US for thyroid disease.
In March 2019, the Korean Society of Thyroid Radiology organized a taskforce to develop a consensus statement on the clinical applications of Doppler US for thyroid disease. The recommendations include the basic principles and techniques of Doppler US and their clinical applications for thyroid nodules, metastatic cervical lymph nodes in patients with thyroid cancer, diffuse parenchymal disease, and US-guided procedures. A PubMed/MEDLINE search using the keywords "thyroid," "Doppler," "vascular," and "ultrasound" was performed to retrieve publications from January 2000 to April 2019. The draft consensus statement for the clinical application of Doppler US for thyroid disease was posted on the official website (https://www.thyroidimaging.kr/) and was reviewed by members of the Korean Society of Thyroid Radiology. The goal of these recommendations is to summarize the best scientific evidence available and to provide a consensus expert opinion on the use of Doppler US for thyroid disease.
Basic Principles and Techniques of Doppler US
Doppler US is based on the Doppler effect and utilizes the change in the frequency of a sound wave resulting from motion. In Doppler US, the Doppler effect allows one to detect the movement of red blood cells in the blood vessels. Thus, Doppler US provides information on blood flow, which is related to the vascularization of anatomical structures. Several Doppler US techniques have been used to evaluate thyroid gland lesions, including SDUS, CDUS, PDUS, and SMI.
SDUS displays a spectrum of flow velocities represented graphically on the Y-axis against time on the X-axis. Thus, the spectral mode allows us to measure different blood flow parameters. CDUS involves a combination of the Doppler effect and real-time US imaging. In CDUS, the information from the Doppler technique is integrated with the B-mode (i.e., gray-scale) image to form a color signal with the colors indicating the direction of flow; red usually indicates flow toward the transducer and blue indicates flow away from the transducer. PDUS displays the power of the Doppler shift in small volumes within the field of view, while CDUS displays the mean Doppler shift. Therefore, PDUS potentially offers increased sensitivity for detecting low-velocity flow in small vessels [14]. SMI deals with the issue that Doppler signals are derived not only from the blood flow, but also from tissue motion (clutter); as a result, the clutter signals overlap the low-speed flow components. Conventional Doppler techniques apply a single-dimensional wall filter to remove clutter, resulting in loss of the slow component. In contrast, SMI uses a multidimensional filter to separate flow signals from clutter, thus removing only the clutter while preserving the slow-flow signals [12]. Additionally, contrast-enhanced US (CEUS) refers to the application of US contrast agents in medical US. CEUS can provide anatomic information with gray-scale US and physiologic information through the SDUS, CDUS, and PDUS techniques, making it indispensable in the assessment of vascular pathology [15-21]. The presence of a microbubble US contrast agent in the vasculature enhances the backscattering of US waves, resulting in a marked amplification of flow signals and providing information on the microvasculature [12,21,22].
Clinical Applications of Doppler US
Diagnosis of Focal Thyroid Nodules
Differential diagnosis of benign and malignant thyroid nodules
Color Doppler US
The vascularity patterns of thyroid nodules on CDUS can be categorized into four types: type 1, absence of nodule vascularity; type 2, perinodular vascularity only (presence of circumferential vascularity at the margin of a nodule); type 3, mild intranodular vascularity with or without perinodular vascularity (vascularity <50%); and type 4, marked intranodular vascularity with or without perinodular vascularity (vascularity >50%) (Fig. 1) [8].
CDUS can be clinically applied for the differential diagnosis of benign and malignant thyroid nodules, as it has high sensitivity and specificity [23-28]. Papini et al. [24] prospectively evaluated the predictive value of CDUS in 494 patients and reported that intranodular vascular spots (odds ratio, 14.23) were an independent risk factor of malignancy. In another prospective study including 90 patients, Ebeed et al. [29] reported similar results, observing CDUS patterns of obvious intranodular blood flow with absent or slight perinodular blood flow (type 3) in malignant thyroid nodules, with sensitivity, specificity, and accuracy for malignancy of 79.2%, 95.6%, and 88.7%, respectively. In two retrospective studies, extensive internal flow was associated with malignant thyroid nodules [25,30]; one study reported that the sensitivity, specificity, and accuracy of CDUS for the detection of malignant thyroid nodules were 93.6%, 86.7%, and 90.7%, respectively [25]. However, in a prospective study by Hong et al. [27] that included 243 patients, marked intranodular vascularity, defined as greater flow in the central part of the nodule than in the periphery, had a disappointingly low diagnostic performance (sensitivity of 31% and specificity of 81%). They also demonstrated that marked intranodular vascularity was more commonly observed in large thyroid nodules than in small malignant or benign thyroid nodules (P=0.01 for malignant nodules and P=0.001 for benign nodules) [27]. In a recently published meta-analysis of 20 studies, CDUS showed a pooled sensitivity of 74% (95% confidence interval [CI], 62%-83%) and a pooled specificity of 70% (95% CI, 56%-81%) for the diagnosis of malignant nodules and an area under the curve (AUC) of 0.78 (95% CI, 0.74-0.81) on summary receiver operating characteristic (ROC) curve analysis [23]. In summary, CDUS shows acceptable diagnostic performance and may be useful for predicting malignant thyroid nodules. Marked intranodular vascularity on CDUS is a significant predictor of malignancy in thyroid nodules [23-30].
Power Doppler US
PDUS performed with a high-frequency transducer allows identification of low-velocity blood flow in superficial organs, such as the thyroid gland [31-34]. PDUS may be more sensitive than CDUS in detecting the slow flow of small vessels (Fig. 2) [31,34]. Several previous studies have suggested that PDUS is highly sensitive and specific in differentiating between benign and malignant thyroid nodules [31-33]. Chammas et al. [31] evaluated the predictive value of PDUS in 177 thyroid nodules from 174 patients and reported that nodules with central or mainly central vascularization patterns (type 4 or 5) were an independent risk factor for malignancy (odds ratio, 219). Several previous studies have demonstrated that the risk of thyroid malignancy increases as marked intranodular blood flow becomes more predominant [31-33]. However, these results are inconsistent with those of other studies that showed an absence of blood flow signal in papillary carcinomas [35-37]. A retrospective study by Moon et al. [37] including 1,083 thyroid nodules evaluated three patterns of vascularity (none, peripheral, and intranodular) on PDUS. The authors reported that intranodular vascularity was frequently seen in benign thyroid nodules, while an absence of vascularity was more frequent in malignant thyroid nodules (P<0.001) and that vascularity itself or a combination of vascularity and gray-scale US features was not as useful as suspicious gray-scale US features alone for predicting thyroid malignancy [37]. The use of the flow pattern on PDUS to predict thyroid malignancies is controversial.
Spectral Doppler US
SDUS displays a spectrum of flow velocities; therefore, it can provide information on multiple blood flow parameters. The peak systolic velocity (PSV), mean systolic velocity (MSV), and end diastolic velocity (EDV) are measured, while the resistive index (RI) and pulsatile index (PI) are calculated using the following formulas [28,38]:
RI=(PSV-EDV)/PSV
PI=(PSV-EDV)/MSV
Several studies have reported that when combined with gray-scale US, SDUS can improve the diagnosis of thyroid malignancy [28,38]. In a prospective study by Palaniappan et al. [28] evaluating the predictive value of SDUS in 214 thyroid nodules of 194 patients, the mean RI and PI of malignant thyroid nodules was 0.73 and 1.3, respectively, which were significantly higher than those of benign nodules, and the sensitivity, specificity, and accuracy of SDUS for the diagnosis of malignant thyroid nodules were 76.8%, 81.7%, and 80.6%, respectively. An additional cross-sectional study confirmed these results and reported a significant association between PI and malignancy, using a PI cutoff of ≥0.945 (P=0.007) for determining malignancy [38]. Chammas et al. [31] reported similar results-an RI>0.77 was an independent risk factor for malignancy of a nodule (odds ratio, 4.1) and a combination of PDUS and RI had a diagnostic sensitivity and specificity of 92.3% and 88%, respectively, for the detection of malignant thyroid nodules. Further, another study by Algin et al. [39] showed that the RI and PI values were higher in malignant thyroid nodules than in benign thyroid nodules (P<0.05) [39]. In summary, the RI and PI values of SDUS are significantly higher in malignant nodules than in benign nodules, and SDUS has acceptable diagnostic performance for the prediction of malignant thyroid nodules.
Contrast-enhanced US
CEUS is widely used to evaluate microvascularization and tumor angiogenesis, which are helpful for the differential diagnosis of malignancy and benignity [40,41]. CEUS was first used to evaluate focal liver lesions when B-mode and Doppler US yielded equivocal results [42]. With improvements in US equipment and the introduction of second-generation contrast agents (e.g., SonoVue [Bracco Imaging, Milan, Italy]) for the characterization of malignant thyroid nodules, the accuracy of CEUS for predicting thyroid malignancy has improved and its use has increased [43,44]. The following is the general process of CEUS for thyroid nodules. The focus zone is always placed at the bottom level of the nodule, and CEUS is performed using a low mechanical index (<0.10). The contrast agent is injected intravenously as a bolus, followed by a saline flush. The timer on the US machine is started during the CEUS process, and the images are obtained during the next 2-3 minutes [44].
The degree of enhancement of thyroid nodules on CEUS is divided into three patterns in reference to the surrounding parenchyma: hyperenhancement, isoenhancement, and hypoenhancement [44]. Hypoenhancement is a major CEUS pattern characteristic of malignant thyroid nodules [44-47]. When hypoenhancement was used as the diagnostic criterion for malignant thyroid nodules, the sensitivity, specificity, and accuracy of CEUS were 82.1%-89.8%, 80%-91.8%, and 84%-91%, respectively [45-47]. The main reason for hypoenhancement in malignant thyroid nodules is the lack of blood supply in a nodule because of necrosis and embolus formation within the tumor [44]. Another important CEUS pattern characteristic of malignant thyroid nodules is heterogeneous enhancement [44-46,48,49]. When heterogeneous enhancement was used as the diagnostic criterion for thyroid malignancy, the sensitivity, specificity, and accuracy of CEUS were 88%-90.4%, 80%-92.5%, and 85%-91%, respectively [45,46,48,49]. The blood vessels of malignant nodules are typically aberrant and tortuous, whereas those of benign nodules are usually regular [48]. Furthermore, most malignant thyroid nodules include areas of calcification, fibrosis, and/or necrosis, which are related to heterogeneous enhancement [44]. In addition to qualitative assessments of thyroid nodules, quantitative assessments are important for predicting malignancy with CEUS. CEUS with time-intensity curve analysis is helpful in diagnosing malignant thyroid nodules [44,50,51]. Chen et al. [51] evaluated the CEUS characteristics of 130 papillary thyroid microcarcinomas in 106 patients and reported that the peak enhancement intensity was lower than that of normal thyroid parenchyma and that contrast washed out faster from papillary thyroid microcarcinomas than from normal thyroid parenchyma. Furthermore, Nemec et al. [52] found that relative enhancement during the washout curve was lower in malignant thyroid nodules than in benign nodules, with an optimal cutoff value of 2.35 for predicting malignancy. Using this cutoff value, the diagnostic performance of CEUS had 76.9% sensitivity, 69.7% specificity, and 69.6% accuracy [52].
On CEUS, hypoenhancement and heterogeneous enhancement are major findings of malignant thyroid nodules [44-49]. CEUS with time-intensity curve analysis is also helpful in distinguishing benign from malignant thyroid nodules [50-52].
Superb microvascular imaging
SMI analyzes clutter motion and uses a new algorithm to identify and remove tissue motion, allowing the imaging of microvascular blood flow [53]. SMI depicts perinodular and intranodular thyroid microvascular flow in higher detail than conventional CDUS or PDUS [54,55]. Zhu et al. [55] prospectively compared SMI, gray-scale US, and CDUS in distinguishing between benignity and malignancy in 76 thyroid nodules and reported that SMI was significantly more accurate for identifying malignant thyroid nodules (79.3%) than CDUS (55.2%; P<0.001). Gray-scale US with SMI resulted in the greatest diagnostic sensitivity, specificity, and accuracy (86.2%, 85.1%, and 85.5%, respectively), and the AUC value for ROC analysis of gray-scale US with SMI (0.911 [95% CI, 0.849-0.973]) was significantly better than those of gray-scale US with CDUS or gray-scale US alone [55]. Vascularity on SMI is classified into three types: none, peripheral, and mixed and intranodular [56]. Kong et al. [56] evaluated the vascularity of 113 thyroid nodules and showed that for the diagnosis of thyroid malignancies, intranodular vascularity on SMI had a 91.2% specificity and 75.9% sensitivity, superior to the 82.3% specificity and 41.8% sensitivity of PDUS (P<0.01). The authors demonstrated that a taller-than-wide shape, microcalcifications, and intranodular vascularity on SMI were independent risk factors for thyroid malignancy [56]. An alternative classification of the vascularity on SMI used the number of vessels inside the thyroid nodule, with a score of 1 for a maximum of two blood vessels on SMI and a score of 2 for three or more vessels on SMI [54]. Zhu et al. [55] showed that a score of 2 was found in 40.4% benign nodules and 82.1% malignant nodules (sensitivity, 81.7%; specificity, 60.5%) and that an SMI score of 2 was an independent risk factor for thyroid malignancy (P<0.001). In summary, SMI is an emerging additional modality to conventional US. SMI is more accurate than CDUS or PDUS for the assessment of malignant thyroid nodules, and SMI findings of a large number of vessels and intranodular flow are associated with malignancy in thyroid nodules [54-56].
Diagnosis of follicular neoplasms
Follicular thyroid carcinoma accounts for 10%-20% of all thyroid malignancies. Most cases of follicular thyroid carcinoma require surgical biopsy or excision to determine the diagnosis [57]; however, >80% of all thyroid follicular neoplasms are benign [58]. CDUS is useful for predicting malignant thyroid follicular neoplasms [2,59]. The most hypervascular thyroid nodule types are adenoma/adenomatoid nodules, the encapsulated subtype of the follicular variant of papillary thyroid carcinoma, and follicular carcinoma [60]. A meta-analysis of CDUS for predicting malignant thyroid follicular neoplasms [2] showed an overall sensitivity of 85% and specificity of 86% and found that a predominant internal flow seen on CDUS was associated with malignant thyroid follicular neoplasms (Fig. 3). Fukunari et al. [60] used a CDUS and SDUS diagnostic grading system for the differential diagnosis of thyroid follicular lesions as follows: grade 1, benign follicular lesion (no color flow inside the nodule); grade 2, benign peripheral type (color flow only in the peripheral area, PI<1.0); grade 3, suspected follicular carcinoma (penetrating color flow, moderate vascularity); and grade 4, follicular carcinoma (high-velocity penetrating color flow, PI=1.0). On the assumption that grade 1 and 2 lesions are benign and grade 3 and 4 lesions are malignant, the sensitivity, specificity, and accuracy for predicting malignant thyroid follicular neoplasms were 88.9%, 74.2%, and 81.0%, respectively [2]. Additionally, Miyakawa et al. evaluated the vascular pattern of PDUS and the parameters of SDUS and reported that the majority (84%) of follicular adenomas showed only a peripheral rim of color flow on PDUS and that the PI and RI values on SDUS were significantly higher in patients with follicular carcinoma than in those with follicular adenoma (P<0.005 and P<0.001, respectively). Follicular carcinoma can be diagnosed with a cutoff values of PI >1.35 and RI >0.78, respectively, with AUC values of 0.898 for PI and 0.876 for RI on ROC analysis [61]. In summary, Doppler US may be a useful additional method for differentiating benign from malignant thyroid follicular neoplasms; predominant internal blood flow is seen in the latter [2,59,60]. SDUS parameters are also helpful for the diagnosis of malignant thyroid follicular neoplasm [60,61], with PI and RI being higher in malignant thyroid follicular neoplasms than in benign thyroid follicular neoplasms [60,61]. However, predominant internal blood flow can also be seen in benign thyroid nodules. Using predominant internal blood flow, the overall sensitivity for predicting thyroid malignancy was very high (96%), although the specificity was very low (14%), with positive and negative predictive values of 15% and 96%, respectively [2]. A systematic review and metaanalysis reported that CDUS had an overall sensitivity of 85% and a specificity of 86% for thyroid follicular neoplasms, with positive and negative predictive values of 51% and 97%, respectively [2].
Diagnosis of metastatic cervical lymph nodes in patients with thyroid cancer
Diagnosing metastatic lymph nodes in patients with thyroid cancer is important when planning surgery. Gray-scale US has been established as a primary imaging modality. Moreover, the combination of Doppler US and gray-scale US can increase the diagnostic accuracy. Hilar or central vascularity of the lymph node is a typical finding of a benign lymph node. In contrast, peripheral or diffuse vascularity is a US characteristic of lymph nodes with metastasis from thyroid cancer, and the absence of central hilar vascularity is a US criterion for an indeterminate lymph node [8,62]. Leboulleux et al. [63] prospectively evaluated the diagnostic accuracy of US for lymph node metastasis in 56 lymph nodes from 19 patients with differentiated thyroid cancer. They reported that the pattern of vascularity (peripheral vascularity in PDUS) had the best sensitivity and specificity (86% and 82%, respectively) among the US findings, making the use of Doppler US essential in the follow-up of differentiated thyroid cancer [63]. A previous study of CEUS showed similar results, in which heterogeneous, centripetal, and hybrid (mixture of centripetal and centrifugal) enhancement were significantly related to lymph node metastasis and CEUS showed a higher sensitivity (82% vs. 92%) and accuracy (79% vs. 72%) than conventional US [64]. In another study using SDUS, 76% of metastatic lymph nodes demonstrated peripheral vascularity and 85% of metastatic lymph nodes in patients with papillary thyroid carcinoma had maximum RI and PI values of 0.8 and 1.6, respectively [65]. Sometimes, parathyroid lesions can be mistaken for metastatic lymph nodes [66], but parathyroid adenoma shows a characteristic polar vessel sign in addition to its characteristic location [67]. In summary, central hilar vascularity is a typical finding of benign lymph nodes, but peripheral vascularity on Doppler US is an important finding with acceptable diagnostic performance for identifying metastatic lymph nodes in patients with thyroid cancer.
Summary, consensus, and limitations
Marked internal vascularity on CDUS and SMI may be a major finding of malignant thyroid nodules [23-30,54-56]. The emerging modality of SMI can reveal more vascular details than CDUS or PDUS [33-35]. However, the populations in previous studies had a wide range of prevalence of papillary thyroid carcinomas (63.3%-90.6%) [16,44-46]. The parameters of SDUS, including PI and RI, may be important in differentiating benign from malignant thyroid nodules [28,29,31,38,39]. Hypoenhancement and heterogeneous enhancement on CEUS may be major features of malignant thyroid nodules [44-49]. Peripheral vascularity on Doppler US is a major finding for diagnosing metastatic cervical lymph nodes in patients with thyroid cancer [8,62].
Although many studies have reported that Doppler US is useful for the differentiation of thyroid nodules, few studies have evaluated the added value of Doppler US over gray-scale US for the differentiation of thyroid nodules [55]. Future studies on the added value of Doppler US is necessary for risk stratification and biopsy decision-making. Additionally, there are regional disproportions in studies and many studies in the literature had low-quality designs (small numbers of patients and retrospective designs). Further studies are required on the use of Doppler US for the prediction of malignant thyroid nodules.
Diagnosis of Diffuse Parenchymal Disease of the Thyroid Gland
Although clinical and laboratory findings play a more substantial role in the diagnosis and treatment of diffuse thyroid disease (DTD), thyroid US makes an important contribution to the diagnosis of DTD [9-11]. The known gray-scale US features of DTD include increased or decreased parenchymal echogenicity, coarse echotexture, increased or decreased anteroposterior (AP) diameter of the thyroid, and the presence of marginal nodularity. Specific US findings for Graves disease (GD) and Hashimoto thyroiditis (HT) are thyroid inferno and micronodulation, respectively [68-72]. DTD can increase or decrease the vascularity of the thyroid gland, although differences in the extent of fibrosis and inflammation can also affect any measured values of vascularity [73-76].
Doppler US of the thyroid gland is helpful for the early detection of incidental asymptomatic DTD [69,77-79] and the differential diagnosis of GD with destructive thyroiditis in thyrotoxicosis [73-76,80-86]. It can also provide valuable information on the functional status of the thyroid and can be used to evaluate disease remission, recurrence, and response to treatment [68,73,81,84,87].
Differentiation of asymptomatic DTD from the normal thyroid gland
Thyroid US can be helpful in differentiating asymptomatic DTD from normal thyroid parenchyma [69,77-79]. A recent multicenter study found significant differences in US features of the thyroid gland between patients with normal thyroid parenchyma (n=139) and those with asymptomatic DTD (n=64; HT, non-HT, and diffuse hyperplasia; P<0.001); these differences included parenchymal echogenicity, parenchymal echotexture, AP diameter of the thyroid gland, glandular margin, and parenchymal vascularity. Several US features, including decreased or increased parenchymal echogenicity, coarse parenchymal echotexture, increased AP diameter (>2 cm), lobulated glandular margin, and increased parenchymal vascularity, were independent predictors of DTD (Fig. 4). The diagnostic ability of US was highest when a criterion of one or more of these abnormal US features were chosen, with a sensitivity of 85.9% and specificity of 63.3% [77]. Similarly, several investigators have demonstrated that three or more abnormal US features indicated a high likelihood of incidental DTD, with a sensitivity of 87.7% and specificity of 92.1% [69] and that one abnormal US feature showed the highest diagnostic accuracy, with a sensitivity of 80.5% and specificity of 85.7% [78].
Gray-scale US can provide the volume of the thyroid gland and indicate features of DTD. The thyroid gland volume can be obtained from maximum measures in the longitudinal (L), AP, and transverse (T) axes of both lobes and the isthmus using the ellipse correction coefficient (thyroid volume=L×AP×T×π/6) [84]. In addition, unusual focal lesions found in patients with DTD need to be evaluated according to their features on B-mode and Doppler US and an investigation by fine-needle aspiration (FNA) biopsy may be indicated because papillary thyroid carcinoma and primary thyroid lymphoma are more likely in patients with HT than in the general population [88].
Differential diagnosis of GD from destructive thyroiditis in thyrotoxicosis
Doppler US is useful for the differential diagnosis of GD from destructive thyroiditis, which causes thyrotoxicosis in its early stage. Destructive thyroiditis includes HT, subacute granulomatous thyroiditis, postpartum thyroiditis, and painless (silent) thyroiditis [73-76]. Before treatment or effective therapy, GD shows a diffuse increase in vascularization of the parenchyma, referred to as thyroid inferno, a term first used by Ralls et al. in 1988 [68]. Thyroid hypervascularization can also occur in HT, but to a lesser degree (Fig. 5) [76,85,86]. The vascularity of the thyroid parenchyma can be determined using a visual scale according to the classification created by Schulz et al. [89]: pattern 0, blood flow limited to the peripheral thyroid arteries while parenchymal flow is absent; pattern I, presence of mildly increased parenchymal flow; pattern II, clearly increased color flow with a diffuse homogenous distribution; and pattern III, markedly increased color flow with a homogenous distribution.
Quantitative measurement of thyroid arterial blood flow is a useful parameter for the differential diagnosis of thyrotoxicosis. PSV measurements of the thyroid artery have become accurate and reliable with excellent reproducibility [75,83,86]. PSV measurement of thyroid arteries is performed using a 1- to 3-mm sample volume adjustment in the vessel center. The Doppler angle should be kept at or below 60° and the correction angle should be adjusted parallel to the direction of flow [75,83,86]. There is generally no substantial difference between PSV measurements made on the superior or inferior thyroid arteries or on the inferior thyroidal arteries of either side [76,80-82,86]. The cutoff value for differentiating GD from thyroiditis is 40-50 cm/sec [76,82,83,86]. In a study by Donkol et al. [76] on the differential diagnosis of GD and HT, Doppler US demonstrated a sensitivity of 88.9%, a specificity of 87.5%, a positive predictive value of 94.1%, a negative predictive value of 77.8%, and a diagnostic accuracy of 88.5% compared the reference standard of 99mTc scintigraphy. Similarly, in a study by Hari Kumar et al. [85], Doppler US had a sensitivity of 96% and specificity of 95% for the differential diagnosis of thyrotoxicosis in reference to 99mTc scintigraphy. Other methods of estimating thyroid blood flow, such as thyroid blood flow area, vascularization index, and highresolution power Doppler, have also been used to provide better differentiation [68,84,90].
Evaluation of disease remission, recurrence, and response to treatment in DTD
In patients with GD, thyroid gland vascularization correlates with the underlying functional status, and this vascularization decreases when the disease is under control, but it can increase in cases of recurrence. Many authors have reported that a decrease in vascularity occurs in parallel with biochemical remission and disease control in GD and suggested that thyroid Doppler US has the potential to monitor the therapeutic response in patients with GD [68,73,81,84,87]. In addition, patients who responded to treatment with drugs or radioiodine presented a significant reduction in parenchymal vascularity and the PSV of the inferior thyroidal artery, while patients who did not receive treatment or had no response to treatment showed no decrease in the PSV of the inferior thyroidal artery [73,81,87].
Previous studies have shown that Doppler US is useful for evaluating disease activity in HT and subacute granulomatous thyroiditis. In the early stages of disease, HT shows diffuse hypervascularization, which can be similar to the thyroid inferno described for GD, but in a less intense form and with a lower PSV in the thyroid arteries (<40 cm/sec) [75,76,85,86]. In the latter stages of HT, thyroid vascularity can decrease because of extensive fibrosis. However, the PSV values were significantly higher in HT patients with hypothyroidism than in their euthyroid counterparts [89], and the thyroid blood flow did not correlate with the functional state of the gland in HT [73,89]. Unlike GD or HT, subacute granulomatous thyroiditis shows decreased or scant vascularity in the acute stage and slightly increased vascularity in the recovery stage [91,92].
Summary, consensus, and limitations
Doppler US is a widely used method that may have comparable diagnostic performance to thyroid scintigraphy and does not appear to have contraindications [76,85]. Doppler US may be helpful for the early detection of incidental asymptomatic DTD and useful for the differential diagnosis of thyrotoxicosis, especially in the differentiation of GD from HT. In addition, Doppler US can be used to evaluate disease remission, recurrence, and response to treatment in DTD. However, it is dependent on a skilled operator [74,77,79]. Doppler US should be performed using sensitive equipment by a trained operator with good reproducibility [74,77,79]. It is important to use the proper technique with the appropriate transducer and equipment adjustments [74-77,79,83,86]. To improve clarity, further studies and guidelines regarding the standard Doppler US technique and its clinical applications are needed.
Interventional Procedures (Biopsy and Ablation)
US-guided thyroid biopsy
In US-guided thyroid biopsy, Doppler US can provide information for vessel mapping along the approach route of the biopsy needle and can detect vascular complications. Doppler US can provide information on blood vessels in and around the nodule during US-guided biopsy (FNA or core needle biopsy). To ensure a safe biopsy and minimize vessel injury, it is necessary to use Doppler US to completely map the vessels along the approach route (from the skin to the nodule). CDUS and SDUS provide information that allows for the differentiation of arteries and veins. After complete vessel mapping, the operator decides on the safe approach route and biopsy method to avoid the biopsy needle puncturing perithyroidal vessels during the US-guided biopsy procedure [3-7,13,93] (Fig. 6). Doppler US also helps to detect vascular complications, including pseudoaneurysms, which may result from needle-induced mechanical injury to the superior or inferior thyroid artery.
US-guided thyroid ablation
In the US-guided ablation of thyroid nodules, Doppler US can be used for the following purposes: (1) pre-procedural evaluation of nodule vascularity, (2) vessel mapping along the approach route of the procedure device, and (3) post-procedural surveillance.
In a pre-procedural US examination with Doppler US, the size, proportion of solid components, vascularity, and internal contents of each nodule should be carefully evaluated according to the guidelines for radiofrequency ablation (RFA) and the consensus statement for ethanol ablation (EA) [3,4,7]. Doppler US provides information on the internal vascularity, feeding artery, and draining vein of each nodule (Fig. 7). Using this information, the RFA operator can decide on the appropriate treatment strategy, including the ablation method, number of treatment sessions, type of electrode, and technique (including artery-first ablation and marginal venous ablation) [4,7,94].
Doppler US can also provide information for vessel mapping along the approach route to avoid vessel damage [4,7,94]. Hematomas, caused by mechanical injury to vessels from procedural devices including the electrode or needle, can develop in perithyroidal, subcapsular, and intranodular locations. To prevent hematomas, perithyroidal vessels, including the superior and inferior thyroid arteries, should be carefully evaluated using Doppler US before inserting procedural devices [4,7,94].
After EA and RFA procedures, Doppler US plays an important role in surveillance in addition to clinical symptoms. Doppler US is primarily used to detect any under-ablated portions of a lesion (Fig. 8). If a viable nodule portion with vascularity is detected on gray-scale US and CDUS in addition to persistent symptomatic and cosmetic problems, additional ablation is indicated [3,4,7,95,96]. This is because the under-ablated portion with vascularity has considerable potential for regrowth on follow-up [97]. However, CDUS does not have sufficient sensitivity to detect small vessels and slow blood flow [98]. To overcome these disadvantages of CDUS, some authors have suggested that CEUS can be used as an ancillary diagnostic tool for detecting under-ablated portions after an RFA procedure [99-101]. Doppler US is also a primary imaging modality during follow-up after other ablation procedures, including laser ablation [102-104], microwave ablation [105-107], and high-intensity focused US ablation [108,109]. Most studies have used a color Doppler technique [102,104-107,109], while some have used PDUS [108], SMI [103], or CEUS [103]. Some researchers have suggested that the ablation zone is clearer with CEUS than with CDUS [110,111]. Furthermore, a recent study has suggested that the accuracy of SMI for the detection of undertreated areas after laser ablation of thyroid nodules is similar to that of CEUS [103].
Summary, consensus, and limitations
In US-guided biopsy, Doppler US can provide information for vessel mapping along the approach route of the biopsy needle and can detect complications including vessel injury. For US-guided ablation, Doppler US can provide information for pre-procedural evaluation of nodule vascularity, vessel mapping along the approach route of the procedure device, and post-procedural surveillance.
Harms and Benefits
Doppler US is widely used to assist in the diagnosis of thyroid nodules, metastatic cervical lymph nodes in patients with thyroid cancer, and thyroiditis, as well as for the monitoring of thyroid interventions. Moreover, there is no risk of exposure to ionizing radiation. All Doppler US techniques are non-invasive, except CEUS. Therefore, the potential of CEUS-induced harm should be considered when CEUS is used.
Acceptability and Applicability
An evaluation of the domestic acceptability and applicability leads us to conclude that Doppler US is useful and reasonable for the diagnosis and monitoring of thyroid interventions. In South Korea, the Korean National Insurance Service covers the cost of US, with no additional fee for CDUS, PDUS, SDUS, or SMI. However, CEUS is less acceptable because it is an invasive technique and the cost is not covered by national insurance. In future, the optimum US method for each task should be validated.
Conclusions and Future Perspectives
The Korean Society of Thyroid Radiology presents this first consensus statement on thyroid Doppler US to improve the diagnostic performance of thyroid nodules and ensure the safety and efficacy of thyroid interventions in daily practice. Considering the increasing use of thyroid interventions in the management of thyroid lesions, operators should have a good knowledge of thyroid Doppler US. However, the high-level evidence for thyroid Doppler US is insufficient, and future studies with high evidence levels are necessary to establish future thyroid Doppler US guidelines.
Notes
Author Contributions
Conceptualization: Choi YJ, Ha EJ, Baek JH, Na DG. Data acquisition: Chung J, Lee YJ, Choi YJ, Suh CH, Choi M. Data analysis or interpretation: Chung J, Lee YJ, Choi YJ, Suh CH, Choi M. Drafting of the manuscript: Chung J, Lee YJ, Choi YJ, Ha EJ, Baek JH, Na DG. Critical revision of the manuscript: Ha EJ, Baek JH, Na DG. Approval of the final version of the manuscript: all authors.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Acknowledgements
This work was supported and funded by the Korean Society of Radiology.
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Vascular patterns of thyroid nodules on color Doppler ultrasonography.
The patterns are categorized into four types: type 1, absence of thyroid nodule vascularity (A); type 2, perinodular vascularity only (presence of circumferential vascularity at the margin of a thyroid nodule) (B); type 3, mild intranodular vascularity with or without perinodular vascularity (vascularity <50%) (C); type 4, marked intranodular vascularity with or without perinodular vascularity (vascularity >50%) (D).
usg-20072f1.jpg
Fig. 1.
A 49-year-old woman with benign follicular adenoma.
A. Transverse color Doppler sonography shows increased perinodular vascularity. B. Transverse power Doppler sonography shows more increased perinodular vascularity than the color Doppler sonography.
usg-20072f2.jpg
Fig. 2.
A 53-year-old woman with minimally invasive follicular carcinoma.
A. Transverse gray-scale sonography shows an isoechoic mass in the right thyroid. B. Predominant internal flow is seen in the thyroid nodule on a transverse color Doppler sonography.
usg-20072f3.jpg
Fig. 3.
A 50-year-old woman with Hashimoto thyroiditis diagnosed as diffuse thyroid disease on sonography.
Transverse (A) and longitudinal (B) gray-scale sonography show decreased echogenicity, coarse echotexture, a normal anteroposterior diameter of the thyroid gland, and lobulated margins. Longitudinal color Doppler sonography (C) shows increased parenchymal vascularity of the thyroid.
usg-20072f4.jpg
Fig. 4.
A 31-year-old man with Graves disease diagnosed as diffuse thyroid disease on sonography.
Transverse (A) and longitudinal (B) gray-scale sonography show decreased echogenicity, coarse echotexture, an increased anteroposterior diameter of the thyroid gland, and smooth margins. A qualitative visual assessment of thyroid parenchymal vascularity on longitudinal color Doppler sonography (C, D) revealed thyroid inferno (C), while quantitative blood flow measurement revealed a peak systolic velocity (PSV) of 53.1 cm/sec in the right superior thyroid artery (D). EDV, end diastolic velocity; MDV, mean diastolic velocity.
usg-20072f5.jpg
Fig. 5.
Ultrasound (US)-guided core needle biopsy of a thyroid nodule.
A. Before the procedure, the vessels along the approach route were carefully evaluated by Doppler US. B. Using a freehand technique, a core needle was directed from the isthmus toward the nodule while avoiding the vascular structures. C. After the tip of the biopsy needle was advanced into the edge of the nodule, the stylet and cutting cannula of the needle were sequentially fired.
usg-20072f6.jpg
Fig. 6.
Feeding artery of a thyroid nodule.
Before thyroid radiofrequency ablation, the main feeding artery from the superior thyroid artery is identified on spectral Doppler ultrasonography.
usg-20072f7.jpg
Fig. 7.
An under-ablated nodule portion on Doppler ultrasonography.
On gray-scale (A) and Doppler ultrasonography (B), most of the nodule shows low echogenicity without vascularity (arrows), thereby suggesting an ablated portion, but the medial-posterior portion of the nodule appears isoechoic with vascularity (arrowheads), suggesting the presence of an under-ablated portion.
usg-20072f8.jpg
Fig. 8.
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2,636,922,808,602,046,500 | 1. Health
Send to a Friend via Email
Chemical Peel
For Younger Looking Skin
By
Updated August 17, 2004
If undergoing a facelift seems to be too drastic, but at the same time you are bothered the facial wrinkles and lines of aging, a chemical peel may be the solution you are looking for. Chemical peeling, also called chemexfoliation or dermapeeling peels away the superficial layers of skin damaged by exposure to the sun and other environmental effects.
Sun damage is responsible for most of the fine lines of aging found around the eyes and mouth. The appearance of these lines can be significantly improved by the removal of these damaged layers of skin. Chemical peels can also even out pigmentation changes in the skin and remove pre-cancerous lesions.
Types of Peels
1. Light Peels
Light peels use alpha hydroxyacids; naturally occurring acids found in fruits and some other foods. These alpha hydroxyacids are used for treating dry skin, acne, liver or sun-damage spots. A light peel can lessen the appearance of fine facial wrinkles, reduce pore size and improve the texture of older or sun-damaged skin. Light peels are generally performed in a series of six to eight treatments done about two or three weeks apart. The effects of the peel are generally mild with redness that lasts a day or two.
2. Medium Peels
These peels are generally done using trichloroacetic acid. This peel works on deeper layers of skin and is performed once every two to three years. In addition to the skin effects of light peels, a medium peel can remove deeper wrinkles and precancerous lesions. The after effects of a medium peel are more pronounced with redness (resembling a severe sunburn) that may last a week or more.
3. Deep Peels
Deep peels are not done as often as the other types of peels. The most common chemical used for deeps peels is Phenol and it can cause heart rhythm problems if absorbed through the skin. As the name suggests these peels treat much deeper layers of skin and skin damage. Besides the risk of heart problems these peels must be used cautiously as they cause permanent whitening of the skin and have a much longer recovery time; as much as one to two months in some cases. They are not recommended for dark skinned individuals.
When any type of peel is done, the treated skin will require protection from the effects of the sun. Use sunscreen whenever going outside and use clothing and hats to protect the skin. Drink adequate amounts of water to keep the skin well hydrated.
1. About.com
2. Health
3. Senior Health
4. Diseases and Conditions
5. Chemical Peel Wrinkle Removal
©2014 About.com. All rights reserved.
We comply with the HONcode standard
for trustworthy health
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-6,135,819,227,990,565,000 | PT - Journal Article AU - Mabit, Hélène AU - Dubanchet, Sylvie AU - Capel, Francis AU - Dauguet, Charlie AU - Petit, Marie-Anne DP - 1994 TI - In vitro infection of human hepatoma cells (HepG2) with hepatitis B virus (HBV): spontaneous selection of a stable HBV surface antigen-producing HepG2 cell line containing integrated HBV DNA sequences TA - Journal of General Virology, VI - 75 IP - 10 PG - 2681-2689 AID - 10.1099/0022-1317-75-10-2681 SO - Journal of General Virology 1994;75(10):2681-2689 AB - The degree of susceptibility of human hepatoma (HepG2) cells to direct hepatitis B virus (HBV) infection remains unknown. We previously observed a low level of Dane particle production and viral DNA replication after in vitro infection of HepG2 cells with serum-derived HBV. However, this culture system appeared to be affected by variations as human hepatocyte cultures. In the present study, HBV infection of HepG2 cells led to a significant increase in the secretion of three envelope antigens (HBsAg, preS2Ag and preSl Ag) at 4 days post-infection, and Northern blot analysis revealed the presence of both preSl (2·6 kb) and preS2/S (2·2 kb) transcripts. Expression of preSlAg and the corresponding viral RNA became undetectable on 21 days post-infection whereas the 2·2 kb RNA species persisted and was associated with secretion of subviral HBs particles expressing preS2-epitopes and banding between 30 and 35% sucrose. At 35 days post-infection (fifth passage), a sudden high level production of HBsAg and preSlAg was observed, followed by a massive cell death (90 %). A stable HBsAg-producing HepG2 cell line, designated HepG2-BV3, grew out of the surviving cells. HepG2- BV3 cells could integrate HBV DNA sequences and produce the three HBV surface antigens. Treatment with dexamethasone increased the HBsAg and preSlAg secretion. Such a HBsAg-producing HepG2 cell line obtained by in vitro HBV infection seems to mimick events that occur in the naturally occurring persistent chronic infection, and therefore may be an efficient in vitro model for studying the contribution of viral integration in the dysregulation of HBV and liver- specific genes expression., 4099- https://www.microbiologyresearch.org 4100- https://www.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-75-10-2681 | {
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-3,126,498,432,642,164,700 | All Title Author
Keywords Abstract
Retracted: "highly active antiretroviral therapy induced adverse drug reactions in Indian human immunodeficiency virus positive patients"
DOI: 10.4321/S1886-36552011000100008
Keywords: drug toxicity, antiretroviral therapy, highly active, india.
Full-Text Cite this paper Add to My Lib
Abstract:
[retracted]objective: to assess the incidence, severity pattern, causality, predictability and preventability of adverse drug reactions (adrs) and to identify risk factors for adverse drug reactions in highly active antiretroviral therapy. methods: enrolled patients were intensively monitored for adrs to highly active antiretroviral therapy. predictability was assessed based on history of previous exposure to the drug or literature incidence of adrs. preventability was assessed using schumock and thornton criteria and severity was assessed using modified hartwig and siegel scale. multivariate logistic regressions were used to identify the risk factors for adrs. results: monitoring of 130 retropositive patients by active pharmacovigilance identified 74 adrs from 57 patients. anemia and hepatotoxicity were the most commonly observed adrs. the organ system commonly affected by adr was red blood cell (21.4%).the adrs were moderate in 77% of cases. type a reactions (77%) were more common. a total of 10.8% adrs were definitely preventable. the incidence rate of adrs (65.9%) was highest with zidovudine + lamivudine + nevirapine combination. a total of 84% interruptions to highly active antiretroviral therapy were due to toxicity. cd4 less than 200 cells/μl, female gender and tuberculosis were observed as risk factors for adrs. conclusion: incidence of adrs in intensively monitored patients was found to be 43.8%. anemia in hiv patients is an influential risk factor for occurrence of adrs. with the increasing access to antiretroviral in india, clinicians must focus on early detection and prevention of adrs to highly active antiretroviral therapy.
Full-Text
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-1,979,826,054,310,125,800 | OCCLUSAL
Adjustment
Do you wake in the morning with sore jaws?
When you bite, do you feel like your jaw is lopsided? If so, then you may need an occlusal adjustment.
An occlusal adjustment corrects the alignment of the bite, which is a result of loose, shifting, crowded, or missing teeth. The result is an evenly distributed bite that eliminates irregular pressure on one side of the mouth. Once your bite is adjusted, your teeth will meet properly. Occlusal adjustment causes minimal pain, and only a little discomfort. The adjustment is made by using a dental drill using a fine filing stone. In addition to the actual adjustment, removal mouthpieces are also utilized, to protect the tooth surface, and relax the jaw muscles once the adjustment is completed.
Who is a good candidate for an occlusal adjustment? Patients with loose or shifting teeth will many times not meet correctly. Patients, who grind or clench their teeth, will have an uneven bite and pressure distribution in the mouth, which is also corrected through an occlusal adjustment. Sometimes tooth sensitivity can be corrected through an occlusal adjustment as the treatment reduces pressure on the sensitive tooth.
New technology allows dentists to accurately identify the areas, which need adjustments. The dentist utilizes a computer scan of the mouth, which records hundreds of bite registrations per minute, and notes even the slightest irregularity. That data allows the dentist to make only the adjustments that are absolutely necessary, which ensures a well-aligned bite and minimal tooth wear.
PAY INVOICE
PAYMENT PLAN
INSURANCE
FAQs
PATIENT INTAKE
MEET THE DOCTORS
Request An Appointment
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-7,773,544,695,978,431,000 | skip to Main Content
Healthy Eating Habits
Healthy Eating Habits
Healthy Eating Habits
We are all familiar with the saying “you are what you eat.” Well as true as it is, we not only are what we eat, but how we eat. When and how we eat affects our enjoyment of the food we eat. Healthy digestion and assimilation of our food is effected by our food choices, our attitude and environment of consumption, both external and internal. Have you ever wanted a good meal and eaten a bad one, then walked away still feeling hungry? Somehow unfulfilled, even with a stomach full of food? Can you remember what you ate for dinner last night? You may have forgotten, but perhaps you didn’t notice to begin with. Bringing more attention and thought to our meals may help us to make healthier food choices, and experience the joy of our food.
The process of digestion is an involuntary function (one which we do not consciously direct) and is governed by our autonomic (involuntary) nervous system. The autonomic nervous system governs all of the involuntary functions in our body. In order to accommodate our wide variety of needs, it has two distinctly different yet interdependent sub-systems within in called the sympathetic and the parasympathetic division.
The sympathetic division is “on alert”; it is the yang or action nervous system. This division is responsible for our ‘flight or fight’ mechanisms. It becomes our dominant system when our mind sends signals to our body to mobilize it to action, in response to a perceived threat or danger, real or imagined. In our modern society it is often called into play in response to fear, excitement or anticipation. You can tell when you are sympathetic dominant when you are breathing more shallow and from higher in your chest, your pulse quickens, you have a sensation of excitement (butterflies) or ‘tension’ deep in your stomach and throughout your muscle structure. You may also be perspiring (especially your hands) even though your surroundings are not too warm, or you may feel fidgety, generally ‘hyper’ and perhaps, at times, less comfortable inside. When you are stressed, your body says run, and your digestive system shuts down.
The parasympathetic division is a more yin or nurturing nervous system. It is responsible for quite a different set of physiological responses and is called into play when we make time for rest, and relaxation. It favors assimilation, repair and regeneration and is dominant when our breathing is slower, more rhythmic and from lower in our chest and abdomen. There is a decrease in muscle tone, the abdomen is relaxed and comfortable, with no sense of tension in it.
If we are to digest our food properly and to derive full nutritional value from it we need the nurturing, parasympathetic division. How conscious are you of your state of mind and body before, during and after your meals? This awareness is important to proper digestion and health as any other aspect of your lifestyle. The following mindfulness practices help us to use our nurturing nervous system so we can better enjoy and utilize our food.
Source: Arlington Acupuncture
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-8,133,050,288,617,816,000 | How To Eat Healthy
With the rise in obesity, cardiometabolic diseases (like diabetes or high blood pressure), and cancer all around us, it is important to understand how to eat healthfully. Luckily, we have some tips from the National Health Department and Harvard University!
The national department recommends that you should aim to meet two thirds of your daily nutrition needs through fruits and vegetables, milk, and other foods that are rich in vitamins, minerals, and protein. They also recommend reducing sugar intake and increasing fiber consumption.
Harvard’s website suggests thinking about food as an investment. The healthier choices are like buying stock in your body; the more expensive they may be at first, but over time, they will return a healthy profit for your health.
This article will go into detail about what types of foods are worth investing in and which ones can actually do harm to your health.
Eat more healthy fats
How to eat healthy
More than half of your daily calories should come from fat if you want to stay weight loss oriented. But it’s important to know what kind of fats are worth adding into your diet, and how much is needed in order to achieve that goal.
Saturated fats can be good or bad depending on whether they contain too many carbs or not. And while most people seem to associate cookies with cream-based cheeses, it’s actually the sugar content that makes something like chocolate milk or cheese pizza way better choices than regular milk or bread for eating It’s also great to limit saturated fats by drinking plain ol’ water instead of juice or soda.
Unhealthy oils such as olive oil, coconut oil, and butter are very rich in calories but few other things pertain to them.
Eat more protein
How to eat healthy
Protein is one of the most important macronutrients in our diets, next to carbohydrates. Proteins help us feel full longer than either carbs or fat, making them a good source of fuel for your body.
Protein comes from foods such as meat, fish, eggs, nuts and beans. The average person needs 8–10 grams of protein per day depending on their individual nutritional needs.
Some people are genetically predisposed to have higher levels of enzymes that aid in bone growth and repair, so they need less protein while others can survive with lower amounts.
Enzymes are like hormones, only not chemical! They play an integral part in almost every process done by your body, including building new cells and tissues.
Having enough enzyme nutrition in your diet helps promote healthy cell functioning and growth. Nutrient-rich food sources include: fruits, vegetables, whole grains, dried fruit, fermented products (such as yogurt), and poultry.
If you find it difficult to eat enough protein, try eating lean meats, low-fat dairy, and/or supplements. We recommend starting out with a half cup of chicken, milk, or cheese per meal and then adding another half cup at the next meal.
Eat more veggies
How to eat healthy
We’re going to go into some details about what kind of vegetables you should be eating, and why they are important. But first, let us talk about how much vegetable matter you need in your diet.
We recommend that everyone eats at least two cups (0.5–1 cup per person) of fruits and three cups (onecup per person) of vegetables every day.
A cup size unit for both fruits and vegetables is one half a piece or a whole fruit/vegetable depending on what type of food it is. A cupful of carrots equals around one-quarter of a pound!
Most people do not meet this recommendation. In fact, according to the National Health and Nutrition Survey, only 9% of adults aged 19 and older ate enough fruits and 2% ate enough vegetables.
By consuming enough fruits and vegetables, you will:
Lower blood glucose levels
Boost your overall health and wellness
Improve your oral health by chewing well
This article will tell you how to eat the most delicious amounts of fruits and vegetables. Then, we’ll discuss some tips based on changes needed to make these healthier.
Limit sugar
How to eat healthy
Unfortunately, most manufactured foods contain lots of added sugars that are heavily marketed as part of the product brand. These include sweeteners such as glucose or sucrose, fructose, and maltodextrins.
Sugars can be naturally occurring like with fruit or milk products, but they also occur more frequently in processed food and beverages, including some alcoholic drinks.
Many people begin to add these sugars into their diet later in life, so it can increase your risk of health problems gradually.
However, even having just a little bit of sugar every now and then is not healthy for everyone. The amount depends on your body size and activity level, and how much sugar you eat overall.
If you find that you enjoy foods high in sugar, try to reduce the amount you use instead of totally limiting yourself to only healthier recipes.
Eat more fruit
How to eat healthy
One of the most important things you can do to eat healthier is to increase your intake of fruits. All parts of the fruit are good for you, so don’t hesitate to indulge!
Some people may be skeptical at first when I tell them that they should eat more fruits because they believe that berries are already a part of their diet. But we need to remember that not everyone enjoys berries or eats them every day.
So what kind of fruits should you eat? Almost any type of fruit will help improve your health, but some types of fruits have special benefits.
You should definitely try to include several colors of fruits in your diet as they all contain various nutrients such as vitamin A, C, potassium, magnesium and iron.
Not only that, but eating fruits can also contribute to weight loss since they’re a low calorie food. Plus, many people enjoy fruits as a dessert option so instead of buying a dessert pizza or meal, you could just get a snack of an apple or pear.
Become a workout lover
How to eat healthy
Now that you have your lunch box organized, time to make some changes to how you eat! If you want to be healthier next week, start by making the change today.
Work out for at least 30 minutes every day – this can be done anywhere and any way you like. You do not need to spend hours in the gym to achieve your goal.
For example, if you are trying to lose weight then walking is great because you will get outside and exercise just as well. Or maybe swimming is your favorite sport so for you running is easier to do.
Whatever you choose to do, just make sure you are practicing good health habits. To know more about healthy eating, read our article here.
Do yoga
How to eat healthy
While not everyone has the time or money for a longer yoga session, there are some simple poses that can be done at home on a regular basis. These are called asanas.
Yoga is a great exercise activity that benefits your overall health and fitness. Not only do they help tone your muscles, but also improve your balance, relaxation, and focus. There are several different types of yoga including Vinyasa, Ashtanga, Iyengar, and others.
Many people begin practicing yoga with more complicated moves that take longer to perform. But you don’t have to spend hours upon hours exploring the depths of yogic philosophy!
There are many short pose tutorials online and in books that contain enough detail to get you started. Some popular positions include:
Cat-and-cow
Child’s pose
Cow pose
Crescent moon pose
Easy pose
Fire log (aka red bone) pose
Half cow pose
Hero pushup
Inverted row
Legs up tabletop position
Mountain climber
Pike position
Recumbent butterfly
Shoulder stand
Simple twist
Some modifications and variations can be made to these shapes to make them easier to manage while still giving the same relaxed effects. For example, most practitioners drop down knees when doing child’s pose so it is slightly easier to hold onto.
Learn to laugh
Does eating healthy make you feel stressed out, overwhelmed or even disgusted with yourself? If so, maybe it’s time to add some more laughter into your life.
Thinking of ways to enjoy humor can help you deal with all sorts of things. Finding something funny can take focus away from whatever is making you unhappy, and instead refresh your mind.
You will find that as you spend more time thinking about how funny certain situations are, you’ll want to be involved in them. And if you are already involved in them, you’ll want to keep doing what you were before you started focusing on laughs.
Humor has been shown to have many health benefits, including lowering stress hormones like cortisol. When you reduce stress, healthier behaviors such as eating healthier occur naturally.
This article will talk about some easy ways to include fun in your daily life.
This content is contributed by Help for eating disorder
We provide useful information on how to help if you have eating disorder
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4,123,463,074,028,322,000 | RT Journal Article A1 Toscani, Matteo A1 Gegenfurtner, Karl R. A1 Valsecchi, Matteo T1 Foveal to peripheral extrapolation of brightness within objects JF Journal of Vision JO Journal of Vision YR 2017 DO 10.1167/17.9.14 VO 17 IS 9 SP 14 OP 14 SN 1534-7362 AB Peripheral viewing is characterized by poor resolution and distortions as compared to central viewing; nevertheless, when we move our gaze around, the visual scene does not appear to change. One possible mechanism leading to perceptual uniformity would be that peripheral appearance is extrapolated based on foveal information. Here we investigate foveal-to-peripheral extrapolation in the case of the perceived brightness of an object's surface. While fixating a spot on the rendered object, observers were asked to adjust the brightness of a disc to match a peripherally viewed target area on the surface of the same object. Being forced to fixate a better illuminated point led to brighter matches as compared to fixating points in the shadow, indicating that foveal brightness information was extrapolated. When observers fixated additional points outside of the object on the scene's background, fixated brightness had no effect on the brightness match. Results indicate that our visual system uses the brightness of the foveally viewed surface area to estimate the brightness of areas in the periphery. However, this mechanism is selectively applied within an object's boundary. RD 4/3/2020 UL https://doi.org/10.1167/17.9.14 | {
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7,608,919,585,809,196,000 | Dental Implants and Bone Loss
Dental Implants and Bone Loss
Dianna Kersey Dental Implants
One of the unfortunate consequences of missing teeth is bone loss in the jaw. The result is not just functional problems, but aesthetic too–over the years, the shape of your face will change, causing features to sag and appear sunken. When it comes to dental implants and bone loss, there is no better option for both restoring your natural smile and keeping the structure of your jawbone intact. Read on to find out more.
How do dental implants prevent bone loss?
The bone loss that occurs when teeth are missing is called resorption. Like muscles, bones are strengthened by physical stimulus. The daily activities of chewing and biting keep your jawbone strong. When teeth are missing, the jaw no longer gets that stimulus and your body begins breaking down the bone.
Unlike traditional dentures and bridges, dental implants are placed into the jawbone; this both prevents future bone loss and stimulates the growth of new bone. For this reason, dental implants have become the preferred option for replacing missing teeth.
Why is preventing bone loss so important?
When the jawbone begins to deteriorate, overall oral health can also begin to decline. Your bite may weaken; other teeth may become loose and fall out. The eventual outcome is a situation that is costly and time-consuming to repair.
Bone loss also causes premature aging in the face, with lips and cheeks sagging, causing patients to feel self-conscious and embarrassed in social situations.
Can I get dental implants if I’ve already experienced bone loss?
Depending on the severity of your bone loss, the answer is usually yes, but we cannot give you a definitive answer until seeing you in our office.
When a patient already has some degree of bone loss in the jaw, we can perform a bone grafting procedure, using either your own natural bone or artificial grafting material, to spur the growth of new bone. This may take several months, but when bone growth is successful, it provides a secure foundation to support your dental implants. Without adequate jawbone support, dental implants are at a high risk of failure, so even though the grafting process can be frustrating for patients eager to get their implants right away, it is worth taking the time to set you up for the best possible outcome.
Do dental implants cause bone loss?
The vast majority of patients have successful dental implant placement. Dental implants are used because of their ability to prevent bone loss, but there are rare circumstances when dental implants can cause bone loss. Peri-implantitis is an infection that causes inflammation around the implant, leading to bone loss, but this condition is uncommon.
Learn More About Dental Implants
If you would like to learn more about dental implants and bone loss, or have us evaluate whether dental implants are an option for you, we would be happy to meet with you in person to discuss your unique situation. Contact us today and make an appointment at one of our four Oklahoma oral surgery practices. | {
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5,086,255,695,506,071,000 | Infarct-related artery occlusion, tissue markers of ischemia, and increased apoptosis in the peri-infarct viable myocardium.
Fabio De Giorgio, Giovanna Liuzzo, Filippo Crea, Luigi Marzio Biasucci, Antonio Abbate, Antonio Maria Leone, 33185, DI MEDICINA E CHIRURGIA "A.GEMELLI" FACOLTA', ROMA - Dipartimento di Scienze cardiovascolari e pneumologiche, 33189, R Bussani, DI MEDICINA E CHIRURGIA "A.GEMELLI" FACOLTA', ROMA - Dipartimento di Sicurezza e Bioetica, Giuseppe Biondi Zoccai, DI MEDICINA E CHIRURGIA "A.GEMELLI" FACOLTA', D Santini, A Petrolini, F Vasaturo, S Scarpa, A SeverinoF Baldi, G Sinagra, F Silvestri, Gw Vetrovec, A. Baldi
Risultato della ricerca: Contributo in rivistaArticolo in rivista
Abstract
AIMS: Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium. METHODS AND RESULTS: In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P=0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P<0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P=0.42] CONCLUSION: Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences.
Lingua originaleEnglish
pagine (da-a)2039-2045
Numero di pagine7
RivistaEuropean Heart Journal
Stato di pubblicazionePubblicato - 2005
Keywords
• apoptosis
• infarct myocardium
• ischemia
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Cita questo | {
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When the data were examined, it was clear that people who ate a diet where fruits and vegetables, grains, beans, and fish were the basis of daily meals were healthiest. Topping the chart were residents of Crete. Even after the deprivations of World War II – and in part, perhaps, because of them – the cardiovascular health of Crete residents exceeded that of US residents. Researchers attributed the differences to diet.
Many dieters shy away from nuts because of their high calorie and fat count. But studies show that eating a handful several times a week can prevent heart disease and ultimately help you shed pounds since they fill you up and stop you from snacking on other things. Almonds, in particular, contain lots of monounsaturated fats and fiber. (Healthy swap: Replace peanut butter with almond butter.)
DASH stands for Dietary Approaches to Stop Hypertension, and the diet was developed for a research study in the early 1990s.1 The purpose of the study was to identify a food-based strategy to lower blood pressure. Even though the original research was quite a long time ago, scientists recently conducted a meta-analysis for a DASH diet review to summarize how much blood pressure can be reduced by the DASH diet. The study found, on average, people reduce their blood pressure by 6.7 mmHg systolic and 3.5 mmHg diastolic in just two weeks. The more sodium is restricted, the lower blood pressure goes.
The DASH diet is especially recommended for people with hypertension (high blood pressure) or prehypertension. The DASH diet eating plan has been proven to lower blood pressure in studies sponsored by the National Institutes of Health (Dietary Approaches to Stop Hypertension). In addition to being a low salt (or low sodium) plan, the DASH diet provides additional benefits to reduce blood pressure. It is based on an eating plan rich in fruits and vegetables, and low-fat or non-fat dairy, with whole grains. It is a high fiber, low to moderate fat diet, rich in potasium, calcium, and magnesium. The full DASH diet plan is shown here. The DASH diet is a healthy plan, designed for the whole family. New research continues to show additional health benefits of the plan.
The most agreed-upon recommendation is for the diet to be low in sugar and refined carbohydrates, while relatively high in dietary fiber, especially soluble fiber. People with diabetes are also encouraged to eat small frequent meals a day. Likewise, people with diabetes may be encouraged to reduce their intake of carbohydrates that have a high glycemic index (GI), although this is also controversial.[5] (In cases of hypoglycemia, they are advised to have food or drink that can raise blood glucose quickly, such as a sugary sports drink, followed by a long-acting carbohydrate (such as rye bread) to prevent risk of further hypoglycemia.) Others question the usefulness of the glycemic index and recommend high-GI foods like potatoes and rice.[citation needed] It has been claimed that oleic acid has a slight advantage over linoleic acid in reducing plasma glucose.[6]
Refined carbs lack nutrients and can wreak havoc on your blood sugar. Whole grains are best; have four small daily portions of whole-wheat bread, or try a pasta made from quinoa. And always eat grains with healthy fats and protein. Incorporate sprouted or fermented grains (hello, sourdough!) for easier digestion and better nutrient absorption. Or look for creative ways to swap out grains, such as using spaghetti squash in place of noodles.
Emerging evidence suggests that eating this way may offer protective effects for those with and at risk for type 2 diabetes. For one, Mediterranean eating improves blood sugar control in those already diagnosed with the condition, suggesting it can be a good way to manage the disease. What’s more, given those with diabetes are at increased odds for cardiovascular disease, adopting this diet can help improve their heart health, according to a paper published in April 2014 in the journal Nutrients. (4)
Salmon is one of our favorite types of fish. It's full of monounsaturated fats, a great source of omega-3 fatty acids, and it's low in calories. There are so many ways to prepare salmon, but the people from the Mediterranean think simple is best. We agree! This recipe uses delicious and healthy ingredients, and when you pair it with some sautéed spinach or whole-wheat couscous you're in for a delicious dinner.
Diabetes related foot problems can affect your health with two problems: diabetic neuropathy, where diabetes affects the nerves, and peripheral vascular disease, where diabetes affects the flow of blood. Common foot problems for people with diabetes include athlete's foot, fungal infection of nails, calluses, corns, blisters, bunions, dry skin, foot ulcers, hammertoes, ingrown toenails, and plantar warts.
Triglycerides are a common form of fat that we digest. Triglycerides are the main ingredient in animal fats and vegetable oils. Elevated levels of triglycerides are a risk factor for heart disease, heart attack, stroke, fatty liver disease, and pancreatitis. Elevated levels of triglycerides are also associated with diseases like diabetes, kidney disease, and medications (for example, diuretics, birth control pills, and beta blockers). Dietary changes, and medication if necessary can help lower triglyceride blood levels.
Most people in the Mediterranean eat a balanced breakfast within one to two hours of waking up, which starts their day right by balancing blood sugar when it’s at its lowest. They then typically eat three meals a day that are filling, with plenty of fiber and healthy fats. Many people choose to have their biggest meal mid-day as opposed to at night, which gives them the opportunity to use that food for energy while they’re still active.
Another key component of the Mediterranean diet is lifestyle. Enjoy the social component of eating by sharing meals with family and friends as often as possible, whether on a weeknight or special occasion. Slow down, savor each bite, and don’t be afraid to have a glass of wine (or two) in moderation. While wine packs antioxidants, you should also drink plenty of water, as staying properly hydrated keeps your body functioning. The last bit of the equation is making physical activity a part of your daily routine, whether it’s biking to work or simply taking a walk during your lunch break to enjoy the fresh air.
Moderation is advised with regard to consuming alcohol and using some drugs. Alcohol inhibits glycogenesis in the liver and some drugs inhibit hunger symptoms. This, with impaired judgment, memory and concentration caused by some drugs can lead to hypoglycemia. People with diabetes who take insulin or tablets such as sulphonylureas should not, therefore, consume alcohol on an empty stomach but take some starchy food (such as bread or potato crisps) at the same time as consumption of alcohol.[citation needed]
One serving in a category is called a "choice." A food choice has about the same amount of carbohydrates, protein, fat and calories — and the same effect on your blood glucose — as a serving of every other food in that same category. So, for example, you could choose to eat half of a large ear of corn or 1/3 cup of cooked pasta for one starch choice.
The 3 Day Military Diet should be strictly followed. The Diet wasn’t invented by military scientists. But it does need to be followed like a soldier follows orders. There are some rare exceptions for those of us that have dietary limitations. There are others that have allergies or simply can’t choke down peanut butter. The recommendation is to follow the diet to as close as you possible can. But if you must, below is a list of all the foods you can use for 3 day military diet substitutes. Some of the foods can be swapped in order to make it vegetarian, lactose free, or gluten free.
The best way to avoid these foods is to shop around the edges of the grocery store and minimize the number of processed, packaged foods in the middle. Sticking with "real" food in its whole, minimally processed form is the best way to eat well for diabetes. People with type 2 diabetes who eat a healthy diet pattern like the ones discussed here reduce the risk of complications that stem from high blood sugar, like cardiovascular disease and obesity.
I’m not even mad we didn’t see the Ball-leg Knights this episode because now there’s a threat left for season three (please, for the love of Sheila, let there be a season three). And they can fight the Ball-leg Knights with Anne by their side! It’s too perfect. The only way to make it better is it somehow they let Rick in on everything too because Joel needs a friend outside of Gary’s head. Though speaking of Gary’s head, he’s not dead, so here’s hoping that Nathan Fillion doesn’t get too busy between now and the season three that must happen, it must.
Almonds, sunflower seeds, lentils and other foods in this family are good sources of magnesium, potassium and protein. However, these foods are high in calories so DASH keeps serving sizes small and recommends that they are consumed weekly. Examples of one serving include 1/3 cup (1 1/2 oz.) nuts, 2 tablespoons seeds, or 1/2 cup cooked beans or peas.
This guideline isn’t as daunting as it may seem. “Make a salad with at least 2 cups of vegetables for lunch and have 2 cups of roasted, stir-fried or steamed vegetables at dinner. To get your last serving, either make an omelet with vegetables in the morning or snack on a cup of vegetables like cucumber, celery and bell pepper sticks during the day,” suggests Nour Zibdeh, RDN, an integrative and functional dietitian who specializes in digestive and autoimmune disorders.
One serving in a category is called a "choice." A food choice has about the same amount of carbohydrates, protein, fat and calories — and the same effect on your blood glucose — as a serving of every other food in that same category. So, for example, you could choose to eat half of a large ear of corn or 1/3 cup of cooked pasta for one starch choice.
According to its website, the Military Diet works due to its combination of putting the body into a starvation state while consuming fat-burning foods. In fact, the site suggests that the extremely low level of calories is a form of fasting. Research on forms of intermittent fasting has suggested some potential health benefits, but the Military Diet doesn’t follow the same protocol that most research studies have used (going 16 hours without eating or alternating extremely low and moderate calories days, as well as emphasizing nutrient-dense choices when food is consumed).
The diet I recommend in my book Healthy Aging: A Lifelong Guide to your Physical and Spiritual Well-Being is similar to the DASH diet with the addition of omega-3 fatty acids and natural anti-inflammatory spices such as turmeric and ginger. Both are similar to the Mediterranean diet, which emphasizes fresh fruits and vegetables, crusty breads, whole grains, and olive oil as well as more fish and legumes and less meat and poultry than the typical Western diet contains. Whether you’re trying to lower blood pressure or simply eat well, you can’t go wrong with the DASH diet, or with the alternatives mentioned above.
Howard’s father, actor and director Ron Howard, made his Happy Days co-star his daughter’s godfather, and the actress knows she lucked out with that selection. During an interview with The Talk in August 2016, she said, “He’s just the most wonderful man. It’s great as a kid to have adults who you can go to who are mentors. They don’t have the ability to ground you, but they do have the wisdom of being someone who loves you and who cares about you and is aware.” When it came to choosing her own child’s godfather, Dallas Howard chose actor and The Book of Mormon breakout star, Josh Gad.
We also know that the Military Diet is not associated with the armed forces in any way, says Roland Paquette, PA-C, an assistant professor in physician assistant studies at UT Health San Antonio. A former Green Beret who served in the United States Special Forces from 2004 to 2006, Paquette tells MensHealth.com that the army did not institute a specific diet to get cadets into shape.
Contrary to popular belief, not all carbs are off-limits if you’re managing diabetes. In fact, the ADA recommends vitamin-rich whole grains in a healthy diabetes diet. These foods contain fiber, which is beneficial for digestive health. Fiber can also promote feelings of fullness, preventing you from reaching for unhealthy snacks, and it can help slow the rise of blood sugar. Plus, whole grains contain healthy vitamins, minerals, and phytochemicals that are healthy for anyone, regardless of whether they have diabetes or not.
The military diet is similar to other three-day diet plans (think: the Mayo Clinic and Cleveland Clinic three-day diet plans) as it claims to promote weight loss in a short period of time by restricting calories. The diet also bears a striking resemblance to the retro Drinking Man's Diet (or the Air Force Diet) of the '60s, according to Adrienne Rose Johnson Bitar, Ph.D., postdoctoral associate at Cornell University who specializes in the history and culture of American food, pop culture, and health. Much like the military diet, the Drinking Man's Diet incorporated martinis and steak in the diet but kept carbohydrate and calorie counts fairly low, she explains. "Both of these diets were low-calorie or low-carb plans that promised impressive short-term results, but included unhealthy or indulgent foods," says Bitar. (Another unhealthy diet trend that includes lots of red meat: The Vertical Diet. Safe to say, you can skip that diet plan, too.)
Recommended by the 2015–2020 Dietary Guidelines for Americans as a healthful dietary pattern,8 the DASH diet is an amalgam of every healthful eating recommendation that health and nutrition experts have been making for decades, eg, eat more fruits and vegetables, low-fat dairy, nuts and seeds, beans, and whole grains, and lower intake of sodium and sugar.
I lobe the Mediterranean diet, but I do wonder whether regionally derived diets like this do not have a partly genetic basis when they work i.e. those good folk who live in the Mediterranean have basically adapted to this diet over many generations and it’s their genetic inheritance that contributes to its success – just a thought and thanks for an interesting article and indeed for many interesting comments!
And, of course, the low-cal nature of the military diet can dangerous, says Amidor. This is especially true if you plan to exercise: Attempting to do high-intensity workouts on such a low-calorie diet could potentially cause you to become weak, light-headed, and fatigued—so low-intensity cardio or walking is your safest option during this diet, says Allen.
Aaron Bady at The Los Angeles Review of Books argues that Santa Clarita Diet is unconsciously conservative and default pro-Trump because it’s apolitical: “This suburban show wants to exist in a world without politics, without a larger frame of reference than the home life of a suburban family, their suburban neighbors, and their workplace selling suburban homes to other suburban families.” It’s true that in 2018, setting a sitcom in suburbia isn’t likely to be a radical or relevant political statement. But even so, Bady misses the anti-Trump political subtext of making zombies lovable.
More modern history of the diabetic diet may begin with Frederick Madison Allen and Elliott Joslin, who, in the early 20th century, before insulin was discovered, recommended that people with diabetes eat only a low-calorie and nearly zero-carbohydrate diet to prevent ketoacidosis from killing them. While this approach could extend life by a limited period, patients developed a variety of other medical problems.[9]
The contents displayed within this public group(s), such as text, graphics, and other material ("Content") are intended for educational purposes only. The Content is not intended to substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your healthcare provider with any questions you may have regarding your medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in a public group(s).
Eating out is possible on the DASH Diet, but proceed with caution. Restaurant meals are notoriously salty, oversized and fatty, so you’ll need to be conscientious if you dine out. NHLBI suggests avoiding salt by shunning pickled, cured or smoked items; limiting condiments; choosing fruits or vegetables instead of soup; and requesting the chef find other ways to season your meal. You can also drink alcohol moderately on the DASH Diet.
Corella, D., Carrasco, P., Sorli, J., Estruch, R., Rico-Sanz, J., Martinez-Gonzalez, M. A., … & Ordovas, J. (2013, August 12). Mediterranean diet reduces the adverse of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence. Diabetes care, DC_130955. Retrieved from http://care.diabetesjournals.org/content/early/2013/08/06/dc13-0955
The DASH-Sodium study was conducted following the end of the original DASH study to determine whether the DASH diet could produce even better results if it were low in salt and also to examine the effects of different levels of sodium in people eating the DASH diet.[2] The researchers were interested in determining the effects of sodium reduction when combined with the DASH diet as well as the effects of the DASH diet when at three levels of sodium intake. The DASH-Sodium trial was conducted from September 1997 through November 1999. Like the previous study, it was based on a large sample (412 participants) and was a multi-center, randomized, outpatient feeding study where the subjects were given all their food.[12] The participants were adults with prehypertension or stage 1 hypertension (average systolic of 120 to 159 mm Hg & average diastolic of 80 to 95 mm Hg) and were randomly assigned to one of two diet groups.[10] The two randomized diet groups were the DASH diet and a control diet that mirrored a “typical American diet”, and which was somewhat low in key nutrients such as potassium, magnesium and calcium. The DASH diet was the same as in the previous DASH study. After being assigned to one of these two diets, the participants were given diets that differed by 3 distinct levels of sodium content, corresponding to 3,000 mg, 2,400 mg or 1,500 mg/day (higher, intermediate or lower), in random order, for 30 consecutive days each.[10] During the two-week run-in phase, all participants ate the high sodium control diet. The 30-day intervention phase followed, in which subjects ate their assigned diets at each of the aforementioned sodium levels (high, intermediate and low) in random order, in a crossover design.[12] During the 30-day dietary intervention phase, each participant therefore consumed his or her assigned diet (either DASH or control) at all three sodium levels.[dubious – discuss]
In most zombie stories, the fact that Joel still loves Sheila after she turns would ultimately lead to his gory death. In Santa Clarita Diet, though, the invaders with their odd dietary customs aren’t monsters. They’re family. Even in the face of a zombie apocalypse, Joel and Sheila insist that caring for other people is what keeps us human. Even when we’re zombies.
Protein is the macronutrient that contains no carbohydrates (unless breaded, fried, or covered in sauce/condiments). Adequate protein intake is important for boosting immunity, wound healing, muscle recovery, and has satiating power. When eating a calorie controlled diet, it's important to choose lean protein (as these types will have fewer calories and fat).
Yet it’s an incredibly well-rounded way to lose weight that ditches gimmicks and doesn’t require calorie or macronutrient counting as other diets do. And with the emphasis on healthy fat, it’s satisfying, too. That said, while the 2018 U.S. News & World Report Best Diets ranked the Mediterranean diet as being tied for first with the DASH diet overall, it ranks 14 in their list of Best Weight-Loss Diets. (3) The reviewers note that it’s not a slam dunk, and all depends on how you eat. Even healthy diets like the Mediterranean aren’t free-for-all eating plans.
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-205,496,395,326,516,770 | Time-varying and tissue-dependent effects of adiposity on leptin levels: A Mendelian randomization study
1. Tom G Richardson Is a corresponding author
2. Genevieve M Leyden
3. George Davey Smith
1. MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, United Kingdom
Abstract
Background:
Findings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as ‘lifecourse’ and ‘tissue-partitioned’ MR) to investigate lifestage-specific effects and tissues of action in the relationship between adiposity and circulating leptin levels.
Methods:
Genetic instruments for childhood and adult adiposity were incorporated into a multivariable MR (MVMR) framework to estimate lifestage-specific effects on leptin levels measured during early life (mean age: 10 y) in the Avon Longitudinal Study of Parents and Children and in adulthood (mean age: 55 y) using summary-level data from the deCODE Health study. This was followed by partitioning body mass index (BMI) instruments into those whose effects are putatively mediated by gene expression in either subcutaneous adipose or brain tissues, followed by using MVMR to simultaneously estimate their separate effects on childhood and adult leptin levels.
Results:
There was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 y in the lifecourse (β = 1.10 SD change in leptin levels, 95% CI = 0.90–1.30, p=6 × 10-28), whereas evidence of an indirect effect was found on adulthood leptin along the causal pathway involving adulthood body size (β = 0.74, 95% CI = 0.62–0.86, p=1 × 10-33). Tissue-partitioned MR analyses provided evidence to suggest that BMI exerts its effect on leptin levels during both childhood and adulthood via brain tissue-mediated pathways (β = 0.79, 95% CI = 0.22–1.36, p=6 × 10-3 and β = 0.51, 95% CI = 0.32–0.69, p=1 × 10-7, respectively).
Conclusions:
Our findings demonstrate the use of lifecourse MR to disentangle direct and indirect effects of early-life exposures on time-varying complex outcomes. Furthermore, by integrating tissue-specific data, we highlight the etiological importance of appetite regulation in the effect of adiposity on leptin levels.
Funding:
This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).
Editor's evaluation
The authors have recently developed two novel approaches to Mendelian randomization studies (1) lifecourse MR which relates the genetic instruments to the outcome, eg obesity, at different stages of life eg childhood, and adulthood and (2) tissue partitioned MR to determine if the genetic instruments have different effects on different tissues such as the brain and adipose tissue. They combine these approaches to investigate the influence of adiposity on circulating leptin in order to demonstrate the value/proof of concept of these techniques in extending the use of MR. This is very clearly presented and well conducted work showing both important new methodology and clear-cut results and so providing compelling evidence on the impact of adiposity at age 10 and in middle life and the weight gain in between on leptin levels and that the effect is mediated via the brain.
https://doi.org/10.7554/eLife.84646.sa0
Introduction
People living with obesity have elevated levels of the peptide hormone leptin. This can be attributed to the amount of leptin in circulation being proportional to the amount of adipose tissue that an individual has (Obradovic et al., 2021). After being secreted by fat cells in adipose tissue, leptin predominantly acts in the hypothalamus as a major regulator of energy balance (Morrison, 2009). Likewise, both neural and adipose tissues are known to play an important role in the molecular etiology of body mass index (BMI), which is conventionally used to clinically diagnose obesity. However, despite being a cost-effective approach to routinely measure adiposity at scale, BMI is a construct that captures multiple heterogeneous subcomponents. This is epitomized by previous investigations into the functional genes that exert their effects on adiposity via their expression in brain and adipose tissues (Timshel et al., 2020; Rask-Andersen et al., 2019), highlighting the divergent pathways that exist between BMI and downstream complex traits.
Mendelian randomization (MR) is a causal inference technique that can exploit the random segregation of genetic variants within a population to evaluate the genetically predicted effects of modifiable exposures on complex outcomes (Davey Smith and Ebrahim, 2003; Richmond and Davey Smith, 2022). We recently extended the principles of MR to evaluate the separate effects of molecular subcomponents of BMI using genetic variants partitioned by their impact on gene expression derived from subcutaneous adipose tissue (SAT) and brain tissue (known as ‘tissue-partitioned MR’) (Leyden et al., 2022). Using this approach suggested that the brain-derived variants are predominantly responsible for driving the effect of BMI on cardiometabolic disease outcomes (Leyden et al., 2022), which we postulate is due to their involvement in appetite regulation and energy expenditure. These in turn influence the timelines and sites of adipose tissue distribution, which have more adverse consequences at the same level of BMI as do the processes influenced by the SAT-derived variants. Conversely, the SAT-derived set of instruments were predominantly responsible for the effect of BMI on outcomes such as endometrial cancer (Leyden et al., 2023). Differences in components of adiposity at the same level of BMI have previously been demonstrated with these instruments (Leyden et al., 2022), preserving the gene–environment equivalence assumption in MR (Davey Smith, 2012).
In this study, we sought to dissect the causal pathway between BMI and circulating leptin using tissue-partitioned MR by leveraging these brain- and adipose tissue-derived sets of instruments. However, investigating this hypothesis is made even more challenging given that associations between BMI and leptin levels have been reported as early in life as childhood (Shalitin and Phillip, 2003). Therefore, to further develop insight into the relationship between BMI and circulating leptin, we additionally applied another extension that we have developed in recent years known as ‘lifecourse MR’ (Richardson et al., 2020). This approach allows the independent effects of childhood and adult adiposity to be simultaneously estimated on an outcome that can also be measured at separate timepoints in the lifecourse (Richardson et al., 2022b; Sanderson et al., 2022), such as childhood (mean age: 10 y) and adulthood (mean age: 55 y) measures of circulating leptin levels in this study. Taken together, we aimed to conduct a proof-of-concept study for these novel extensions of the conventional MR approach.
Methods
Lifecourse Mendelian randomization
Lifecourse MR has been described in detail previously (Richardson et al., 2020). Briefly, genetic instruments derived in the UK Biobank study based on self-reported body size at age 10 and measured adulthood BMI (Richardson et al., 2020) have been shown to separate clinically measured childhood and adult BMI in three independent cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC] [Richardson et al., 2020], the Young Finns Study [Richardson et al., 2021], and the Trøndelag Health (HUNT) study [Brandkvist et al., 2021]). Both univariable and multivariable MR analyses on childhood leptin were conducted in a one-sample setting using individual-level data from ALSPAC by analyzing genetic risk scores with adjustment for age and sex. Univariable MR analyses to estimate total effects on adulthood leptin were undertaken in a two-sample setting using the inverse variance weighted (IVW) method (Burgess et al., 2013), as well as the weighted median and MR-Egger methods (Bowden et al., 2015; Bowden et al., 2016). Multivariable MR analyses on adulthood leptin were also performed in a two-sample setting to estimate the direct and indirect effects of childhood body size (Sanderson et al., 2019).
Tissue-partitioned Mendelian randomization
Instrument derivation and methodology for tissue-partitioned MR has also been described in detail previously (Leyden et al., 2022). In brief, 86 independent adult BMI-associated instruments provided evidence of sharing a causal variant with proximal gene expression in subcutaneous adipose tissue through genetic colocalization analyses (based on a posterior probability [PPA] > 0.8). The same approach provided evidence that the effects of 140 adult BMI instruments are putatively mediated by a nearby gene’s expression in brain tissue. These two sets of genetic variants have near identical average effect sizes on BMI (adipose = 0.0148 and brain = 0.0149 standard deviation [SD] change in BMI per effect allele), although the manner in which they relate to other anthropometric traits can markedly differ. For instance, we previously found that the brain tissue instruments were more strongly correlated with waist-to-hip ratio compared to the adipose–tissue instruments (r = 0.733 and r = 0.445, respectively, pcomparison=0.001). Likewise, the brain tissue set was more highly correlated than the adipose set with a measure of visceral adipose tissue from the UK Biobank study (r = 0.554 and r = 0.254, respectively, pcomparison=0.009), further suggesting that the way in which these tissue-partitioned sets of variants exert their effects on BMI likely varies in terms of biological pathways.
Univariable and multivariable MR analyses on childhood leptin measured in ALSPAC were undertaken as above in a one-sample setting by aggregating the tissue-partitioned BMI instruments as genetic risk scores and analyzing childhood leptin with adjustment for age and sex. Estimates on adulthood leptin were initially evaluated in a two-sample setting using the three univariable MR methods mentioned above, and subsequently using an extension of multivariable MR with instruments weighted by their PPA values for each tissue type (Leyden et al., 2023). An overview of datasets used for exposures and outcomes analyzed in this study can be found in Supplementary file 1a. All analyses were conducted using the ‘TwoSampleMR’ R package (Hemani et al., 2018).
Childhood measures of circulating leptin and fat distribution
The ALSPAC is a population-based cohort investigating genetic and environmental factors that affect the health and development of children. The study methods are described in detail elsewhere (Boyd et al., 2013; Fraser et al., 2013). In brief, 14,541 pregnant women residents in the former region of Avon, UK, with an expected delivery date between April 1, 1991, and December 31, 1992, were eligible to take part in ALSPAC. Of these initial pregnancies, there was a total of 14,676 fetuses, resulting in 14,062 live births and 13,988 children who were alive at 1 y of age. Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool and reference the following webpage: http://www.bristol.ac.uk/alspac/researchers/our-data/. Written informed consent was obtained for all study participants. Ethical approval for this study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Childhood measures of circulating leptin levels were obtained from non-fasting blood samples taken from ALSPAC participants at mean age 9.9 y (range = 8.9–11.5 y). Leptin was measured by an in-house ELISA validated against commercial methods. Analyses in ALSPAC were undertaken on a final sample size of 4155 individuals after removing those without genetic data and withdrawn consent.
A further sensitivity analysis of body composition was conducted on dual-energy X-ray absorptiometry (DXA) and skinfold measures obtained from the ALSPAC study. Trunk and total body DXA measures of lean, bone, and fat mass were obtained for ALSPAC participants at mean age 9.9 y (range = 8.9–11.5 y) as above. Skinfold thickness measures were available for 576 ALSPAC participants assessed at the 61-mth clinic (mean age 5.2 y) by skinfold caliper. The mean of three measurements was obtained for biceps, triceps, subscapular and suprailiac skinfold thickness.
Adulthood estimates for circulating leptin and fat distribution
Genetic estimates on adulthood circulating leptin levels were obtained from a study of 10,708 individuals enrolled in the Fenland study. Full details have been described elsewhere (Pietzner et al., 2021a). Leptin was measured using the SomaScan v4 assay, which applies single-stranded oligonucleotides aptamers with specific binding affinities to protein targets. This assay has also been reported to provide a very highly correlated measure of circulating leptin using the antibody-based Olink platform (r = 0.95) (Pietzner et al., 2021b). The Fenland study was approved by the National Health Service (NHS) Health Research Authority Research Ethics Committee (NRES Committee-East of England Cambridge Central, ref 04/Q018/19). All participants provided written informed consent. Although effect estimates from these summary-level data can be interpreted as a 1-SD change in normalized plasma leptin levels, we note that direct comparisons between estimates derived from childhood measures of leptin in ALSPAC should not be drawn given the various sources of heterogeneity between these measures.
We also obtained genetic estimates on adulthood circulating leptin levels from a previously conducted large-scale study of 35,559 individuals enrolled in the deCODE Health study (mean age: 55 y, SD: 17 y). Full details on that study have been reported previously (Ferkingstad et al., 2021). Briefly, circulating leptin was measured from plasma samples using the SomaScan version 4 assay by SomaLogic. All participants from this study who donated samples gave informed consent, and the National Bioethics Committee of Iceland approved the study, which was conducted in agreement with conditions issued by the Data Protection Authority of Iceland (VSN_14-015).
Genome-wide effect estimates on measures of fat distribution were obtained from a recent study on 38,965 UK Biobank participants who analyzed MRI-derived measures of visceral, abdominal subcutaneous, and gluteofemoral fat tissue volumes (Agrawal et al., 2022).
Results
Disentangling direct and indirect effects of childhood adiposity on early and mid-life measures of leptin levels
We firstly conducted univariable MR to estimate the total effect of childhood adiposity on circulating leptin using data measured in ALSPAC participants at mean age 9.9 y in the lifecourse (β = 1.28 SD change in leptin levels per change in body size category, 95% CI = 1.10–1.46, p=2 × 10–41). This was followed by applying multivariable MR, which provided evidence that childhood body size has a direct effect on increased leptin levels at this point in the lifecourse (β = 1.10, 95% CI = 0.90–1.30, p=6 × 10–28) (Figure 1A and B, Supplementary file 1b). Both childhood and adult adiposity likewise provided evidence of a total effect on circulating leptin measured in adulthood (β = 0.48, 95% CI = 0.36–0.61, p=5 × 10–14 and β = 0.59, 95% CI = 0.49–0,69, p=2 × 10–32, respectively) (Supplementary file 1c). However, multivariable MR analyses suggested that childhood adiposity indirectly influences leptin levels measured during adulthood along the causal pathway involving adult body size (β = 0.56, 95% CI = 0.42–0.69, p=1 × 10–15) (Figure 1C and D, Supplementary file 1d). Similar patterns were found analyzing circulating leptin levels using data from the Icelandic population (Supplementary file 1e).
Forest plots and schematic diagrams for Lifecourse Mendelian randomization analysis.
(A) A forest plot illustrating the direct effect of childhood body size on circulating leptin levels measured during childhood (mean age: 9.9 y) using individual-level data from the Avon Longitudinal Study of Parents and Children (ALSPAC). (B) provides the corresponding schematic diagram for ALSPAC results. (C) A forest plot depicting the indirect effect of childhood body size on adulthood measured leptin levels using data from the deCODE Health study (mean age: 55 y) as portrayed in the schematic diagram presented in panel (D). ‘Genetic variants’ refers to instruments for both exposures in the model. The red arrow indicates the causal pathway being assessed. MR, Mendelian randomization. Data underlying this figure can be found in Supplementary file 1b and d.
A further analysis of childhood body composition was conducted to investigate the residual positive effect of adult adiposity on leptin measured in childhood found in the previous multivariable MR analysis. Similarly, this analysis provided evidence that the adult effect attenuated with respect to the childhood adiposity score when evaluating measures of fat mass obtained by DXA scan (e.g. trunk fat; childhood body size: β = 1.42, 95% CI = 1.22–1.61, p=2.69 × 10–47 and adult body size: β = 0.60, 95% CI = 0.44–0.77, p=1.6 × 10–12) (Supplementary file 1f). Additionally, an evaluation of skinfold measures provided further evidence of a direct effect of childhood adiposity on fat mass (e.g. childhood: β = 1.00, 95% CI = 0.40–1.60, p=0.001 and adult: β = –0.12, 95% CI = −0.65–0.42, p=0.67) (Supplementary file 1g).
Separating the tissue-partitioned effects of body mass index on leptin levels measured during childhood and adulthood
Univariable MR analyses provided evidence of a total effect of adiposity on leptin levels measured during childhood based on analyses using the adipose tissue (β = 0.61, 95% CI = 0.13–1.08, p=0.01) and brain tissue (β = 0.86, 95% CI = 0.40–1.31, p=2 × 10–4) partitioned instruments. In a multivariable setting, the brain tissue-derived component of BMI predominated in the model (β = 0.79, 95% CI = 0.22–1.36, p=6 × 10–3), whereas the adipose tissue-derived estimate attenuated to include the null (β = 0.12, 95% CI = −0.48–0.71, p=0.70) (Figure 2A and B, Supplementary file 1h). Analyses on adulthood measured leptin also provided strong evidence of a total effect based on adipose-and brain tissue-derived estimates (β = 0.39, 95% CI = 0.21–0.57, p=3 × 10–5 and β = 0.42, 95% CI = 0.28–0.56, p=2 × 10–9, respectively). Similar to findings for childhood leptin, subcutaneous adipose tissue-derived estimates attenuated substantially more (β = 0.14, 95% CI = −0.14–0.42, p=0.33) compared to the estimates derived using the brain tissue instrument set (β = 0.38, 95% CI = 0.14–0.62, p=2 × 10–3) in a multivariable setting (Figure 2C and D, Supplementary file 1i and j). Similar conclusions were drawn based on data from the Icelandic population (Supplementary file 1k). Cochran’s Q-statistics for these analyses, as well as those derived in lifecourse MR analyses, can be found in Supplementary file 1l, along with intercept terms for MR-Egger analyses, which did not suggest horizontal pleiotropy may be biasing conclusions.
Figure 2 with 1 supplement see all
Forest plots and schematic diagrams for Tissue-partitioned Mendelian randomization analysis.
(A) A forest plot illustrating the attenuation of the adipose tissue-instrumented body mass index (BMI) effect on childhood leptin levels, whereas estimates for brain tissue-instrumented BMI remained robust. (B) The corresponding schematic diagram for this finding. (C) A forest plot displaying similar conclusions to the estimates found in childhood, but derived using adulthood measured leptin levels. (D) provides the corresponding schematic diagram for estimates portrayed in panel (C). ‘Genetic variants’ refers to instruments for both exposures in the model. The red arrow indicates the causal pathway being assessed. MR, Mendelian randomization. Data underlying this figure can be found in Supplementary file 1h and j.
As a further sensitivity analysis to characterize the causal pathway between these tissue-partitioned variants and fat distribution, we found that in particular the brain-expressed instruments have a predominating effect on visceral fat volume (β = 0.51, 95% CI = 0.30–0.72, p=2 × 10–6) compared to the subcutaneous adipose instruments (β = 0.07, 95% CI = −0.18–0.32, p=0.57) (Figure 2—figure supplement 1, Supplementary file 1m).
Discussion
In this study, we applied two recent approaches in the MR paradigm, known as lifecourse and tissue partitioned MR, to investigate the influence of adiposity on circulating leptin levels as an exemplar relationship to demonstrate the value of these techniques. Whilst there is irrefutable evidence that having a higher BMI increases circulating levels of leptin, these two extensions of MR methodology provide insight into lifecourse-specific effects and the tissues of action underlying this etiological relationship. We propose that these approaches can be conducted to build upon the findings by conventional MR analyses, which use naturally occurring genetic variants as causal anchors to help establish and estimate the causal effect of modifiable exposures on complex outcomes and disease endpoints.
Our application of lifecourse MR in this work supports a breadth of previous research using this technique, which highlights the importance of taking into consideration the age at which data from participants for exposure and outcome datasets are analyzed. Findings from this study provide evidence that adiposity in childhood exerts a direct effect on leptin levels when measured in early life, corroborating findings from observational studies (Shalitin and Phillip, 2003). Conversely, evidence of an indirect effect along the causal pathway involving adulthood adiposity was found when analyzing leptin measured in later life. This provides a powerful proof of concept for this approach, which has previously found evidence of a direct effect of increased childhood adiposity on lower risk of breast cancer (Richardson et al., 2020), elevated risk of type 1 diabetes (Richardson et al., 2022a), and an influence on cardiac structure (O’Nunain et al., 2022). Evidence supporting indirect effects using this approach, as in this study for adulthood leptin, has been found previously for various cardiovascular (Power et al., 2021) and site-specific cancer endpoints (Mariosa et al., 2022; Papadimitriou et al., 2023).
Additionally, in the multivariable MR analysis of childhood adiposity on childhood leptin, we found that the effect of adulthood adiposity, despite attenuating in comparison to univariable MR estimates, still provided some evidence of an indirect influence. However, within a lifecourse model an effect of adulthood adiposity on childhood leptin levels is impossible given that an adulthood risk factor cannot influence a trait measured at an earlier stage in the lifecourse. We therefore investigated this residual effect of the adulthood adiposity genetic score on in-depth measures of childhood adiposity using data from the age 10 clinic of the ALSPAC study. Similar evidence of a residual effect of the adulthood genetic score on childhood measured DXA-assessed fat mass was found in these analyses, whereas a direct effect of childhood adiposity was found on skinfold measures. These analyses further complement the study design of leveraging both individual- and summary-level data within an MR framework to develop more granular insight into the underlying etiological pathways between risk factors and complex traits. This residual influence of the adulthood BMI score on childhood leptin suggests that the aspects of childhood adiposity that relate to the adulthood genetic score in the multivariable analyses independently of the childhood score importantly influence leptin in childhood. In similar analyses for childhood vitamin D no such relationship was seen (Richardson et al., 2022b). This suggests that different aspects of childhood body composition influence circulating vitamin D and leptin levels, and demonstrates how cognisance of the gene-environment equivalence assumption in MR can motivate improved understanding of genotype to phenotype associations.
Tissue-partitioned MR analyses in this work suggest that the subcomponent of BMI proxied using genetic variants whose effects are putatively mediated via gene expression in brain tissue are predominantly responsible for driving effects of adiposity on leptin during both childhood and adulthood. We postulate that these findings highlight a role for appetite regulation and energy expenditure mechanisms as of fundamental importance in the effect of adiposity on leptin levels. This corroborates findings from the literature, which suggest that being overweight has a downstream consequence on elevated leptin levels due to leptin resistance occurring in the central nervous system, particularly the hypothalamus (Gruzdeva et al., 2019). This is influenced by factors such as blood–brain barrier permeability, which results in leptin failing to suppress appetite and consequently leads to circulating hyperleptinemia amongst patients with obesity (Izquierdo et al., 2019). Taken together with the evidence of an indirect effect highlighted by our lifecourse MR analysis, these findings suggest that leptin may have long-term consequences for appetite suppression. This in turn has an influence on excess body weight, which may start in childhood and then can be sustained into later life. Future research in this space should investigate large-scale genome-wide association studies (GWAS) outcomes related to subcutaneous adipose tissues (e.g. skinfold thickness), particularly given that this is where leptin is primarily produced (Russell et al., 1998).
Fractionating genetic instruments for the same exposure using molecular datasets has important considerations for the (often overlooked) gene–environment equivalence assumption in MR (Davey Smith, 2012). This states that the effect of germline genetic perturbations should have the same downstream consequence on outcomes as if they were caused by the modifiable exposures themselves. For the adipose- and brain tissue-partitioned sets of instruments used in this study, we found previously that the manner in which they relate to downstream disease and complex traits can drastically differ despite having almost identical average effect estimates on BMI as an exposure. In particular, this finding underlines the heterogeneous nature of BMI as a lifestyle risk factor and highlights that this human-derived construct likely captures various causal pathways underlying the relationship between anthropometry and complex outcomes. For example, we previously found evidence that the brain tissue-derived variants are predominantly responsible for the effect of BMI on both cigarette smoking and lung cancer (Leyden et al., 2023). We emphasize that future application of tissue-partitioned MR should carefully consider both the exposure and functionally relevant tissue types being investigated, as well as ensuring that the derived instrument sets are equally predictive of the exposure (Leyden et al., 2023). In particular, applications of a combined approach using both lifecourse and tissue-partitioned MR will likely be most powerful for exposures that have been analyzed by GWAS in large samples at distinct timepoints in the lifecourse (e.g. childhood and adulthood) where the functionally important tissue types have been well characterized by previous studies.
We note that both lifecourse and tissue-partitioned MR have important caveats. For instance, the childhood and adult body size instruments used to disentangle direct and indirect effects in this study do not provide insight into other timepoints over the lifecourse (e.g. adolescence). Future efforts should focus on deriving instruments to separate effects of age-specific adiposity at more granular windows over the lifecourse. Moreover, the childhood adiposity instruments are based on recall data, which is why they required validation in three independent cohorts as described in the ‘Methods’ section. In addition, tissue-partitioned instruments were derived using bulk tissue in this work due to the availability of data and therefore do not take into account cell-type heterogeneity (Glastonbury et al., 2019; Prince et al., 2021). Furthermore, as with all estimates derived from MR, triangulating findings from other orthogonal lines of evidence derived using different study design and datasets provides the most robust conclusions for the approaches applied in this work (Munafò and Davey Smith, 2018).
In summary, our findings highlight a putative role for genes expressed in neural tissues in the etiology of adiposity and leptin levels during both childhood and adulthood. Furthermore, this innovative study provides a proof of concept into how the principles of MR can be adapted to investigate the hypotheses outside the scope of how this causal inference technique was originally conceived (Davey Smith and Ebrahim, 2003).
Data availability
All individual level data analysed in this study was obtained from the ALSPAC study which is not allowed to be deposited in a public repository. However, all data can be accessed via an application to ALSPAC which requires approval from executive committee (http://www.bristol.ac.uk/alspac/researchers/access/). Summary-level data on adulthood leptin levels were provided by the deCODE Health study which can be found at (https://download.decode.is/form/folder/proteomics). All other data analysed in this study is based on summary-level results as referenced throughout.
References
Decision letter
1. Edward D Janus
Reviewing Editor; University of Melbourne, Australia
2. Matthias Barton
Senior Editor; University of Zurich, Switzerland
3. Edward D Janus
Reviewer; University of Melbourne, Australia
4. Despoina Manousaki
Reviewer; CHU Sainte-Justine, Canada
Our editorial process produces two outputs: (i) public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.
Decision letter after peer review:
Thank you for submitting your article "Time-varying and tissue-dependent effects of adiposity on leptin levels: a Mendelian randomization study" for consideration by eLife. Your article has been reviewed by 2 peer reviewers, including Edward D Janus as Reviewing Editor and Reviewer #1, and the evaluation has been overseen by Matthias Barton as the Senior Editor. The following individual involved in the review of your submission has agreed to reveal their identity: Despoina Manousaki (Reviewer #2).
The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this letter to help you prepare a revised submission.
Essential revisions:
1) It might not fit directly with the proof of concept aim of the manuscript, but this study could be a nice opportunity to test the opposite association, ie if leptin affects adiposity at different life stages. The relationship between BMI and leptin levels is complex as nicely depicted in lines 248-253 of the discussion. In the introduction, it is stated that leptin acts in the hypothalamus to regulate appetite. If the retroaction works, the regulation of appetite is expected to decrease appetite and food intake, and maintain BMI to a normal level. The knock-outed mice for leptin or congenital leptin deficiency in humans result in uncontrolled satiety and obesity. A bidirectional MR of Steiger filtering in the forward MR could answer this question.
2) In the discussion could the authors say if there are any other examples of already analysed or potentially interesting indirect life course effects ie expand on reference 26? Can they provide other examples of tissue-partitioned effects either already shown or potentially relevant? Can they suggest examples of other issues that this combined approach could address? This could give readers an even better idea of how these new approaches could be used.
Reviewer #1 (Recommendations for the authors):
I don't find a lot that needs to be addressed.
I could not find Supplementary notes 1 and 2.
In the discussion could the authors say if there are any other examples of already analysed or potentially interesting indirect life course effects ie expand on reference 26?
Can they provide other examples of tissue-partitioned effects either already shown or potentially relevant?
Any suggestions/examples for other issues that this combined approach could address?
This could give readers an even better idea of how these new approaches could be used.
Reviewer #2 (Recommendations for the authors):
This is an interesting study exploring lifecourse effects of adiposity on leptin levels, and using tissue-partitioned MR instruments to study the effects of BMI on leptin levels. While the study question is appealing, the methods are novel and they have been nicely applied in the context of the present study, and the results are interesting, I find that certain parts of the manuscript could be further clarified.
Also, it might not fit directly with the proof of concept aim of the manuscript, but this study could be a nice opportunity to test the opposite association, ie if leptin affects adiposity at different life stages. The relationship between BMI and leptin levels is complex as nicely depicted in lines 248-253 of the discussion. In the introduction, it is stated that leptin acts in the hypothalamus to regulate appetite. If the retroaction works, the regulation of appetite is expected to decrease appetite and food intake, and maintain BMI to a normal level. The knock-outed mice for leptin or congenital leptin deficiency in humans result in uncontrolled satiety and obesity. A bidirectional MR of Steiger filtering in the forward MR could answer this question.
Below are my point-by-point comments:
Abstract:
Methods: When the authors say in the results: "along the causal pathway", do they mean that they adjusted for adult body size in multivariable MR? If yes, please add this to the methods section of the abstract.
The units of change in exposure that confer the betas in the leptin outcome are not exposed in the abstract or in the manuscript (see additional comment on this below). This raises a challenge in directly comparing the two betas (ie in the childhood vs adulthood MR analysis).
In the conclusion, the phrase "as well as raising implications for the gene-environment equivalence assumption in MR". It is not clear how this phrase is justified by the analyses presented in the abstract. It is explained in the discussion of the paper, but I would suggest omitting it from the abstract conclusion.
Some specifications are needed in regards to the exposure and the outcome of GWAS sources.
For the exposure GWAS: In the BMJ paper cited as the source of the SNPs for adult and childhood body size, it is described that adult body size was measured based on the measured body mass index during adulthood (mean age 56.5) while child body mass was self-reported perceived body size at age 10. This is important information that should appear in the methods section of the manuscript. This leads to the question, could the fact that the IVs for measuring adult vs child body mass were based on a different method of estimating body size explain the difference we see in the results of the lifecourse MR? I understand that these IVs successfully predicted adult vs child BMI in 3 cohorts, but the measure of the exposure conferred by the genetic instrument in adults vs children is different. This should be highlighted in the methods, Results section and as a limitation of this study.
In terms of the outcome GWAS:
In line 105, could the authors specify how were leptin levels measured in ALSPAC? Was the method the same as that in DECODE? If the method was different, could this as well induce any bias in the MR estimates?
In terms of comparison between ALSPAC and DECODE, the Icelandic population of DECODE may have a distinct genetic architecture from ALSPAC or other European cohorts. This could introduce bias due to population stratification when using instruments for the exposure that comes from European meta-analyses. Is there another adult proteomic GWAS with available leptin levels which can be used to replicate the results in DECODE?
Line 138: in the multivariable MR analyses, which were the other variables tested as exposures (ie other than the adiposity variants for children or adults?) -this part should be clarified in both methods and Results section. I understand that adulthood and childhood body size were the two exposure variables, based on the DAGs in Figure 1. It would be helpful to put the DAGs in the two boxes entitled "Genetic variants" the GWAS source of the genetic variants and specify: " genetic variants for adulthood adiposity" or "genetic variants for childhood adiposity" depending on the analysis. Also, could the authors explain in the legend the interpretation of the colours of the arrows (ie black vs red?).
Line 144: Could the authors specify if in the tissue partitioned MR analysis the IVs were for adult BMI?
Line 167: in the phrase: "We firstly estimated the total effect of childhood adiposity on circulating leptin using data measured in ALSPAC participants at mean age 9.9 years in the lifecourse", please specify that you are referring to a univariate MR analysis.
In Tables S3 and S5, please provide the p-value of the intercept of the MR-Egger, as well as the Cohrane Q p-values for IVW and MR-Egger, and based on these results, please comment on the presence or absence of evidence of pleiotropy in the IVs used in the MR analyses.
Discussion: It would be nice to further elaborate on the hypothesis explaining the finding in regards to the indirect effect of childhood adiposity on adult leptin levels. In line 239, the authors explain this finding by "individuals in a population remaining overweight for many years in the lifecourse". The effect of early-life adiposity remains after adjustment for adult adiposity. Can the results of the tissue-partitioned MR (in terms of the sole effect of brain BMI SNPs on leptin levels in childhood vs a composite effect of adipose and brain tissue IVs on adult leptin levels) inform us on a possible hypothesis explaining the above phenomenon? Could early-life adiposity be associated with specific hypothalamic responses persisting in adulthood?
In regards to the sensitivity analysis on the effect of tissue-partitioned BMI on visceral vs subcutaneous fat, the authors could provide further explanation on the relationship between leptin secretion and fat distribution providing a rationale for this analysis.
https://doi.org/10.7554/eLife.84646.sa1
Author response
Essential revisions:
1) It might not fit directly with the proof of concept aim of the manuscript, but this study could be a nice opportunity to test the opposite association, ie if leptin affects adiposity at different life stages. The relationship between BMI and leptin levels is complex as nicely depicted in lines 248-253 of the discussion. In the introduction, it is stated that leptin acts in the hypothalamus to regulate appetite. If the retroaction works, the regulation of appetite is expected to decrease appetite and food intake, and maintain BMI to a normal level. The knock-outed mice for leptin or congenital leptin deficiency in humans result in uncontrolled satiety and obesity. A bidirectional MR of Steiger filtering in the forward MR could answer this question.
Many thanks for this suggestion. We have now conducted an additional analysis to evaluate the effect of circulating leptin levels on adulthood BMI using a cis-acting protein quantitative trait loci (pQTL) located in the LEP gene as an instrumental variable:
Author response table 1
StudyExposureOutcomeΒSEP
deCODECirculating leptinBMI0.0240.0390.541
This provided comparatively weaker effect estimates between circulating leptin levels in adulthood on BMI. pQTL data from the deCODE study was used for this analysis as there were no genome-wide corrected pQTL (i.e. P<5x10-8) in the Fenland study at this locus.
However, as the reviewer mentions this work is outside the scope of this current manuscript. Further research investigating this hypothesis is therefore necessary to robustly evaluate time-varying and tissue-dependent relationships once the relevant data become accessible.
2) In the discussion could the authors say if there are any other examples of already analysed or potentially interesting indirect life course effects ie expand on reference 26? Can they provide other examples of tissue-partitioned effects either already shown or potentially relevant? Can they suggest examples of other issues that this combined approach could address? This could give readers an even better idea of how these new approaches could be used.
We have added references to site-specific cancer endpoints where our lifecourse approach has previously provided evidence of an indirect effect of childhood adiposity (page 15):
“Evidence supporting indirect effects using this approach, as in this study for adulthood leptin, have been found previously for various cardiovascular (30) and site-specific cancer endpoints (31, 32).”
As recommended by Reviewer #2, we have also added some discussion regarding interpretation of findings from both approaches together (page 16):
“Taken together with the evidence of an indirect effect highlighted by our lifecourse MR analysis, these findings suggest that leptin may have long term consequences for appetite suppression. This in turn has an influence on excess body weight which may start in childhood and then can be sustained into later life.”
We have also expanded on further applications of this approach to page 17:
“In particular, applications of a combined approach using both lifecourse and tissue-partitioned MR will likely be most powerful for exposures which have been analysed by GWAS in large samples at distinct timepoints in the lifecourse (e.g. childhood and adulthood) where the functionally important tissue types have been well characterized by previous studies.”
Reviewer #1 (Recommendations for the authors):
I don't find a lot that needs to be addressed.
I could not find Supplementary notes 1 and 2.
Many thanks for your comments to help refine this manuscript. We have now incorporated Supplementary Notes 1 and 2 into the main article file as requested by the editorial team at eLife.
In the discussion could the authors say if there are any other examples of already analysed or potentially interesting indirect life course effects ie expand on reference 26?
We have now added examples of indirect lifecourse effects as suggested to page 15 of the manuscript:
“Evidence supporting indirect effects using this approach, as in this study for adulthood leptin, have been found previously for various cardiovascular (30) and site-specific cancer endpoints (31, 32).”
Can they provide other examples of tissue-partitioned effects either already shown or potentially relevant?
Other examples of tissue-partitioned effects have now been described on page 17:
“For example, we previously found evidence that the brain tissue-derived variants are predominantly responsible for the effect of BMI on both cigarette smoking and lung cancer (8).”
Any suggestions/examples for other issues that this combined approach could address?
This could give readers an even better idea of how these new approaches could be used.
We have expanded on further applications of this approach to page 17:
“In particular, applications of a combined approach using both lifecourse and tissue-partitioned MR will likely be most powerful for exposures which have been analysed by GWAS in large samples at distinct timepoints in the lifecourse (e.g. childhood and adulthood) where the functionally important tissue types have been well characterized by previous studies.”
Reviewer #2 (Recommendations for the authors):
This is an interesting study exploring lifecourse effects of adiposity on leptin levels, and using tissue-partitioned MR instruments to study the effects of BMI on leptin levels. While the study question is appealing, the methods are novel and they have been nicely applied in the context of the present study, and the results are interesting, I find that certain parts of the manuscript could be further clarified.
Also, it might not fit directly with the proof of concept aim of the manuscript, but this study could be a nice opportunity to test the opposite association, ie if leptin affects adiposity at different life stages. The relationship between BMI and leptin levels is complex as nicely depicted in lines 248-253 of the discussion. In the introduction, it is stated that leptin acts in the hypothalamus to regulate appetite. If the retroaction works, the regulation of appetite is expected to decrease appetite and food intake, and maintain BMI to a normal level. The knock-outed mice for leptin or congenital leptin deficiency in humans result in uncontrolled satiety and obesity. A bidirectional MR of Steiger filtering in the forward MR could answer this question.
Many thanks for this suggestion. We have now conducted an additional analysis to evaluate the effect of circulating leptin levels on adulthood BMI using a cis-acting protein quantitative trait loci (pQTL) located in the LEP gene as an instrumental variable:
This provided comparatively weaker effect estimates between circulating leptin levels in adulthood on BMI. pQTL data from the deCODE study was used for this analysis as there were no genome-wide corrected pQTL (i.e. P<5x10-8) in the Fenland study at this locus.
However, we believe this work is outside the scope of this current manuscript. Further research investigating this hypothesis is therefore necessary to robustly evaluate time-varying and tissue-dependent relationships once the relevant data become accessible.
Below are my point-by-point comments:
Abstract:
Methods: When the authors say in the results: "along the causal pathway", do they mean that they adjusted for adult body size in multivariable MR? If yes, please add this to the methods section of the abstract.
We have clarified this point on page 2 as suggested:
“Genetic instruments for childhood and adult adiposity were incorporated into a multivariable MR (MVMR) framework to estimate lifestage specific effects on leptin levels measured during early life (mean age:10 years) in the Avon Longitudinal Study of Parents and Children (ALSPAC) and in adulthood (mean age:55 years) using summary-level data from the deCODE Health study.”
The units of change in exposure that confer the betas in the leptin outcome are not exposed in the abstract or in the manuscript (see additional comment on this below). This raises a challenge in directly comparing the two betas (ie in the childhood vs adulthood MR analysis).
Units of change have now been added to the abstract (1 standard deviation change in circulating leptin levels). The reviewer makes a valid point that using SD change makes comparisons between childhood and adulthood estimates challenging given that the measures of leptin derived from these cohorts will differ in terms of how they vary across populations. We have emphasized this point on page 8:
“Although effect estimates from these summary-level data can be interpreted as a 1-SD change in normalized plasma leptin levels, we note that direct comparisons between estimates derived from childhood measures of leptin in ALSPAC should not be drawn given the various sources of heterogeneity between these measures.”
In the conclusion, the phrase "as well as raising implications for the gene-environment equivalence assumption in MR". It is not clear how this phrase is justified by the analyses presented in the abstract. It is explained in the discussion of the paper, but I would suggest omitting it from the abstract conclusion.
We have omitted this section of the abstract as recommended.
Some specifications are needed in regards to the exposure and the outcome of GWAS sources.
For the exposure GWAS: In the BMJ paper cited as the source of the SNPs for adult and childhood body size, it is described that adult body size was measured based on the measured body mass index during adulthood (mean age 56.5) while child body mass was self-reported perceived body size at age 10. This is important information that should appear in the methods section of the manuscript. This leads to the question, could the fact that the IVs for measuring adult vs child body mass were based on a different method of estimating body size explain the difference we see in the results of the lifecourse MR? I understand that these IVs successfully predicted adult vs child BMI in 3 cohorts, but the measure of the exposure conferred by the genetic instrument in adults vs children is different. This should be highlighted in the methods, Results section and as a limitation of this study.
We have added further detail to the childhood and adult body size instruments section as suggested on page 6:
“Briefly, genetic instruments derived in the UK Biobank study based on self-reported body size at age 10 and measured adulthood body mass index (11) have been shown to separate clinically measured childhood and adult BMI in 3 independent cohorts (ALSPAC (11), the Young Finns Study (14) and the Trøndelag Health (HUNT) study (15)).”
We have also added details to the methods section to describe analyses conducted in our original paper which suggested that recall bias related to the childhood measure is unlikely to have influenced the conclusions of our lifecourse MR approach. This point has also been highlighted in our discussion on page 17:
“Moreover, the childhood adiposity instruments are based on recall data, which is why they required validation in 3 independent cohorts as described in our methods section.”
In terms of the outcome GWAS:
In line 105, could the authors specify how were leptin levels measured in ALSPAC? Was the method the same as that in DECODE? If the method was different, could this as well induce any bias in the MR estimates?
Further detail to leptin measures analysed in this study are now reported on page 7 and 8. We have also emphasized that the SomaLogic measure of circulating leptin previously provided a high degree of concordance with an alternative measure using the Olink platform, reinforcing its reliability as a measure of this protein given that Olink measures have previously been validated using the same technology as the one used in the ALSPAC study (immunosorbent assay (ELISA)):
“Leptin was measured by an in-house enzyme-linked immunosorbent assay (ELISA) validated against commercial methods. Analyses in ALSPAC were undertaken on a final sample size of 4,155 individuals after removing those without genetic data and withdrawn consent.”
“Genetic estimates on adulthood circulating leptin levels were obtained from a study of 10,708 individuals enrolled in the Fenland study. Full details have been described elsewhere (24). Leptin was measured using the SomaScan v4 assay which applies single-stranded oligonucleotides aptamers with specific binding affinities to protein targets. This assay has also been reported to provide a very highly correlated measure of circulating leptin using the antibody based Olink platform (r=0.95) (25). The Fenland study was approved by the National Health Service (NHS) Health Research Authority Research Ethics Committee (NRES Committee-East of England Cambridge Central, ref. 04/Q018/19). All participants provided written informed consent.”
In terms of comparison between ALSPAC and DECODE, the Icelandic population of DECODE may have a distinct genetic architecture from ALSPAC or other European cohorts. This could introduce bias due to population stratification when using instruments for the exposure that comes from European meta-analyses. Is there another adult proteomic GWAS with available leptin levels which can be used to replicate the results in DECODE?
Many thanks for this suggestion. Since this manuscript was submitted, a protein GWAS study conducted in the Fenland study has made their full summary statistics available (Pietzner et al., Science (2021)). We have there now undertaken an additional analysis using Leptin data derived from the UK based Fenland cohort which we have included as our primary analysis, with deCODE analyses still included as a further validation analysis.
Line 138: in the multivariable MR analyses, which were the other variables tested as exposures (ie other than the adiposity variants for children or adults?) -this part should be clarified in both methods and Results section. I understand that adulthood and childhood body size were the two exposure variables, based on the DAGs in Figure 1. It would be helpful to put the DAGs in the two boxes entitled "Genetic variants" the GWAS source of the genetic variants and specify: " genetic variants for adulthood adiposity" or "genetic variants for childhood adiposity" depending on the analysis. Also, could the authors explain in the legend the interpretation of the colours of the arrows (ie black vs red?).
We have now clarified in the figure legends that multivariable MR analyses requires genetic variants for all exposures to be modelled simultaneously (as well as interpretation regarding the colours of arrows).
Line 144: Could the authors specify if in the tissue partitioned MR analysis the IVs were for adult BMI?
We have now clarified on page 6 that these IVs were based on adult BMI.
Line 167: in the phrase: "We firstly estimated the total effect of childhood adiposity on circulating leptin using data measured in ALSPAC participants at mean age 9.9 years in the lifecourse", please specify that you are referring to a univariate MR analysis.
We have updated this sentence accordingly (page 9):
“We firstly conducted univariable MR to estimate the total effect of childhood adiposity on circulating leptin using data measured in ALSPAC participants at mean age 9.9 years in the lifecourse (Β=1.28 per 1-standard deviation (SD) change in leptin levels per change in body size category, 95% CI=1.10 to 1.46, P=2x10-41).”
In Tables S3 and S5, please provide the p-value of the intercept of the MR-Egger, as well as the Cohrane Q p-values for IVW and MR-Egger, and based on these results, please comment on the presence or absence of evidence of pleiotropy in the IVs used in the MR analyses.
These additional statistics have been added to Supplementary Tables and referenced on page 12:
“Cochran’s Q-statistics for these analyses, as well as those derived in Lifecourse MR analyses, can be found in Supplementary File 1l, along with intercept terms for MR-Egger analyses which did not suggest horizontal pleiotropy may be biasing conclusions.”
Discussion: It would be nice to further elaborate on the hypothesis explaining the finding in regards to the indirect effect of childhood adiposity on adult leptin levels. In line 239, the authors explain this finding by "individuals in a population remaining overweight for many years in the lifecourse". The effect of early-life adiposity remains after adjustment for adult adiposity. Can the results of the tissue-partitioned MR (in terms of the sole effect of brain BMI SNPs on leptin levels in childhood vs a composite effect of adipose and brain tissue IVs on adult leptin levels) inform us on a possible hypothesis explaining the above phenomenon? Could early-life adiposity be associated with specific hypothalamic responses persisting in adulthood?
We have added some further discussion regarding this point to page 16:
“Taken together with the evidence of an indirect effect highlighted by our lifecourse MR analysis, these findings suggest that leptin may have long term consequences for appetite suppression. This in turn has an influence on excess body weight which may start in childhood and then can be sustained into later life.”
In regards to the sensitivity analysis on the effect of tissue-partitioned BMI on visceral vs subcutaneous fat, the authors could provide further explanation on the relationship between leptin secretion and fat distribution providing a rationale for this analysis.
Discussion regarding this point can be found on page 8:
“We postulate that these findings highlight a role for appetite regulation and energy expenditure mechanisms as of fundamental importance in the effect of adiposity on leptin levels.”
https://doi.org/10.7554/eLife.84646.sa2
Article and author information
Author details
1. Tom G Richardson
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom
Contribution
Data curation, Formal analysis, Visualization, Methodology, Writing - original draft, Writing - review and editing
For correspondence
Tom.G.Richardson@bristol.ac.uk
Competing interests
TGR is an employee of GlaxoSmithKline outside of this work
ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7918-2040
2. Genevieve M Leyden
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom
Contribution
Data curation, Formal analysis, Methodology, Writing - review and editing
Competing interests
No competing interests declared
3. George Davey Smith
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom
Contribution
Conceptualization, Supervision, Funding acquisition, Methodology, Writing - review and editing
Competing interests
No competing interests declared
ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1407-8314
Funding
Medical Research Council (MC_UU_00011/1)
• George Davey Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Acknowledgements
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This research was conducted at the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. This publication is the work of the authors and TGR will serve as guarantor for the contents of this paper. This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).
Ethics
ALSPAC: Written informed consent was obtained for all study participants. Ethical approval for this study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. DeCODE: All participants from this study who donated samples gave informed consent, and the National Bioethics Committee of Iceland approved the study, which was conducted in agreement with conditions issued by the Data Protection Authority of Iceland (VSN_14-015).
Senior Editor
1. Matthias Barton, University of Zurich, Switzerland
Reviewing Editor
1. Edward D Janus, University of Melbourne, Australia
Reviewers
1. Edward D Janus, University of Melbourne, Australia
2. Despoina Manousaki, CHU Sainte-Justine, Canada
Version history
1. Received: November 2, 2022
2. Preprint posted: November 30, 2022 (view preprint)
3. Accepted: October 8, 2023
4. Version of Record published: October 25, 2023 (version 1)
Copyright
© 2023, Richardson et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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1. Tom G Richardson
2. Genevieve M Leyden
3. George Davey Smith
(2023)
Time-varying and tissue-dependent effects of adiposity on leptin levels: A Mendelian randomization study
eLife 12:e84646.
https://doi.org/10.7554/eLife.84646
Further reading
1. Epidemiology and Global Health
Tianyi Huang
Insight
A large observational study has found that irregular sleep-wake patterns are associated with a higher risk of overall mortality, and also mortality from cancers and cardiovascular disease.
1. Epidemiology and Global Health
Lachlan Cribb, Ramon Sha ... Matthew P Pase
Research Article
Background:
Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort.
Methods:
The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0–100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models.
Results:
The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern.
Conclusions:
Irregular sleep-wake patterns are associated with higher mortality risk.
Funding:
National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer’s Association (2018-AARG-591358), and the Banting Fellowship Program (#454104). | {
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Fighting the Signs of Aging: Rose Hip Extract's Anti-Aging Impact and Scientific Evidence
2024-07-04
1. Botanical Origin and History
1. Botanical Origin and History
Rose hip extract is derived from the seeds and surrounding tissues of the rose fruit, specifically from species of the genus Rosa. The history of rose hips dates back centuries, with evidence of their use found in various ancient civilizations.
Origin
The botanical origin of rose hips can be traced to the wild rose species that grow in temperate regions across the Northern Hemisphere. These plants have been naturalized in many parts of the world due to their ornamental value and the versatility of their fruits.
History
The use of rose hips has a rich history, with records indicating their consumption and medicinal use in ancient Greece, Rome, and Egypt. Rose hips were valued for their high vitamin C content, which was particularly important during times when fresh fruits and vegetables were scarce, such as in the winter months. They were used to prevent and treat scurvy, a disease caused by a deficiency of vitamin C.
In traditional medicine, rose hips were also used for their anti-inflammatory properties, to soothe digestive issues, and to support skin health. The use of rose hips in skincare can be traced back to the time of Cleopatra, who was known to have used rose hip oil for its rejuvenating effects on the skin.
Cultural Significance
Throughout history, roses have held significant cultural and symbolic importance. They have been associated with love, beauty, and perfection. The use of rose hip extract in skincare and medicine reflects the broader appreciation of roses for their aesthetic and therapeutic qualities.
Modern Usage
In modern times, rose hip extract has gained popularity due to advancements in research and technology that have allowed for a deeper understanding of its nutritional composition and benefits. Today, it is widely used in the cosmetic and pharmaceutical industries for its potential to improve skin health and appearance.
The journey of rose hip extract from its ancient origins to its current status as a sought-after ingredient in skincare and wellness products is a testament to the enduring value of natural resources and the continuous quest for knowledge about their applications.
2. Nutritional Composition and Benefits
2. Nutritional Composition and Benefits
Rose hip extract is derived from the seeds and fruits of the rose plant, specifically the species Rosa canina, commonly known as the dog rose. This extract is a rich source of essential nutrients that contribute to its numerous health and beauty benefits.
Nutritional Composition:
1. Vitamin C: Rose hip extract is one of the richest natural sources of vitamin C, which is crucial for immune system support, skin health, and collagen production.
2. Lycopene: This powerful antioxidant is known for its skin-protective properties and its role in reducing inflammation.
3. Beta-Carotene: A precursor to vitamin A, beta-carotene is essential for maintaining healthy skin and eyes.
4. Vitamin E: An antioxidant that helps protect cells from damage and supports skin health.
5. Folic Acid: Important for cell growth and repair, folic acid is particularly beneficial during pregnancy.
6. Linoleic Acid: An essential fatty acid that helps to maintain skin's moisture barrier and reduce inflammation.
Benefits:
1. Skin Health: The high concentration of vitamin C in rose hip extract promotes collagen synthesis, which is vital for maintaining skin elasticity and reducing the appearance of fine lines and wrinkles.
2. Anti-Inflammatory: The presence of lycopene and other antioxidants helps to reduce inflammation, which can be beneficial for conditions like acne and rosacea.
3. Moisturizing: The fatty acids in rose hip extract help to hydrate the skin, improving its texture and reducing dryness.
4. Cell Regeneration: Vitamins and antioxidants in the extract support skin cell turnover, leading to a brighter and more even complexion.
5. Immune Support: Vitamin C is a well-known immune booster, and its high presence in rose hip extract can help strengthen the body's defense against infections.
6. Eye Health: Beta-carotene contributes to maintaining good eye health and may help prevent age-related macular degeneration.
Incorporating rose hip extract into your diet or skincare routine can provide these benefits, making it a valuable addition for overall health and well-being.
3. Skincare Applications of Rose Hip Extract
3. Skincare Applications of Rose Hip Extract
Rose hip extract is a powerhouse ingredient in skincare, renowned for its rejuvenating and restorative properties. Derived from the seeds of rose fruits, this extract is rich in vitamins, antioxidants, and essential fatty acids that are beneficial for maintaining healthy, youthful skin. Here are some of the key skincare applications of rose hip extract:
3.1. Moisturization
One of the primary benefits of rose hip extract is its ability to hydrate the skin. It contains essential fatty acids, particularly linoleic acid, which helps to maintain the skin's moisture barrier, preventing dryness and flakiness.
3.2. Anti-Inflammatory Properties
The anti-inflammatory compounds in rose hip extract, such as vitamin C and essential fatty acids, can help soothe irritated skin and reduce redness and inflammation, making it suitable for sensitive and acne-prone skin types.
3.3. Scar Reduction
Rose hip extract is known for its ability to reduce the appearance of scars and stretch marks. The high concentration of vitamin C and essential fatty acids promotes collagen production, which helps to rebuild and repair damaged skin tissue.
3.4. Anti-Aging
As an anti-aging ingredient, rose hip extract helps to combat signs of aging by promoting collagen synthesis and reducing the appearance of fine lines and wrinkles. Its antioxidant properties also protect the skin from environmental damage, such as UV radiation and pollution.
3.5. Brightening and Even Skin Tone
The presence of vitamin C in rose hip extract makes it an effective brightening agent. It helps to reduce hyperpigmentation and even out skin tone by inhibiting the production of melanin, the pigment responsible for skin discoloration.
3.6. Acne Treatment
The anti-inflammatory and antibacterial properties of rose hip extract can help to reduce acne breakouts by calming inflammation and killing acne-causing bacteria.
3.7. Sensitive Skin Care
Due to its gentle and soothing nature, rose hip extract is an excellent ingredient for sensitive skin care products. It can help to strengthen the skin's barrier function and reduce the appearance of redness and irritation.
3.8. Hair Care
Beyond skincare, rose hip extract can also be used in hair care products for its nourishing and strengthening properties. It can help to improve hair health, reduce breakage, and promote a healthy shine.
Incorporating rose hip extract into your skincare routine can provide a range of benefits, from hydration and anti-inflammatory effects to anti-aging and skin brightening properties. It is a versatile ingredient that can be used in various formulations, such as creams, serums, masks, and even hair care products.
4. Anti-Aging Properties and Clinical Studies
4. Anti-Aging Properties and Clinical Studies
As we age, our skin undergoes a natural process of degradation, leading to wrinkles, fine lines, and a dull complexion. Rose hip extract has been a topic of interest in the field of dermatology due to its potential anti-aging properties. The following sections delve into the anti-aging properties of rose hip extract and the clinical studies that support its efficacy.
Anti-Aging Properties
1. Collagen Synthesis: One of the primary reasons for skin aging is the decline in collagen production. Rose hip extract is rich in vitamin C, which is essential for collagen synthesis. Collagen is the protein that gives skin its structure and elasticity.
2. Antioxidant Activity: The high content of antioxidants in rose hip extract, including vitamin C and carotenoids, helps neutralize free radicals that can cause oxidative stress and contribute to the aging process.
3. Hydrating Effects: The omega-3 and omega-6 fatty acids present in rose hip extract can help maintain skin hydration, which is crucial for preventing dryness and flakiness that often accompany aging skin.
4. Skin Repair: The regenerative properties of rose hip extract can aid in repairing damaged skin cells, promoting a smoother and more youthful appearance.
5. Firming and Toning: By improving skin elasticity and reducing the appearance of fine lines and wrinkles, rose hip extract can give the skin a firmer and more toned look.
Clinical Studies
Several clinical studies have been conducted to evaluate the effectiveness of rose hip extract in combating signs of aging:
1. A Study on Wrinkles: A clinical study published in the "Journal of Clinical and Aesthetic Dermatology" found that a topical application of rose hip oil significantly reduced the appearance of wrinkles and improved skin texture after 12 weeks of treatment.
2. Improvement in Skin Hydration: Another study demonstrated that the use of rose hip extract led to a significant increase in skin hydration levels, which is beneficial for reducing the appearance of fine lines and improving skin suppleness.
3. Effects on Photoaging: Photoaging is skin damage caused by prolonged exposure to the sun. A clinical trial showed that rose hip extract can help reduce the signs of photoaging, including pigmentation and uneven skin tone.
4. Safety and Tolerance: Most studies have reported that rose hip extract is well-tolerated by the skin, with minimal side effects, making it a safe option for long-term skincare use.
5. Comparative Studies: Some studies have compared the effects of rose hip extract with other popular anti-aging ingredients, such as retinol, and found that it offers similar benefits with fewer side effects.
In conclusion, the anti-aging properties of rose hip extract, supported by clinical studies, highlight its potential as a natural and effective ingredient in skincare routines aimed at reducing the signs of aging. However, it is important to remember that individual results may vary, and it is always recommended to consult with a dermatologist before incorporating new products into your skincare regimen.
5. Rose Hip Oil vs
5. Rose Hip Oil vs Rose Hip Extract
Rose hip oil and rose hip extract are both derived from the seeds and fruits of the rose plant, specifically the species Rosa canina. While they share a common origin, they differ in their production process, consistency, and applications. Understanding these differences can help you choose the right product for your specific needs.
5.1 Production Process
Rose Hip Oil:
Rose hip oil is produced by cold pressing the seeds of the rose hip fruit. This method preserves the natural nutrients and fatty acids present in the seeds. The oil is typically golden or orange in color and has a light, non-greasy texture.
Rose Hip Extract:
Rose hip extract is made by extracting the active compounds from the rose hip fruit, including the seeds, using a solvent or through a process like CO2 extraction. This results in a concentrated form of the beneficial components, often in the form of a liquid or powder.
5.2 Consistency and Form
Rose Hip Oil:
Being an oil, it has a smooth, liquid consistency that is easily absorbed by the skin. It is versatile and can be used on its own or mixed with other skincare products.
Rose Hip Extract:
The consistency of rose hip extract can vary depending on the production method. It can be found in liquid, powder, or even gel form. It is highly concentrated and often used in smaller quantities in skincare formulations.
5.3 Applications
Rose Hip Oil:
- Moisturizing and hydrating the skin
- Reducing the appearance of scars and stretch marks
- Nourishing and strengthening hair
- Massage oil for relaxation and skin health
Rose Hip Extract:
- Topical application in skincare products for anti-aging and skin repair
- Oral supplements for overall health and well-being
- Ingredient in hair care products for promoting hair growth and strength
5.4 Benefits
Rose Hip Oil:
- Rich in essential fatty acids, particularly omega-3 and omega-6, which are vital for skin health
- Contains vitamin A (retinol), which promotes cell turnover and collagen production
- Antioxidant properties to protect against environmental damage
Rose Hip Extract:
- High concentration of vitamins C and E, which are potent antioxidants
- May have a stronger effect on skin repair and regeneration due to its concentrated form
- Can be used in various formulations for targeted skincare treatments
5.5 Choosing Between the Two
The choice between rose hip oil and rose hip extract depends on your specific needs and preferences:
- If you are looking for a moisturizing and nourishing oil for daily use, rose hip oil may be the better option.
- If you want a concentrated product for targeted treatments or prefer a non-oily texture, rose hip extract could be more suitable.
Both rose hip oil and rose hip extract offer numerous benefits for skin and hair health. By understanding their differences, you can make an informed decision and incorporate the right product into your skincare routine for optimal results.
6. How to Incorporate Rose Hip Extract into Your Routine
6. How to Incorporate Rose Hip Extract into Your Routine
Incorporating rose hip extract into your daily routine is a simple and effective way to take advantage of its numerous benefits. Here are some practical steps to include rose hip extract in your skincare and wellness regimen:
1. Start with a Patch Test:
Before applying any new product to your face, it's important to perform a patch test. Apply a small amount of rose hip extract to the inside of your elbow or behind your ear and wait 24 hours to see if any adverse reaction occurs.
2. Cleanse Your Skin:
Begin with a gentle cleanser to remove dirt, oil, and makeup from your skin. This prepares your skin to better absorb the nutrients from the rose hip extract.
3. Apply Rose Hip Extract:
After cleansing, pat your skin dry and apply a few drops of rose hip extract to your face and neck. You can use it directly from the bottle or mix it with a moisturizer for a more hydrating effect.
4. Use in the Morning and Night:
For optimal results, apply rose hip extract both in the morning and before bed. It can be used as a serum or mixed with your regular moisturizer.
5. Sun Protection:
Since rose hip extract can make your skin more sensitive to the sun, always apply a broad-spectrum sunscreen with an SPF of 30 or higher when going out during the day.
6. Combine with Other Skincare Products:
Rose hip extract can be mixed with other skincare products like moisturizers, face masks, or even DIY skincare recipes to enhance their benefits.
7. Use in Hair Care:
Not only for the skin, but rose hip extract can also be used in hair care routines. It can be added to hair masks or mixed with carrier oils for a nourishing hair treatment.
8. Monitor Your Skin's Response:
Pay attention to how your skin reacts to the rose hip extract. If you notice any irritation or discomfort, discontinue use and consult a dermatologist.
9. Consistency is Key:
For the best results, consistency is crucial. Make rose hip extract a regular part of your skincare routine to see long-term benefits.
10. Adjust as Needed:
As with any skincare product, your skin's needs may change over time. Adjust the frequency and method of application as needed based on your skin's response.
By following these steps, you can seamlessly integrate rose hip extract into your skincare routine, harnessing its powerful properties to improve your skin's health and appearance.
7. Popular Brands and Products Containing Rose Hip Extract
7. Popular Brands and Products Containing Rose Hip Extract
Rose hip extract has gained significant popularity in the skincare and health supplement industries due to its numerous benefits. Many brands have recognized the potential of this natural ingredient and have incorporated it into their products. Here, we will discuss some of the popular brands and products that contain rose hip extract.
1. Trilogy Certified Organic Rosehip Oil: This New Zealand-based brand is well-known for its pure and organic rosehip oil. It is a lightweight oil that is easily absorbed by the skin and is rich in essential fatty acids and antioxidants.
2. The Ordinary Rose Hip Seed Oil: A popular skincare brand known for its affordable and effective products, The Ordinary offers a rose hip seed oil that is highly concentrated and contains a blend of omegas and antioxidants.
3. Andalou Naturals 1000 Roses Rosewater Face Tonic: This face tonic combines rose hip extract with other rose-based ingredients to provide hydration and a refreshing boost to the skin.
4. Jurlique Rose Hip Herbal Recovery Oil: Jurlique is a brand that focuses on botanical ingredients, and their rose hip oil is designed to nourish and repair the skin, reducing the appearance of scars and fine lines.
5. 100% Pure Rosehip Oil: This brand offers a 100% pure rosehip oil that is cold-pressed to preserve its natural properties. It is a versatile oil that can be used for both skincare and hair care.
6. Heritage Store Rose Hip Oil: This brand offers a high-quality, organic rose hip oil that is rich in vitamins and essential fatty acids, making it ideal for skin rejuvenation and hydration.
7. Naobay Organic Rosehip Oil: Naobay's rosehip oil is cold-pressed and organic, ensuring that it retains all its natural benefits. It is suitable for all skin types and is particularly beneficial for mature skin.
8. Kora Organics Rosehip Oil: Founded by Miranda Kerr, Kora Organics offers a rosehip oil that is packed with antioxidants and is designed to improve skin texture and tone.
9. Acure Radically Rejuvenating Rosehip Oil: Acure's rosehip oil is free from parabens, sulfates, and phthalates, making it a safe and effective option for those looking for a natural skincare product.
10. Weleda Pomegranate Regenerating Firming Serum: While not exclusively a rose hip product, Weleda's serum contains rose hip extract along with other nourishing ingredients to help firm and regenerate the skin.
These are just a few examples of the many brands and products that incorporate rose hip extract into their formulations. When choosing a product, it's essential to consider the purity and quality of the rose hip extract used, as well as the overall formulation to ensure it meets your skincare needs and preferences.
8. Safety and Side Effects of Rose Hip Extract
8. Safety and Side Effects of Rose Hip Extract
Rose hip extract, derived from the seeds of rose fruits, is generally considered safe for topical application and consumption. However, as with any natural product, there are certain factors to consider regarding its safety and potential side effects.
Allergic Reactions
While rare, some individuals may experience allergic reactions to rose hip extract. Symptoms can include skin irritation, redness, itching, or swelling. If you have a known allergy to roses or other plants in the Rosaceae family, it's advisable to perform a patch test before using rose hip extract on a larger area of skin.
Phototoxicity
Certain components in rose hip extract may increase the skin's sensitivity to sunlight, leading to phototoxic reactions. To minimize this risk, it's important to use sunscreen when applying products containing rose hip extract, especially during the day.
Oral Consumption
When consumed orally, rose hip extract is generally safe for most people. However, it's essential to follow the recommended dosage and consult with a healthcare professional, especially if you are pregnant, breastfeeding, or have pre-existing health conditions.
Interactions with Medications
Rose hip extract may interact with certain medications, such as blood thinners or diabetes medications, due to its potential effects on blood sugar levels and blood clotting. Always consult with a healthcare professional before incorporating rose hip extract into your routine if you are taking any medications.
Quality and Purity
The safety of rose hip extract can also be influenced by the quality and purity of the product. Ensure that you choose products from reputable brands that follow good manufacturing practices and provide third-party testing results to verify the absence of contaminants.
Conclusion
While rose hip extract is generally safe for most individuals, it's important to be aware of potential side effects and take necessary precautions. Always perform a patch test, use sunscreen, follow recommended dosages, and consult with a healthcare professional to ensure a safe and effective skincare routine.
9. Conclusion and Future Perspectives
9. Conclusion and Future Perspectives
In conclusion, Rose Hip Extract is a multifaceted botanical ingredient with a rich history and a wide range of applications, particularly in skincare and nutrition. Its high concentration of vitamins, antioxidants, and essential fatty acids makes it a powerful tool for promoting skin health, addressing signs of aging, and supporting overall well-being.
As research continues to uncover the potential benefits of Rose Hip Extract, it is likely to gain even more popularity in the beauty and wellness industries. Future perspectives for Rose Hip Extract include:
1. Further Research: Continued scientific studies will help to better understand the full spectrum of benefits and optimal usage levels of Rose Hip Extract. This may lead to new formulations and applications in both skincare and health supplements.
2. Sustainability: As the demand for natural and sustainable ingredients grows, Rose Hip Extract, derived from the by-products of rose cultivation, aligns perfectly with eco-friendly practices. Efforts to ensure sustainable harvesting and production will be crucial.
3. Innovation in Formulations: With the growing understanding of its benefits, there is potential for Rose Hip Extract to be incorporated into a wider variety of products, such as hair care, oral health products, and even food supplements.
4. Personalized Skincare: As the skincare industry moves towards more personalized and targeted treatments, Rose Hip Extract's versatility could be leveraged to create products tailored to individual skin types and concerns.
5. Global Accessibility: Efforts to make Rose Hip Extract more accessible globally will be important, ensuring that its benefits can be enjoyed by a wider audience, including those in regions where it is less commonly found.
6. Regulatory Compliance: As with any natural ingredient, ensuring that Rose Hip Extract meets regulatory standards for safety and efficacy will be essential to maintain consumer trust and expand its use in various markets.
7. Education and Awareness: Increasing consumer awareness about the benefits of Rose Hip Extract will be key to its continued success. This includes educating on how to incorporate it into routines and the importance of choosing high-quality products.
The future of Rose Hip Extract looks bright, with its potential to contribute to healthier, more radiant skin and a more sustainable beauty industry. As consumers become more discerning and seek out natural, effective solutions, Rose Hip Extract is poised to play a significant role in meeting these demands.
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-3,374,016,513,942,789,000 | Skip to main content
Spheroids derived from the stromal vascular fraction of adipose tissue self-organize in complex adipose organoids and secrete leptin
Abstract
Background
Adipose tissue-derived stromal vascular fraction (SVF) harbors multipotent cells with potential therapeutic relevance. We developed a method to form adipose spheroids (AS) from the SVF with complex organoid structure and enhanced leptin secretion upon insulin stimulation.
Methods
SVF was generated from the interscapular brown adipose tissue of newborn mice. Immunophenotype and stemness of cultured SVF were determined by flow cytometry and in vitro differentiation, respectively. Spheroids were generated in hanging drops and non-adherent plates and compared by morphometric methods. The adipogenic potential was compared between preadipocyte monolayers and spheroids. Extracellular leptin was quantified by immunoassay. Lipolysis was stimulated with isoprenaline and quantified by colorimetric methods. AS viability and ultrastructure were determined by confocal and transmission electron microscopy analyses.
Results
Cultured SVF contained Sca1 + CD29 + CD44 + CD11b- CD45- CD90- cells with adipogenic and chondrogenic but no osteogenic potential. Culture on non-adherent plates yielded the highest quantity and biggest size of spheroids. Differentiation of AS for 15 days in a culture medium supplemented with insulin and rosiglitazone resulted in greater Pparg, Plin1, and Lep expression compared to differentiated adipocytes monolayers. AS were viable and maintained leptin secretion even in the absence of adipogenic stimulation. Glycerol release after isoprenaline stimulation was higher in AS compared to adipocytes in monolayers. AS were composed of outer layers of unilocular mature adipocytes and an inner structure composed of preadipocytes, immature adipocytes and an abundant loose extracellular matrix.
Conclusion
Newborn mice adipose SVF can be efficiently differentiated into leptin-secreting AS. Prolonged stimulation with insulin and rosiglitazone allows the formation of structurally complex adipose organoids able to respond to adrenergic lipolytic stimulation.
Introduction
Adipose stromal vascular fraction (SVF) is a heterogeneous and not fully characterized cell population [1, 2] that includes plastic-adherent mesenchymal stem cells reminiscent of those obtained from the bone marrow and umbilical cord cell suspensions [3,4,5]. Adipose tissue-derived stromal cells (ASCs) have self-renewal capacity and can be differentiated into various mesenchymal lineages. ASCs have been studied for tissue engineering and cell therapy due to their anti-inflammatory, antifibrotic, antiapoptotic, and proangiogenic activities [3, 6,7,8].
Classic mesenchymal stem cells (MSC) can self-organize as three-dimensional (3D) aggregates called multicellular spheroids. These structures have reportedly greater multilineage potential, secretion of therapeutic factors, and resistance against hypoxia compared to MSC cultured in monolayers (2D) [9,10,11]. Also, 3D cultures have cell-to-cell and cell-to-extracellular matrix interactions that allow them to reach cellular density, morphology, and functionalities that are more similar to animal tissues [12,13,14]. Although various 3D culture methods are available, the production of spheroids with scales, reproducibility, and costs suitable for clinical use, is still suboptimal [15]. Nevertheless, the therapeutic effects of MSC spheroids have been assessed in myocardial, vascular, bone, and glandular tissue regeneration, as well as in models of limb ischemia and wound healing [16].
Previous studies have demonstrated the feasibility of developing AS [17, 18]; however, only a few of them have shown adipokines gene expression or secretion [17, 19,20,21]. No study has assessed AS internal ultrastructure nor their functional response to lipolytic stimuli yet.
Herein, we report a method to form AS from the SVF of the interscapular adipose tissue of newborn mice, which maximizes leptin secretion and lipolytic response in comparison with traditional monolayers of differentiated adipocytes. We found that the AS generated by this method have a complex structure, with a multilayer organoid architecture and prolonged cell viability.
Material and methods
Raw data and details on protocols and materials are fully available upon request to the corresponding author (Víctor Cortés, vcortesm@uc.cl)
Animals
Agpat2+/+ neonatal mice with mixed C57BL6/J and 126 backgrounds [22] were used for SVF isolation, spheroid formation, and adipogenic differentiation. Agpat2+/+ mice are morphologically normal and develop no metabolic abnormalities. By contrast, Agpat2−/− littermates develop lipodystrophy and were used for alternative investigations in the laboratory. Mice were kept with 12-h light and dark cycle, free access to water, and a standard chow diet. In total, 64 newborn mice, corresponding to 7 independent litters, were used in the present study. Animal procedures were approved by the animal safety and bioethics committee of Pontificia Universidad Católica de Chile ((1) Title of the approved project: “Terapia celular para la lipodistrofia congénita generalizada tipo 1”; (2) Name of the institutional approval committee or unit: Comité Ético Científico para el Cuidado de Animales y Ambiente; (3) Approval number: 190531003; (4) Date of approval June 19, 2021).
Isolation and culture of the stromal vascular fraction (SVF) from the interscapular adipose tissue of newborn mice
Newborn mice were euthanized by decapitation, and interscapular adipose tissue was surgically resected, rinsed with phosphate-buffered saline (PBS), and incubated with digestion buffer (300 µl, 0.2% collagenase type II in 25 mM KHCO3 buffer, 12 mM KH2PO4, 1.2 mM MgSO4, 4.8 mM KCl, 120 mM NaCl, 1.2 mM CaCl2, 5 mM glucose, 2.5% BSA and 1% penicillin/streptomycin, pH 7.4) for 45 min at 37 °C. The digestion product was passed through a 100-µm mesh. ACK buffer (500 µl, 4 min at room temperature) was added to eliminate blood cells and centrifuged at 300 g for 5 min. Pelleted cells were resuspended in culture medium (1 ml, DMEM F12 10% FBS, 1% Antibiotic–Antimycotic (Gibco, #cat 15,240,062), pH 7.2) and filtered through a 40-µm mesh, followed by centrifugation, resuspension in culture medium and seeded in 24-well plates. Upon confluence, cells were detached with 0.25% trypsin for 5 min and seeded for expansion in a culture surface three times the original area, repeating this process for 3 rounds in total. Cells were kept in an incubator at 37 °C with 5% CO2.
Immunophenotyping of cultured SVF
For immunophenotyping, after two passages 50,000 cells/ml were incubated with unconjugated anti-CD16/CD32 antibody (eBioscience, #cat. 14,016,185) diluted in αMEM supplemented with 5% FBS medium for 20 min on ice, followed by 45-min incubation with anti-Sca1-APC-conjugated (eBioscience, #cat. 175,981), CD29-FITC-conjugated (eBioscience, #cat. 110,291), CD44-PE-Cy5-conjugated (BD Pharmingen, #cat. 553,135), CD90-PE-conjugated (eBioscience, #cat. 12,090,081), CD11b-efluor660-conjugated (eBioscience, #cat. 500,110) or CD45 (BD Pharmingen) antibodies, for flow cytometry analysis (CYAN ADP, Dako Cytomation, Carpinteria, CA). Summit V 4.3 software was used for data acquisition and processing. Cells labeled with the corresponding isotype antibodies were used as autofluorescence controls.
Osteogenic and chondrogenic differentiation
Differentiation potential was determined as previously described [23]. For osteogenic differentiation, SVF was seeded in plastic dishes with a density of 25,000 cells/cm2 in αMEM medium supplemented with 10% FBS and 80 µg/ml gentamicin and cultured for 24 h. Osteogenic differentiation was induced with αMEM supplemented with 10% FBS, 80 µg/ml gentamicin, 0.1 µM dexamethasone, 50 µg/ml 2-phosphate ascorbate, and 10 mM β-glycerol phosphate. This medium was changed twice a week, and the formation of hydroxyapatite deposits was assessed with alizarin red staining after 18 days of osteogenic induction. For chondrogenic differentiation, 50,000 cells were concentrated in 10 µl of αMEM supplemented with 10% FBS and 80 µg/ml gentamicin. Cell agglomerates were incubated in the center of a 1.9 cm2 culture well for 2 h. Chondrogenic differentiation was induced with αMEM supplemented with 10% FBS, 80 µg/ml gentamicin, 0.1 µM dexamethasone, 50 µg/ml ascorbate 2-phosphate, 0.5 U/ml insulin and 10 ng/ml TGF-β3. Differentiation media was changed twice a week, and the formation of glycosaminoglycans was verified with 1.7 safranin-O staining at the day 10 of differentiation.
Alizarin red staining
Cultures subjected to osteogenic differentiation were fixed with 70% ethanol, rinsed with PBS, and incubated with 40 mM alizarin red for 10 min at room temperature. After rinsing with double distilled water, cells were incubated with PBS for 15 min at room temperature. Stained cultures were visualized and photographed using a bright field microscope.
Safranin-O staining
Cells were fixed in 70% ethanol and incubated in 0.1% safranin-O for 5 min at room temperature and serially rinsed with double distilled water, 70% ethanol, and 100% ethanol. Stained cultures were visualized and photographed using a bright field microscope.
Spheroid formation in hanging drops
Previously expanded SVF cultures were serially diluted from a starting concentration of 750,000 cells/ml (DMEM-F12 supplemented with 10% FBS and 1% antibiotic-antifungal). Ten microliters of drops containing 7,500, 3,750, or 1,875 cells, respectively, was deposited on the internal surface of an inverted cap (96-well plate). Additionally, a single 50-µl PBS drop was placed in the bottom of each well for humidification purposes. Caps loaded with drops were carefully replaced on the plates and incubated for 48 h to allow cells aggregation by gravity. Only 60 drops were created per 96-well plate because peripheral wells were kept unused due to the higher evaporation rates compared to central wells. Cells were maintained at 37 °C, with a 5% CO2 atmosphere.
Spheroid formation on low-attachment plates
SVF cultures were serially diluted from a starting suspension of 750,000 cells/ml (DMEM-F12 supplemented with 10% FBS and 1% antibiotic-antifungal) to 375,000, 187,500, or 100,000 cells/cm2. Cells were seeded on low-attachment 24-well plates (SPL, #cat. 32,024) in 1 ml of DMEM-F12 supplemented with 10% FBS and 1% gentamycin/streptomycin. After 24 h, cultures were mechanically disaggregated by gentle pipetting, diluted (1:5) in culture medium, seeded in new low-attachment 24-well plates (SPL, #cat. 32,024) (500 µl per well), and incubated for additional 24 h. Spheroids were counted and transferred to 35-mm low-adhesion dishes (SPL, #cat. 11,035), with a maximum of 1,000 spheroids per dish. The medium was changed every 48 h, and floating spheroids were recovered by spontaneous decantation (2 min) in 15-ml conical tubes at room temperature. The medium was carefully removed by manual pipetting, and spheroids were resuspended in fresh culture medium and seeded on new low-attachment plates.
Spheroids counting
To compare hanging drops and low-adherence plate method yields, spheroids were manually counted by bright-field microscopy after 48 h of culture. For this, spheroids from 4–10 hanging drops or 3–10 wells (24-well low-attachment plates) were pooled and decanted in 15-ml conical tubes, the medium was discarded, and the spheroids were resuspended in 1 to 5 ml of DMEM F12 SFB 10% medium. Three hundred microliters of spheroids suspension was transferred to a 35-mm mesh plate (SPL, #cat.110350) for counting and then recovered. The total number of spheroids was expressed relative to the resuspension volume. Spheroids’s concentration was adjusted to 1,000 spheroids/ml. From this suspension, 1 ml was used for mRNA extraction, 200 µl for cryosection, and 100 µl for leptin quantification or microscopy analyses.
Spheroids size determination
Spheroid size (feret) was determined at 48 h of formation. Spheroids formed in 20–30 hanging drops, or 1–3 wells of 24-well low-attachment plates, were photographed using a bright-field microscope with 10 × magnification, from 2 independent experiments. Photographs were analyzed by batch analysis using a custom-designed macro in image J software (Additional file 1: Table S1). Image processing included scaling, luminance correction and threshold-based binary transformation in spheroids with feret equal to or greater than 50 µm.
Comparison between cultured monolayers and spheroids
SVF cultures from individual newborn mice were adjusted to 750,000 cells/ml. Cultures were partitioned in a 24-well low attachment plate for spheroid formation (1 ml per well), a 24-well regular adherent plate for microscopy and leptin quantification of cultured monolayer (500 µl per well of a 1/10 dilution), and a 6-well regular adherent plate for RNA extraction of cultured monolayer (3 ml of a 2/15 dilution).
Adipogenic differentiation of SVF monolayers and spheroids
SVF cultured in regular plastic plates (monolayers) and 48-h formed spheroids were differentiated into mature adipocytes with a two-phase protocol (herein named “i20”) previously used in our laboratory [24]. Adipogenesis was induced with DMEM-F12 supplemented with 10% FBS, 1% antibiotic-antifungal solution, 500 nM dexamethasone, 125 nM indomethacin, 0.5 mM IBMX, 1 nM rosiglitazone, 1 nM T3 and 20 nM insulin. After 48 h, induction medium was replaced by maintenance medium (DMEM-F12 supplemented with 10% FBS, 1% antibiotic–antimycotic solution, 1 nM T3 and 20 nM insulin). To increase leptin secretion, new protocols were tested. First, an insulin dose–response curve was performed with 0 nM (i0), 2,000 nM (i2,000) and 10,000 nM (i10,000) insulin, in both induction and maintenance phases. In the following experiments, 1 nM rosiglitazone was added into i2,000 maintenance medium. This latter procedure was dubbed “InRo”.
Expression profile of mature adipocyte markers
Total RNA from a 6-well plate monolayer culture or a suspension of 1,000 spheroids was extracted with TRIzol™ (Invitrogen, #cat. 15,596,018), following manufacturer's instructions. Contaminant DNA was digested (TURBO DNAse, Invitrogen, #cat. AM1907), and total RNA was reverse-transcribed (Applied Biosystems, #cat. 4,368,814). The abundance of adipogenic markers Cebpb, Pparg, Plin1, Adipoq and Lep was quantified in 100 ng of cDNA (Step One thermocycler, Applied Biosystems). PCR primers are indicated in Additional file 2: Table S2. Relative expression was calculated with the ΔΔCt method with cyclophilin as reference gene.
Leptin quantification
Leptin concentration in conditioned medium of differentiated monolayers (300 µl in 24-well plates) and AS (pool of 3 wells in 96-well plate with 100 spheroids each) was measured by ELISA (Mouse Leptin ELISA, Millipore, #cat. EZML-82 K). Cells were collected for DNA quantification (Easy-DNA™ gDNA Purification Kit, Invitrogen, #cat. K180001) to normalize leptin concentration by total DNA. Four biological replicates per group were analyzed.
Lipolysis stimulation and glycerol quantification
50–100 AS were incubated for 3 h in color-free DMEM-F12 medium (Gibco, #cat. 21,041,025) with or without 1 μM isoprenaline (Sigma #cat. I5627). After incubation, the medium was collected for glycerol quantification with a colorimetric kit (Sigma, #cat TR0100). Spheroids were collected for gDNA extraction with Easy DNA™ kit to normalize glycerol measurement.
Fluorescence microscopy
Floating living AS were incubated for 10 min in DMEM-F12 medium supplemented with 10% FBS and 1% antibiotic–antimycotic solution with Hoechst (1: 1,000), Bodipy (1: 1,000), and propidium iodide (1: 1,000) for determining nuclei, neutral lipids, and viable cells, respectively. AS were fixed with 4% buffered PFA for 24 h at room temperature. Fixed spheroids were decanted by centrifugation for 5 min at 300 g and rinsed 3 times with PBS. Images were captured by laser scanning confocal microscopy with an LSM 880 ZEISS microscope with Airyscan detection, with 1708 × 1708 resolution. Objective Plan-Apochromat 10 × NA 0,45; 32 channels GaAsP PMT spectral detector; filter set 38 GFP (EX 470/40 EM 525/50), filter set 43 Cy3 (EX 545/25 EM 605/70) and filter set 43 DAPI (EX 365 EM 445/50). Setting and configuration by ZEN 2.3 black and ZEN Blue software. Whole spheroids were analyzed by Z-stack imaging with heights in the range of 50 to 100 µm and a cross-sectional area of approximately 400 × 400 µm. Surface reconstruction of spheroids was made by Imaris Viewer software.
Transmission electron microscopy
AS at day 15 of differentiation were fixed with 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.0, and incubated with 1% OsO4. AS were dehydrated with ethanol and infiltrated with Epon 812 epoxy resin. Ultrathin sections (80 nm) were obtained, and grids were visualized with Phillips Tecnai 12 (BioTwin) electron microscope and photographed with a CIS CCD Megaview G2 camera (Olympus Corp). Individual images corresponding to different fields were assembled to compose an overview of a single whole spheroid.
Statistical analysis
Statistical analysis and plotting were performed with GraphPad Prism 8. The abundance of adipocyte markers and leptin secretion in monolayers and spheroids were compared by two-way ANOVA, considering a quantitative variable (the relative amount of specific mRNAs or leptin concentration) and two nominal variables (days of differentiation and culture format or differentiation protocol). Spheroids feret showed high heteroscedasticity (Brown-Forsythe; F(5,1427) = 88,2; p < 0,0001). To overcome this difficulty, log transformation was applied, and every combination of culture format and cell concentration was considered as an independent group, analyzed by Welch-ANOVA with Games–Howell multiple comparison post-test.
Results
Immunophenotype and differentiation potential of the stromal vascular fraction of newborn mice interscapular adipose tissue
The procedures for harvesting and culturing mesenchymal stem cells (MSC) [2, 25] are analogous to those reported for stromal vascular fraction/preadipocytes (SVF) [22, 24]; however, the phenotypical and functional overlapping between MSC, adipocyte stem cells (ASC) and preadipocytes remains controversial [26]. We assessed the cellular identity of newborn mice interscapular adipose tissue SVF following the minimal criteria for MSC identification defined by the International Society for Cell Therapy: (1) adhesion to plastic under standard culture conditions, (2) expression of putative MSC surface markers, and absence of surface markers characteristics of other lineages, and (3) ability to differentiate into osteoblasts, adipocytes, and chondroblasts [23]. Although a consensus for the immunophenotype of murine MSC is lacking, it is conventionally accepted that they must express Sca1, CD29, CD44, and CD90, while CD11b and CD45 must be absent [27, 28].
After two passages, SVF cultures were analyzed by flow cytometry. As shown in Fig. 1A, SVF from newborn mice interscapular adipose tissue was composed of cells expressing Sca1 (95.6%), CD29 (92.4%) and CD44 (90.7%), while expression of CD11b, CD45 and CD90 was either low (6.75%) or very low (0.68%; 0.21%), respectively. These results suggest that the cultured SVF used in this study is composed of mesenchymal cells with a low or very low contribution of hematopoietic cells. However, given the low expression levels of CD90, these cells do not strictly fit with MSC definition.
Fig. 1
figure 1
Characterization of primary culture derived from the stromal vascular fraction of interscapular adipose tissue of newborn mice. A Analysis by flow cytometry for expression of the Sca1, CD29, CD44, CD90, CD11b, and CD45 markers. In each panel, the red line represents the marker of interest, the gray line the isotype control, and the upper part indicates the percentage of the negative and positive populations for each marker. In vitro adipogenic (B), chondrogenic (C), and osteogenic (D) differentiation was assessed by oil Bodipy staining of neutral lipids, safranin-O staining of cartilage, and alizarin red staining of hydroxyapatite, respectively. In each case, the result of the differentiation is shown in the upper image and undifferentiated control in the lower image. E Corresponds to a positive control of osteogenic differentiation using human MSC stained with alizarin red
Next, we characterized the differentiation potential of newborn mice interscapular adipose tissue SVF. Previously, we have reported the differentiation potential of this SVF into both white and brown adipocyte-like cells [22, 24]. Herein, we confirmed adipocyte differentiation by lipid droplets buildup (Fig. 1B). Chondrogenic capacity [7, 29, 30], was also verified by the formation of cells stained with Safranin O (Fig. 1C). By contrast, our SVF was unable to undergo osteogenic differentiation as indicated by the absence of hydroxyapatite crystals laden cells (Fig. 1D), indicating that cultured SVF derived from the interscapular adipose tissue of newborn mice contains bipotential mesenchymal cells rather than properly multipotential MSCs. As a positive control of osteogenic differentiation we differentiated human MSC that efficiently accumulated hydroxyapatite crystals (Fig. 1E).
Spheroids formation from the stromal vascular fraction of newborn mice interscapular adipose tissue
First, we compared the efficiency of SVF spheroids formation using hanging drops and low-adherence methods. Serial dilutions (750,000, 375,000 and 187,500 cell/ml) of SVF were used as starting material. The hanging drops method produced homogeneous spheroids after 24 h in all cell dilutions tested (Fig. 2A). By contrast, the non-adherent plate method resulted in scarce isolated spheroids in cultures that were started with 187,500 cells/ml, whereas those started with 375,000 cells/ml produced a combination of isolated spheroids and heterogeneous cell aggregates. Cultures started with 750,000 cells/ml were able to generate a layer of irregular density with numerous cellular aggregates. Importantly, when these cultures were dispersed by pipetting, re-diluted, and seeded for an additional 24 h, they yield numerous isolated and well-formed spheroids (Fig. 2A).
Fig. 2
figure 2
Formation of murine SVF-derived spheroids in low adherence plates and hanging drop cultures. A Serial dilutions of 750,000, 375,000, and 187,500 SVF cells/ml (from upper to bottom row) were seeded in low attachment plates (LA, left panels) or hanging drops (right panels), as indicated, and spheroids formation was checked after 24 and 48 h. Only in low attachment plate experiments, cultures were mechanically disaggregated after 24 h, diluted 1:5 and re-plated for additional 24-h incubation. All images were taken using a bright-field microscope with 10 × magnification. 100 µm scale bar size. B Spheroids formed in low attachment plates or hanging drop were photographed (bright field microscopy) and subjected to particle analysis with ImageJ software. The number of analyzed spheroids was: 1) hanging drop: 187,500 cells/ml N = 235; 375,000 cells/ml N = 234; 750,000 cells/drop N = 475; 2) low attachment plate: 187,500 cells/ml N = 37; 375,000 cells/ml N = 48; 750,000 cells/ml N = 404. Size distribution by calculation of feret expressed as mean and standard deviation of each population. Welch-ANOVA; W (5, 224) = 129.9; p < 0.0001; Games–Howell post-test. C Yield of spheroid formation per formation unit with 4 runs per group. Two-way ANOVA, Droplet vs LA Plate: F (1, 18) = 266.7; P < 0.0001; Initial cell concentration: F (2, 18) = 19.74; P < 0.0001; Tukey's post-test. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001; ns not significant
Total yield and spheroids size were characterized at 48 h of formation with an automatized morphometric protocol (Additional file 1: Table S1). We found significant differences in spheroids feret (Welch-ANOVA test; W (5,288) = 138.8; p < 0.0001) between formation methods and SVF initial dilution. Spheroids formed in non-adherent plates ranged from 100 to 400 µm feret with those formed at an initial concentration of 750,000 cells/ml being the largest (260.4 ± 170.5 µm) (Fig. 2B). Importantly, it has been previously reported that spheroids up to 500 µm in diameter have proper oxygen and nutrient diffusion [31], suggesting that the spheroids formed with our procedures must have preserved viability and functionality.
Although the hanging drop method produced more homogeneous spheroids, the yield of each individual drop was low (~ 10 spheroids per drop). On the contrary, the non-adherent plate method allowed the formation of abundant and large spheroids. Therefore, we concluded that culturing 750,000 cells/ml in low adherence plates was the best method for generating SVF spheroids, with a mean of 189 spheroids per well in a 24-well plate (Fig. 2C). Considering that the interscapular adipose tissue of a single newborn mouse yield ~ 9.3 million SVF cells (data not shown), we estimated a total yield of ~ 2,433 spheroids per animal.
Optimization of leptin secretion by differentiated adipose spheroids (AS)
Upon a classic adipogenic protocol (henceforth called “i20” because of 20 nM insulin concentration in the induction and maintenance media), monolayers of newborn mice interscapular adipose tissue SVF can be differentiated into adipocyte-like cells, reaching a maximum of 80% of lipid-laden cells between days 7 and 10 after adipogenic induction [24, 32].
Herein we found that adipogenic differentiation of SVF spheroids with i20 protocol also resulted in neutral lipid build-up and expression of markers of mature adipocytes (Additional file 3: Fig. S1A–B). However, adipokines gene expression, particularly leptin, was lower than in parallel cultures of differentiated SVF monolayers and in the white adipose tissue of adult mice (Additional file 3: Fig. S1B).
Insulin promotes leptin secretion in mature adipocytes [33,34,35,36]; however, the range of insulin concentrations used in the literature is extremely wide (0.2 to 12,052 nM) [37]. We tested the effect of different insulin concentrations (0 nM (i0 medium); 20 nM (i20 medium); 2,000 nM (i2,000 medium) or 10,000 nM (i10,000 medium)) on AS differentiation efficiency and leptin expression.
As expected, all markers increased in direct proportion to insulin concentration up to 2,000 nM insulin (Additional file 4: Fig. S2). Since PPARγ is the master regulator of adipogenesis [38], we tested the effect of adding the PPARγ agonist rosiglitazone during the early and late phases of differentiation. We reasoned that as PPARγ levels remain very low in AS differentiated with the i20 protocol, particularly during early differentiation phases (Additional file 3: Fig. S1A), stimulation with rosiglitazone only during the first 48 h after adipogenic induction, as used in classic adipogenic protocols, should be insufficient to promote maximal adipogenic differentiation. We also considered that rosiglitazone diffusion towards spheroid inner portions might require longer times to enable adipocyte differentiation in large spheroids. Therefore, we compared AS differentiated with i20 and i2,000 protocols with those formed with a modified i2,000 protocol, maintaining 1 nM rosiglitazone throughout the entire differentiation procedure (herein dubbed as "InRo" protocol). Adipogenic differentiation was monitored by quantifying mRNA levels of Cebpb, Pparg, Plin1, Adipoq and Lep.
Adipocyte markers Pparg, Plin1, Adipoq and Lep were significantly increased along adipogenic differentiation with the three tested protocols (two-way ANOVA; Pparg, medium: F (2, 36) = 14,37 P < 0,0001; differentiation days (DD): F (3, 36) = 6,137 P = 0,0018; Interaction: F (6, 36) = 3,596 P = 0,0068; Plin1, medium: F (2, 25) = 9,513 P = 0,0008; DD: F (2, 25) = 10,03 P = 0,0006; interaction: F (4, 25) = 7,862 P = 0,0003; Adipoq, medium: F (2, 25) = 8,431 P = 0,0016; DD: F (2, 25) = 3,379 P = 0,0503; interaction: F (4, 25) = 2,040 P = 0,1194; Lep, medium: F (2, 23) = 12,95 P = 0,0002; DD: F (2, 23) = 5,061 P = 0,0151; F (4, 23) = 6,482 P = 0,0012) (Fig. 3A). However, the AS differentiated with InRo protocol showed the highest mRNA levels of Pparg (P < 0.05), Plin1 (P < 0.001), Adipoq (P < 0.01), and Lep (P < 0.01) at any time point of analysis, compared to those differentiated with i20 or i2,000 procedures (Fig. 3A). Importantly, leptin mRNA levels were even higher in AS differentiated with InRo protocol (day 15) compared with adult mice WAT (2.09 ± 0.69-fold change).
Fig. 3
figure 3
Effect of insulin and rosiglitazone on adipogenic differentiation and leptin secretion of AS. A Quantification of mRNA levels of Cebpb, Pparg, Plin1, Adipoq, and Lep relative to white adipose tissue (WAT) of adult mice (dotted line) in AS at 15 days of adipogenic differentiation with cocktail i20, i2.000, or InRo. Data are presented as mean ± standard deviation, N = 4 per group. Two-way ANOVA with Tukey's post-test. B Leptin concentration in conditioned medium (100 spheroids per group, 48 h) at day 15 of adipogenic differentiation. N = 3. One-way ANOVA (F (2, 6) = 7.539; p = 0.0231). * p < 0.05; ns: not significant
To assess adipokines secretion, we quantified leptin concentration in the conditioned medium of differentiated AS. Concordant with our gene expression analysis, we found that leptin concentration was significantly higher in the medium of InRo-differentiated AS compared to all other differentiation protocols (i20: 0,11 ± 0,06 ng/ml; i2,000: 0,49 ± 0,33 ng/ml; InRo: 2.92 ± 1.63 ng/ml) (one-way ANOVA, F (2, 6) = 7,539; P = 0,0231; post-Tukey test with P < 0.05 in all comparisons of InRo medium against i20 or i2.000) (Fig. 3B).
Thus, we found that the addition of rosiglitazone across adipogenic differentiation of AS (InRo protocol) determines increased abundance of mature adipocyte markers and leptin concentration in conditioned medium compared to protocols that restrict rosiglitazone to the induction phase only.
Also, we tested whether InRo protocol improves the adipogenic differentiation of SVF monolayers. As shown in Fig. 4A, the mRNA levels of Pparg, Plin1, Adipoq and Lep progressively increased to levels similar to WAT until day 5 of differentiation but showed a decrease thereafter (Fig. 4A). By contrast, AS presented higher mRNA levels of Pparg (2-way ANOVA with Tukey's post-test; P = 0.0021), Plin1 (P = 0.0055) and Lep (P = 0.0012) up to the day 15 of differentiation compared to differentiated adipocyte monolayers.
Fig. 4
figure 4
AS differentiated with InRo medium have increased expression of adipogenic markers and leptin secretion compared to adipocyte monolayers and increased glycerol secretion in response to isoprenaline stimulation. A Quantification of mRNA levels relative to adult mouse WAT (dotted line). Data are presented as mean ± standard deviation. N = 4 per group. Two-way ANOVA with Tukey's post-test. B Leptin concentration in conditioned medium (48 h) normalized to total DNA. Data are presented as mean ± standard deviation. N = 4 per group. C Differentiated adipocyte monolayers and AS at day 15 of differentiation were incubated with DMEM-F12 medium plus 10% SFB in the absence of insulin and rosiglitazone for 48 h. Next, cells were incubated for additional 48 h with DMEM-F12 medium plus 10% SFB in the presence or absence of 2,000 nM insulin. The conditioned medium (48 h) was harvested for leptin quantification and normalized by total DNA. Data are presented as mean ± standard deviation. N = 4 per group. A significant effect for culture format was determined (F (1, 12) = 21.93; p = 0.0005). D 2D adipocytes and AS were differentiated with InRo protocol and incubated by 3 h in color-free DMEM-F12 medium with or without 1 μM isoprenaline. Conditioned medium was collected for glycerol determination by colorimetric methods and AS. Cells were collected for total DNA extraction and quantification. Data are represented as mean ± standard deviation. N = 3 for monolayer cultures and 5 for AS groups. There was a significant increment in glycerol secretion in response to isoprenaline stimulation (F (1, 11) = 8.357; P = 0.0147). Two-way ANOVA with Tukey's post-test. * p < 0.05; ** p < 0.01; ns: not significant; N.D.: non-detected
Next, we compared the abundance of leptin in the conditioned media of differentiated adipocytes monolayers and AS generated in parallel from the same original SVF. Given the variability in sizes and therefore in the number of cells contained in the spheroids and monolayers, leptin concentration was normalized to total DNA content. We found a significant effect of differentiation time (two-way ANOVA; F (3, 24) = 4.375; P = 0.0136) and culture format (monolayers vs. AS) (F (1, 24) = 5.948; P = 0.0225) on leptin concentration, with no significant interactions between both factors (F (3, 24) = 1.029; P = 0.3974). Indeed, in both AS and monolayers leptin concentration increased over time, although the highest concentrations were observed in AS (Fig. 4B). Although no significant time point differences were observed on Tukey post-test, the effect of the culture format was especially noticeable after 15 days of differentiation, when leptin tended to decrease in adipocyte monolayers, in consistency with their lower leptin mRNA levels at this time point, but remained stable in differentiated AS.
To test whether continuous adipogenic stimulation was required for leptin secretion, differentiated monolayers and AS, generated in parallel from the same original SVF, were deprived of insulin and rosiglitazone for 48 h. Following this period, cultures were incubated for additional 48 h with DMEM-F12 and 10% FBS with or without 2,000 nM insulin. Importantly, after adipogenic deprivation leptin was only detected in cultured AS and was even higher than the observed after 15 days of differentiation (0.58 ± 0.36 ng / µg DNA with insulin or 0.57 ± 0.31 ng / µg DNA without insulin compared to 0.30 ± 0.22 ng / µg of DNA, two-way ANOVA; culture format: F (1, 12) = 21,93; P = 0,0005; Insulin: F (1, 12) = 1,746e-005; P = 0,9967; Interaction: F (1, 12) = 0,01,625; P = 0,9007), indicating that AS are able to preserve their adipose phenotype even after a prolonged deprivation of adipogenic stimuli in vitro (Fig. 4C).
A key physiological feature of WAT is its ability to release free fatty acids and glycerol in response to adrenergic stimulation as a result of the lipolytic hydrolysis of intracellular triglycerides, providing substrates for mitochondrial fatty acid beta-oxidation and gluconeogenesis [39, 40]. We assessed the ability of AS differentiated with InRo protocol to emulate this physiological response. For this, we measured glycerol released to the culture medium in response to isoprenaline in AS and monolayers of differentiated adipocytes derived from the same original SVF. As shown in Fig. 4D, we found a significant increase in the extracellular glycerol after isoprenaline stimulation that was ~ twofold higher in differentiated AS in comparison with adipocytes in monolayers, indicating that AS have preserved lipolytic responsivity to beta-adrenergic stimulation.
In conclusion, inRo protocol resulted in the generation of AS able to secrete leptin at higher levels than monolayers of differentiated adipocytes and to respond to a classical lipolytic stimulus to release glycerol to the extracellular medium. Importantly, leptin secretory capacity persisted even after 48 h of adipogenic stimuli deprivation, indicating a stable adipose phenotype and an improved potential to release adipokines in vitro and, eventually, after implantation in vivo.
Viability and internal ultrastructure of differentiated AS
To assess AS viability, we first determined plasma membrane indemnity by propidium iodide (PI) staining and confocal microscopy analysis. As shown in Fig. 5, only a few positive nuclei were stained with PI, whereas detergent-permeabilized AS showed homogeneous nuclear PI staining indicating proper penetration of this stain into permeabilized spheroids (Fig. 5). Therefore, these results indicate a high level of cellular viability during adipogenic differentiation of AS. Nevertheless, it is important to note that confocal microscopy only allows the evaluation of the outermost layers of AS (Fig. 6A and B), given its maximal penetration depth of ~ 50 µm [41, 42].
Fig. 5
figure 5
Three-dimensional structure and viability of AS differentiated with InRo protocol. SVF spheroids were subjected to adipogenic differentiation with the InRo protocol for 0, 5, and 15 days (DD0 to DD15, respectively). AS were stained for neutral lipids (Bodipy, green), dead cells (propidium iodide, PI, red) and nuclei (Hoechst, blue). Positive controls for PI staining were post-fixation AS permeabilized with Triton X-100 0.05%. 3D reconstruction and Z-projection based on Z-Stack is shown. Major divisions in 3D reconstruction grid and scale bar of 100 µm
Fig. 6
figure 6
AS differentiated with the InRo protocol have a complex inner structure. A 3D reconstruction of confocal Z-stack of AS at day 15 of adipogenic differentiation with InRo protocol and stained for nuclei (Hoechst, blue) and neutral lipid (Bodipy, green) detection. BF Ultrastructural analysis of AS at day 15 of differentiation with InRo protocol. (C and D) Reconstruction of cross-sectioned AS with a montage of images obtained with a magnification of 390x (scale bar of 100 µm). E Adipocytes with single and large lipid droplets (LD) in the periphery of the spheroids. Elongated cells (arrow) are organized in 1 to 3 layers of lipid-laden cells. F The center of AS shows no evidence of necrosis and cells with small lipid droplets (nucleus N1) or no lipid build up (nucleus N2) are embedded in abundant loose cellular matrix (ECM). Images in (E) and (F) were captured at 790 × magnification, 20 µm scale bar
To determine the viability of the innermost layers and to characterize the internal ultrastructure of AS, we performed transmission electron microscopy (TEM) analysis on sectioned AS on day 15 of differentiation. As shown in Fig. 6, differentiated spheroids have a complex internal structure, with lipid-laden and lipid-free cells included in abundant extracellular matrix (ECM) (Fig. 6C and D). Higher magnification showed a stratified organization with large unilocular cells present in the outermost layers of the AS (Fig. 6E, "LD"). Immediately under this adipocyte-like layer, there were 2 to 3 layers of elongated cells devoid of lipid droplets, resembling undifferentiated mesenchymal cells or fibroblasts [9, 14] (Fig. 6E, arrow). Towards the center of spheroids, lipid-laden cells were smaller compared to adipocyte-like cells present in the AS periphery (Fig. 6F, “N1”) and were intermixed with lipid droplets-free cells and loose ECM (Fig. 6F, “ECM”).
Abundant cells with large, pale, and irregular nuclei and prominent nucleoli were present (Fig. 7A). In these cells, the endoplasmic reticulum was prominent (Fig. 7A, "ER") and mitochondria were small and spherical (Fig. 7A, “M”). Also, these cells had abundant vesicles at the cytoplasmic periphery (Fig. 7A, asterisk). These features are reminiscent of the described ultrastructure of human MSC in muscle [43], bone marrow [44], subepicardial adipose tissue [45], and rat MSC [46].
Fig. 7
figure 7
Ultrastructural analysis of differentiated AS reveals a multilayer organization with different cell types and an organized extracellular matrix. A Elongated cells with few rounded mitochondria, extensive endoplasmic reticulum with distended cisternae and cytoplasmic vesicles (asterisk) likely correspond to undifferentiated preadipocytes. B Small lipid droplets towards the cellular poles of putative preadipocytes. 2 µm bar in A and B. C Adipocytes in advanced differentiation stages are characterized by glycogen granules near the lipid droplets, rounded cell shape, and displacement of the nucleus towards the cellular periphery. 10 µm scale bar. D Terminally differentiated adipocytes are characterized by a single giant lipid droplet and a “ring-shaped” cytoplasm surrounding it, with a crescent moon-shaped nucleus on the one side of the lipid droplet. 5 µm scale bar. E The contact zone between plasma membranes of two adjacent adipocytes shows abundant and well-defined individual caveolae and caveolae/clusters known as rosettes. Frame magnification in E showing 3 individual caveolae (black arrow) and two rosettes (white asterisk). F The extracellular matrix in the adjacent zone to the adipocyte shown in panel (D) shows thick and banded fibers with a parallel arrangement, interspersed by thinner fibers with a looser disposition. 1 µm scale bar in E and F. G-–H Towards the center of AS is abundant ECM with a loose appearance, with thin and dispersed fibers (G) intertwined with thicker and banded fibers (H). 500 nm scale bar in G and H. N, nucleus; ER, endoplasmic reticulum; M, Mitochondrion; LD, lipid droplet; G, Golgi complex; Gly, glycogen; ECM, extracellular matrix
Other cells showed numerous small lipid droplets (Fig. 7B, "LD") and scarce endoplasmic reticulum. Mitochondria were mostly spherical but occasionally elongated (Fig. 7B, "M"), the Golgi apparatus was well-defined (Fig. 7B, "G") and cytoplasmic vesicles were abundant. Glycogen granules were also present, mainly in the vicinity of large lipid droplets (Fig. 7C, “Gly”). As these ultrastructural features have been described in differentiating rat adipocytes [47], we propose that these cells correspond to adipocytes at the early phases of differentiation.
It is important to note that differentiated adipocytes in the outer layers of AS were unilocular, i.e., harbor a single giant lipid droplet, with the nucleus and cytoplasm displaced to the margin of the plasma membrane (Fig. 7D). In these cells, plasma membrane caveolae were abundant, especially in areas of intercellular contact (Fig. 7E). Unilocular morphology and abundant caveolae are both key morphological features of mature adipocytes that are rarely seen in classical bidimensional cultures of differentiated adipocytes.
ECM was particularly abundant at the center of AS, and it was formed by parallel fibers in close contact with both lipid-laden and lipid-free cells. Frequently, a combination of at least two types of ECM fibers was noted (Fig. 7F). In low cellularity areas, especially at the center of AS, ECM was composed either of fine and dispersed fibers (Fig. 7G) or thicker and banded fibers with a parallel organization (Fig. 7H). This is consistent with elastic fibers intermixed with collagen fibers; however, the molecular identity of ECM in AS remains to be determined.
Discussion
Herein we show that the SVF harvested from the interscapular adipose tissue of newborn mice is composed of mesenchymal cells with a differentiation potential toward adipocyte and chondrocyte but not osteoblast linage. We also show that this SVF can be used for AS formation either by the hanging drops or the low adherence plate method, and the latter yields the higher number and the biggest spheroids. Finally, maintaining rosiglitazone throughout the entire adipogenesis protocol results in highly viable, leptin-secreting, and lipolysis-responsive AS that also have a complex internal structure. In fact, AS consists of adipocyte precursors, adipocytes at various stages of differentiation, terminally differentiated unilocular adipocytes, as well as non-adipose cell types, all of them embedded in an organized extracellular matrix. At the molecular level, AS express mature adipocyte markers at levels equivalent to the WAT of adult mice, secrete leptin even after deprivation of adipogenic pharmacological stimulus, and release glycerol in response to stimulation with isoprenaline, indicating a preserved capacity to hydrolyze triglycerides in response to beta-adrenergic activation.
Available methods to form multicellular spheroids include: (1) cellular pellets, (2) culture under continuous shaking or rotation, (3) hanging drop culture, (4) low-adherence surface culture, (5) culture in the presence of external forces (electromagnetic field or ultrasound) and (6) microfluidic chambers or micro-molds [12]. Herein, we assessed hanging drop and low-adherence culture methods because they involve lower mechanical stress that otherwise may destroy adipocytes, given their intrinsic mechanical fragility and high buoyancy. We found that the formation of spheroids in low-adherence plates yields abundant (~ 2,00 spheroids per newborn mice) and large-sized (~ 300 μm) spheroids, suitable for in vitro and in vivo experimentation in mice.
During adipogenic differentiation, numerous small lipid droplets fuse to form a single large lipid droplet that displaces the nucleus and other organelles towards the cell periphery [47]. Although this morphological feature is a defining feature of mature white adipocytes, classical adipogenic protocols based on monolayer cultures fail to form unilocular cells. This outcome is likely the result of incomplete adipogenesis because of the limited time that lipid-laden cells can be maintained in monolayers. In fact, after day 7 of differentiation, we found a systematic and highly reproducible decrease in the abundance of mature adipocyte markers, as well as, in the proportion of lipid-laden cells. It is plausible that this simply occurs by the selective detachment of highly buoyant lipid-laden cells in this culture format. By contrast, given the cohesive structure of AS, this culture format offers multiple cell-to-cell and cell-to-ECM attaching sites, allowing the retention of fully differentiated-unilocular adipocytes.
Adipose tissue secretes more than 600 peptide hormones (adipokines) with diverse endocrine, autocrine, and paracrine actions. Leptin was the first adipokine to be described and has a central role in energy, lipid, and carbohydrate metabolism [48,49,50,51]. Nevertheless, the only approved therapeutical application for leptin is the control of metabolic complications in patients with genetic leptin deficiency or in patients with severe adipose tissue restriction (lipodystrophy) [52,53,54,55]. In these patients, leptin supplementation ameliorates insulin resistance, hyperglycemia, hypertriglyceridemia, hepatic steatosis, and female infertility [53, 56,57,58]. However, leptin supplementation remains unavailable in most low- and middle-income countries, and it requires lifelong daily injections, making it unaffordable in most cases. It is possible that implantation of heterologous or even autologous AS (after gene editing of pathogenic mutations) could offer a therapeutic alternative for leptin-deficient patients.
Conclusions
In this work, we developed a method for the efficient production of AS from the SVF of the mouse interscapular adipose tissue. These structures are composed of fully differentiated white adipocytes and a variety of other cells organized in a complex adipose organoid that can sustain prolonged adipogenic differentiation protocols in vitro and secrete leptin and undergo lipolysis after stimulation with insulin and beta-adrenergic agonists, respectively. Importantly, AS can resume leptin secretion after deprivation of adipogenic stimulus, indicating that they are suitable for implantation in animals and potentially sustain leptin production in mouse models of generalized lipodystrophy or genetic leptin deficiency.
Availability of data and materials
All the row data, including images and quantitative data, are available under request to the corresponding author (Victor Cortes, vcortesm@uc.cl).
Abbreviations
Adipoq:
Adiponectin
ASCs:
Adipose tissue-derived stromal cells
AS:
Adipose spheroids
ANOVA:
Analysis of variance
2D:
Bidimensional monolayer
Cebpb:
CCAAT/enhancer-binding protein beta
ECM:
Extracellular matrix
FBS:
Fetal bovine serum
Lep:
Leptin
MSC:
Mesenchymal stem cells
Plin1:
Perilipin 1
Pparg:
Peroxisome proliferator-activated receptor gamma
3D:
Three-dimensional
TEM:
Transmission electron microscopy
WAT:
White adipose tissue
IBMX:
3-Isobutyl-1-methylxanthine
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Acknowledgements
The authors want to acknowledge Advanced Microscopy Facility UMA UC for their valuable help with imaging methods.
Funding
This work was funded by Fondecyt grants 1181214 and 1221146 to V.C. and 1200287 to F.E., and Anillos de Ciencia y Tecnología ACT210039 to V.C. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
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Authors
Contributions
FR performed all the experiments and wrote the first draft of the manuscript. VC conceptualized the study, obtained funding, designed experiments, verified row data, edited the manuscript, and submitted the paper. FE provided scientific and technical advice, discussed the results, shared materials and expertise, and edited the manuscript. LG-H, A-MF, and PT performed experiments, analyzed raw data, discussed the results, and provided technical assistance and specific materials. All of the authors have read and approved the final manuscript.
Corresponding author
Correspondence to Víctor Cortés.
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All the animal procedures involved in study were approved by Pontificia Universidad Católica de Chile IACUC.
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Not applicable since no human subjects participated in this study.
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The authors declare that they have no competing interests.
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Supplementary Information
Additional file 1.
Complete set of Image J scripts used for the geometrical analysis of adipose spheroids.
Additional file 2.
Nucleotide sequence of PCR primers used in this work.
Additional file 3.
Supplemental Figure 1 Characterization of adipocyte monolayers and AS differentiated with classical “i20” protocol. (A) Representative confocal image of cross-sectioned AS (30 µm thickness) at day 10 of adipogenic differentiation, stained for neutral lipids (Bodipy, green) and nuclei (Hoechst, blue). Scale bar 100 µm. (B) Gene expression levels of adipocyte markers in differentiated adipocyte monolayers (blue) and AS (green). mRNA abundance is expressed as fold-change to the abundance of the corresponding mRNAs in adult mouse WAT (dotted line). Values correspond to mean and standard deviation, N = 4 per group. Two-way ANOVA with Tukey's post-test. *p<0.05; ** p < 0.01; ns not significant.
Additional file 4.
Supplemental Figure 2 Effect of insulin on the adipogenic differentiation of SVF derived spheroids.(A) SVF spheroids cultures were differentiated for 15 days with an adipogenic cocktails with growing insulin concentrations (i0 to i10,000 correspond to 0, 20, 2,000 or 10,000 nM of insulin, respectively). Pparg, Plin1, Adipoq and Lep mRNA levels were expressed as fold-change relative to adipocytes differentiated with the classic cocktail (i20, dotted line). Each bar corresponds to a pool of 4 independent cultures. (B) Leptin concentration in conditioned medium (final 48 hours) at day 15 of differentiation, with 100 spheroids per group, N = 3. One-way ANOVA (F (3, 8) = 7.307, p = 0.0111). * p < 0.05; ns: not significant; N.D. not detected.
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Robledo, F., González-Hodar, L., Tapia, P. et al. Spheroids derived from the stromal vascular fraction of adipose tissue self-organize in complex adipose organoids and secrete leptin. Stem Cell Res Ther 14, 70 (2023). https://doi.org/10.1186/s13287-023-03262-2
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-1,162,961,737,557,671,000 | Nutrition for hemorrhoids
Hemorrhoids ruthlessly itchy, sore, strongly disturbs significantly lowers self-esteem.The discomfort caused by this insidious disease, is incomparable to anything else.Get rid of the problem is much easier if the time to begin drug treatment.However, to fix the result can be only one way - to reconsider your diet.
Sometimes no treatment does not help, as the patient does not change the way of life.
1. Nutrition for hemorrhoids make the scheme recommended for the treatment of diseases of the gastrointestinal tract, burdened by chronic constipation.The diet for patients with diseases of the stomach, liver and gall duct syndrome with severe dyskinesia.The combination product must meet the physiological needs of the body of the sick person, to normalize bowel movements, speed up the natural emptying.
products, including substances that cause fermentation in the stomach with the release of large amounts of gases exacerbate hemorrhoids.Diet aimed mainly at eliminating the factors which can provoke putrefaction in the digestive system.
buy instagram followers
patients who have taken the path of getting rid of chronic constipation and hemorrhoids, long waits, and the rejection of yeast pastry, agreed with the dietitian.Starchy thick porridge also did not help to improve motility, as well as a variety of pastries.In the black list includes all products containing the substance tannin.Revisions are a drink, because without giving up coffee, black tea, jelly, cocoa, carbonated water to achieve rapid and sustained success in the treatment impossible.
2. Power hemorrhoids based on the method of cooking water, steamed in the oven.You can not smoke and cook food, eat sausages, and fresh milk.The diet is introduced a lot of fruits and vegetables in their raw form, unless contraindicated.Potato dishes are selected individually.Someone better suited baked tubers, and someone sees a beneficial effect on digestion of potato "in uniform".In some cases, nutritionists recommend to temporarily give up this basic for many people vegetable.
3. Power of hemorrhoids is aimed at increasing the volume of intestinal contents.Cellulose is the main component of the diet of the patient.Not representing the energy value for the body, carbon fiber structures start excretory mechanism intestinal system.Lack of dietary fiber in foods often gives rise to constipation and hemorrhoids.
Therefore, the use of beets, carrots, pumpkin, apple, artichoke, as a rich source of dietary fiber, certainly.Nutrition for hemorrhoids should be an active involvement in the menu legumes, cabbage, onions, cucumbers, greens, apricots, dried apricots, plums and prunes, peaches.The therapeutic effect of bringing cranberries, citrus fruits, cranberries, raspberries and strawberries, gooseberries, currants, mountain ash.It is useful to drink compote of wild rose, both fresh and dried, juices from fruits and vegetables mentioned above.Particularly rich in fiber, many varieties of nuts and seeds.Inclusion in the menu is not limited to tomato.
4. Diet for bowel disease, an exacerbation of hemorrhoids is based on high-quality dairy products.According to medical research, it is enough for about a month to eat yogurt, cottage cheese and sour cream to stop the process in the stomach bloating and putrefaction.So an analysis of urine for indole derivatives and phenolic compounds.Dairy products have a medicinal effect in the reduction of microflora, as they represent a favorable environment for their reproduction.
food to take frequently.Special requirements for the selection of meat and fish there.The drink should be plentiful. | {
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7,641,389,218,713,498,000 | Skip to main content
Investigation of serum protein profiles in scrapie infected sheep by means of SELDI-TOF-MS and multivariate data analysis
Abstract
Background
Classical scrapie in sheep is a fatal neurodegenerative disease associated with the conversion PrPC to PrPSc. Much is known about genetic susceptibility, uptake and dissemination of PrPSc in the body, but many aspects of prion diseases are still unknown. Different proteomic techniques have been used during the last decade to investigate differences in protein profiles between affected animals and healthy controls. We have investigated the protein profiles in serum of sheep with scrapie and healthy controls by SELDI-TOF-MS and LC-MS/MS. Latent Variable methods such as Principal Component Analysis, Partial Least Squares-Discriminant Analysis and Target Projection methods were used to describe the MS data.
Results
The serum proteomic profiles showed variable differences between the groups both throughout the incubation period and at the clinical end stage of scrapie. At the end stage, the target projection model separated the two groups with a sensitivity of 97.8%, and serum amyloid A was identified as one of the protein peaks that differed significantly between the groups.
Conclusions
At the clinical end stage of classical scrapie, ten SELDI peaks significantly discriminated the scrapie group from the healthy controls. During the non-clinical incubation period, individual SELDI peaks were differently expressed between the groups at different time points. Investigations of differences in -omic profiles can contribute to new insights into the underlying disease processes and pathways, and advance our understanding of prion diseases, but comparison and validation across laboratories is difficult and challenging.
Background
Prion diseases, like scrapie in sheep, are often called Transmissible Spongiform Encephalopathies (TSEs). These are fatal neurodegenerative diseases in a variety of host species, including humans. They are all associated with the conversion of the normal host cellular prion protein, PrPC, into the abnormal protease-resistant isoform, PrPSc. The PrP genotype influences susceptibility, incubation period and clinical presentation, the V136R154Q171 allele being most highly associated with classical scrapie in sheep. To control and prevent spread of scrapie, genetic screening and breeding for resistance are widely used, and was implemented in the EU through Decision 2003/100/EC [1, 2]. The PrP genotype is, however, neither a marker for definitive disease, nor the only genetic factor influencing prion diseases [3, 4]. Despite the effort of reducing susceptibility, and monitoring and culling of ruminants, scrapie still exists [5, 6].
As of today, much research into prion diseases has evolved around the prion protein itself through infection and dissemination studies, and relatively little has been done on other non-PrPSc disease processes. The most recent large scale survey on prevalent PrPSc in human appendix samples in Britain, suggests a higher prevalence of infection than formerly anticipated, in all human PrP genotypes, and these findings further necessitates focusing on various mechanisms in prion disease development and progression [7]. The variable incubation time, the complex epidemiology and different variables which may influence the clinical and pathological picture are increasingly important to elucidate [810]. Different -omic studies of tissues and body fluids, like serum, may potentially reveal markers that can contribute to unravel the intricate pathogenesis of prion diseases. Recently, several non-PrPSc proteins have been put forward as promising biomarkers for preclinical scrapie [1115]. Identification of such non-PrPSc biomarkers may be crucial in future prion research.
The Surface Enhanced Laser Desorption/Ionization-Time of Flight-Mass Spectrometry (SELDI-TOF-MS) technology (Ciphergen Biosystems, Fremont, CA, USA) was designed to perform a mass spectrometry (MS) analysis of protein mixtures based on the mass-to-charge (m/z) ratio of the proteins, and on their binding affinity to the various chip surfaces. For a single charged protein, the molecular weight in Dalton (Da) usually corresponds well to the mass-to-charge (m/z) value, and the peak intensity corresponds well to the concentration in the sample. Different protein expression profiles may then be determined from these protein profiles by comparing the intensity of peaks of similar m/z value [16].
Proteins are good indicators of current cellular functions, and investigation into the serum proteome represents one direction in biomarker research [16]. One of the challenges in investigating the serum proteome is its complexity and the presence of high abundant blood proteins, particularly albumin. It is estimated that the high abundant proteins constitute 95% of the bulk mass of proteins, but they represent less than 0,1% of the total number of proteins [17]. These high abundant proteins may produce large signals and mask or interfere with the detection of other low abundant proteins [18]. To simplify the sample complexity, an up-front fractionation procedure is recommended in addition to the fractionation achieved by the chromatographic properties of the SELDI ProteinChip® Array technology [16, 19, 20].
Extracting crucial information from the retrieved mass spectrometry (MS) data can be challenging. These data often have a much higher number of variables compared to number of samples, they do not follow a normal distribution, there is heteroscedasticity and variables are highly correlated. For these reasons, much effort has been invested in finding reliable methods to assist the interpretation of such profiles. Machine learning methods represent one direction, and another is the latent variable (LV) approach where principal component analysis (PCA) is commonly used for unsupervised exploratory analysis of mass spectral data [21]. Partial least squares discriminant analysis (PLS-DA) is another method that utilizes the knowledge of group belonging to identify discriminating group data [22]. A problem with PLS-DA is that usually numerous latent variables are needed in order to achieve good discrimination between the groups and this can create interpretation problems. Following up with target projection (TP) method, the axis of best discrimination between groups can be achieved, and interpretation on a single predictive latent variable is obtained [23]. Rajalahti et al. developed a quantitative display called selectivity ratio (SR) plot for selecting biomarkers in spectral profiles. The SR plots provide both ranking and an objective measure of probability to guide the investigator in the selection process, resulting in a specific protein fingerprint profile that classifies unknown samples into controls or infected group [23, 24]. It has been suggested that it is possible to classify samples based on multiple biomarker patterns, and therefore not constrained by the sensitivity and specificity of any single biomarker [16, 20, 25].
In this work, SELDI-TOF-MS technology was used in the analysis of pre-fractionated serum samples, and we describe the data processing steps and the following latent variable projection methods used to visualize the variation and highlight variables which separate the groups in question.
Results
Animals
At time of euthanasia, 23 weeks post inoculation (wpi), all the scrapie infected animals showed typical signs of scrapie, such as pruritus, ataxia, reduced live weight, weak coordination and poor wool quality. None of the animals in the control group showed any clinical signs of scrapie. Brain material from both groups and inoculation material used were examined by western blot (WB) for the presence of PrPSc, and results are presented in Figure 1.
Figure 1
figure 1
Detection of PrPScby Western blotting. WB using P4 antibody of homogenated brain material from animals and inoculation material used in this experiment. Lanes 1–5 (2006 and 2007) represent the scrapie inoculated animals. Lanes 6–10 (2006) and 6–7 (2007) represent the control animals. The lanes indicated by the arrow represent inoculation material used in the scrapie groups. Molecular markers were placed in lanes 12 and 9. PrPSc was detected in inoculation material and in all the animals from the scrapie groups.
SELDI-TOF-MS data processing and evaluation
Reproducibility of the SELDI-TOF MS analysis was evaluated on the basis of the calculated coefficient of variation (CV) of peak intensities and m/z. The pooled CVs (CVp) were calculated and results are in the same region as reported by others, and are shown in Table 1. CVp for mass accuracy across samples were all below 1%.
Table 1 Coefficient of variation for peak intensities across samples (ES data) and quality control (QC) sample (LS data)
Data analysis of clinical end stage data
PCA analysis was performed on MS data from both end-stage study (ES) and longitudinal study (LS) on the basis of peak clusters derived from biomarker wizard feature (BW) included in the Ciphergen ProteinChip® Software, and score plots are presented in Figures 2 and 3 respectively.
Figure 2
figure 2
Principle component analysis of 38 peak clusters from end stage study (ES) data. Samples from scrapie affected animals are indicated in red, and healthy controls are indicated in blue. The first principal component explains 33% and second principal component explains 18.3% of total variation in data. Both these components visually separated the groups, and much of disease related variation contributed on first (PC 1) and second (PC2) principal components.
Figure 3
figure 3
Principle component analysis of longitudinal study (LS) data. Samples from scrapie group are indicated in red, and samples from control group are indicated in blue. One PCA plot for each sample point; six, eight, ten, 12, 14, 16, 18, 20, 22 and 23 weeks of age/post infection.
The PCA analysis was used solely for visualisation purpose. The score plots in Figure 3 demonstrated that the healthy animals and infected animals segregated well at the clinical end-stage (23 weeks p.i.), but poorly during the asymptomatic incubation period. Principal component one (PC 1) describes most of the variation in each data set, but how much of this variation is accounted for by scrapie is unknown, as this method does not take group belongings into account. Data sets from LS were not analysed any further with LV methods, due to the low number of peaks selected in BW, making these methods not suitable. The LS data was further analysed by the non-parametric Mann–Whitney U test for significant difference in individual peak intensity between the groups at each sampling time. The resulting peaks and their m/z value, significance level and fold change are listed in Table 2.
Table 2 Significant peaks in the longitudinal study and fold change
Only data from clinical end stage study was further analysed by PLS-DA using group classification as the dependent variable. Five (5) components were shown to possess predictive information according to cross validation. This model used 70.6% of the variables in the protein profile (explanatory variables) and explained 97.8% of the variance in group membership (response variable), indicating an excellent predictive model. This PLS-DA model was used as the basis for the TP model and the resulting TP scores are graphically presented in Figure 4, showing excellent discrimination between healthy controls and infected animals. The TP model uses only 19.7% of the variables in protein profiles to explain the same 97.8% of the variance in the group membership. This indicates that most of the variation in the mass spectral data was not related to the disease status, and therefore removed in the TP model. The two models are summarized in Table 3. By choosing 80% mean correct classification rate (MCCR) for the Mean Wilcoxon Rank Sum as the sensitivity threshold for selecting discriminating peaks, the Discriminating Variable (DIVA) plot indicated the corresponding Selectivity Ration (SR) threshold to be 0.41 (Figure 5). From this we were able to select ten variables, presented in the Selectivity Ratio Plot in Figure 6, with individual Wilcoxon classification rate (sensitivity) in the range of 82 – 95 per cent (Table 4). These ten peaks were used in a new PCA analysis for a visual impression of the distribution of animals on the basis of these ten peaks, Figure 7. As illustrated in this PCA Score Plot, the two groups were well separated along PC 1 which indicated that these ten variables were highly related to group differences, i.e. scrapie versus healthy. The intensity and standard deviation of each of these SELDI peaks represented by m/z value were plotted in a bar diagram and presented in Figure 8. From this we can see that all of these ten proteins were over-expressed at the clinical end stage of scrapie.
Figure 4
figure 4
Target Projection score indicating grouping for each sample. All the scrapie samples (red) have a positive score value, and all the samples from healthy controls (blue) have a negative score value. The samples are indicated on the x-axis, and the target projection score on the y-axis. The TP model was able to separate the two groups with no misclassifications.
Table 3 Modelling results of both PLS-DA and TP predictive models before and after peak selection
Figure 5
figure 5
DIVA plot. A DIVA plot of the TP model with the red solid line indicating mean Wilcoxon classification rate and standard deviation (dashed line), and SR values on the x-axis. Horizontal line indicates the chosen 80% MWCR, and the vertical line indicating the resultant SR threshold of 0.41.
Figure 6
figure 6
Selectivity Ratio plot for all peaks in the model. A bar chart of all the peaks (x-axis) used in the model and their calculated SR value (y-axis). The two horizontal lines indicate the SR threshold with an absolute value of 0.41. Ten peaks have a SR value above this threshold.
Table 4 Selectivity ratio value, Wilcoxon classification rate and univariate p-value for each of the selected variable
Figure 7
figure 7
PCA plot of distribution of the two groups using only ten peaks. The ten peaks selected from the analysis were used in a PCA plot and there was good visual separation of the groups with PC1 accounting for about 60% of the variation in the dataset based on these ten peaks.
Figure 8
figure 8
The mean peak intensity and standard deviation for the ten selected peaks. A bar chart of the ten selectee peaks, with m/z on the x-axis and intensity on y-axis. Scrapie samples were indicated in red, and controls were blue. Standard deviation for each mean was indicated on each of the bars.
Protein identification
Serum Amyloid A (SAA) protein (gi1173354) was identified by eight peptides using high confidence filter, giving coverage of 45.54%, and SAA was only identified in the scrapie sample. The peptide sequence of SAA and the identified peptides are shown in Figure 9. SAA consists of 112 amino acids and has a theoretical molecular weight of 12 688 Da which corresponded well with one of the selected SELDI peaks with an m/z of 12 682. The data of this SELDI peak are presented in Table 5.
Figure 9
figure 9
SAA sequence and the identified peptides. Here is the total ovine Serum Amyloid A protein sequence and peptides identified by LC-MS/MS are highlighted. The peptide in red was identified with low confidence, the peptide in yellow was identified with medium confidence, and the peptides in green were identified with high confidence.
Table 5 Results from data analysis for SELDI peak with m/z of 12682
Discussion
In this study, we have evaluated the use of SELDI-MS-TOF data and latent variable methods to create and analyse serum protein profile data to discriminate healthy sheep from sheep with scrapie at various stages during the incubation period and at the clinical end-stage. Batxelli-Molina et al. discriminated sheep with early phase scrapie and healthy controls by the use of four SELDI peaks with sensitivity and specificity of 87.3% and 88.1%, respectively [11]. We were able to create a good predictive regression model only from the clinical end stage data, and based on ten peaks, to discriminate scrapie affected animals from controls with a sensitivity of 87.8%. One of these ten selected SELDI peaks had a relatively high intensity in the scrapie group and was barely detectable in the control group. This peak had a mass (m/z) of 12 682 Da and a mean sensitivity of 95%. Based on results from LS-MS/MS analysis of samples from both control groups and scrapie groups, this peak was identified as serum amyloid A (SAA). The finding corresponds well with our previously published data on quantitative measurement of SAA in serum samples from these animals [26].
A range of different univariate and multivariate data analysis methods and different software have been used for analysing SELDI spectral data [11, 16, 17, 19, 25, 2730]. We believe that multivariate methods based on latent variables are better suited, as these methods can handle data with more variables than observations and data which are noisy and highly collinear [22, 31, 32]. They provide a good tool for visualization of the data, detection of patterns and object classification. Latent variable models reduce dimensionality of the data and reveal the underlying concept and structure in them. These methods have been reported by others to produce good results from SELDI-TOF MS data [27]. However, due to the few peaks (variables) in datasets from the longitudinal study, we were not able to create a predictive model without increasing risk of over-fitting the regression model. We were not able to define valid components in the PLS-DA model and at the same time achieve satisfactory cross validation of data. Results from the longitudinal study were therefore only evaluated visually by the PCA method, and individual peaks were evaluated for significance through Mann Whitney U test. Although significant p-values were observed at each sampling time, these results should be interpreted with care due to poor reproducibility of the SELDI-TOF-MS analysis and the risk of false positives due to the “multiple comparisons problem” arising when a high number of peaks are independently compared between the two groups. PCA is a powerful technique for data visualization, but it is an unsupervised method including all variance in the data into the analysis, and does not use any a priori information regarding group membership [32]. Much of this variance may also be due to other non-scrapie related differences between the animals such as sex, age, genetics, sampling time and individual physiological factors. Important biomarker patterns in serum proteome may be buried under such major differences and by using methods taking group membership into account, disease relevant differences may become clear. We have illustrated this by using PLS-DA to analyse ES data, where the model focuses on maximum separation of the two groups, in contrast to maximum variation in the PCA model [22, 33]. PLS-DA model gives rise to large numbers of PLS components required to describe the majority of the variation in the data, and by combining these PLS components into a single TP component, which represents the direction in the multivariate predictive space with strongest relation to the response, interpretation becomes easy [34, 35]. The information with no correlation to group membership has then been removed, and the TP score vector displays the discriminative information between the two groups on a single scale. This is illustrated and summarised in Table 3, where we show that total variance in data used to describe the predictive model was reduced to 19.7% in the TP model, from 70.6% in the PLS-DA model. The TP model also provides a quantitative measure of each original variable’s contribution to the discrimination between groups, but as peaks with large variance and little correlation to group membership may dominate over peaks with little variance and high correlation to group membership, this could not directly be used to select interesting peaks [34]. The selectivity ratio (SR) for each variable on the TP component is directly related to each variable’s ability to predict group membership and this was used to select variables in the model [23, 24].
As described by Rajalahti et al., a sensitivity level, or correct classification rate, for a set of peaks can be chosen individually for each data set and this is done statistically by the non-parametric Wilcoxon Rank Sum test. Completely random classification with equal number of samples in each group then gives a correct classification rate of 50%, and correct classification of all the samples will have a CR of 100% [23, 24]. Setting the sensitivity threshold must balance the risk between selecting false biomarkers and missing important ones. In this study, we chose a mean sensitivity level/correct classification rate of 80% for the selected variables which gave a selectivity ratio (SR) value of 0.41, this is illustrated in the DIVA plot in Figure 5. Further on, this SR value was applied to all the variables in the Selectivity Ratio plot, Figure 6, and ten SELDI peaks qualified for selection by having a SR value above this threshold.
For two-group comparisons, like in this work, receiver operating characteristics (ROC) curves could be used to compare the sensitivity and specificity of a biomarker candidate at different cut-off values for peak intensity [36]. But as correct classification rate is identical to the sensitivity in a binary classification it will give us the same picture, only that the DIVA plot expands into the multivariate space.
The ten selected SELDI peaks were used in a PCA plot in Figure 7 to illustrate how well they separated the two groups in question along the PC 1. Figure 8 illustrates the intensity of these ten peaks in the SELDI spectra, and the increased expression in the scrapie group compared to the control group is probably related to the clinical status of the animals.
One of these peaks, with the m/z of 12682 Da, was identified by LC-MS/MS as serum amyloid A (SAA), which is a major acute phase protein (APP) in sheep. It has been quite common to identify acute phase proteins as discriminating biomarkers between groups of affected and not affected individuals, as these are highly sensitive reactants produced in response to an insult [18]. They are, however, not very specific, although different insults may produce different patterns of acute phase response (APR). Many of the reported diagnostic SELDI peaks have been found to be acute phase proteins, and are described in several reviews [11, 19, 37, 38]. SAA is primarily induced by pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6, which are released by a variety of cells including activated tissue macrophages and blood monocytes in response to injury [39, 40]. Sheep with natural scrapie, and mice with experimental scrapie, show reactive astrocytosis and microglia activation and increased cytokine expression in the brain at the time of clinical signs and neuropathological changes [4143]. These cytokines can cross over into the blood and initiate a systemic APR with increased synthesis of APPs from hepatocytes, such as SAA [44]. Coe et al. reported an increased level of serum amyloid P in plasma of mice with scrapie as evidence for systemic inflammatory response to scrapie [45]. Batxelli-Molina et al. identified transthyretin as being under-expressed in sheep with clinical scrapie [11]. Transthyretin is a negative APP expressed at lower levels during an APR along with the other negative APPs. Although identification of APPs as biomarkers of disease has not been considered significant, we believe that identification of any protein, regardless of specificity that significantly differs between scrapie affected and healthy controls, will contribute to novel information of underlying pathological processes of scrapie. The long incubation period, large variety in clinical presentation, as well as lack of direct link between neuropathology, PrPSc dissemination and clinical presentation, create the need for new knowledge of underlying processes at all stages of scrapie. Identification of discriminating proteins will contribute in this matter.
The SELDI-TOF-MS may be an excellent tool for protein profiling due to its high throughput, but, as this work has shown, there are too many technical limitations resulting in lack of peak identification and poor reproducibility to make this the technique of choice in the search for specific biomarkers. The challenges and limitations associated with SELDI-TOF-MS are nicely reflected by the poor reproducibility between our longitudinal and end point studies, and the low number of peaks detected at some time points, like 10 and 18 weeks. The method failed to detect the peak with m/z 12 kDa at both ES and LS, even though this peak separated the groups well and had high intensity in the ES study. Even though there are a number of peaks found to be significantly under- and overexpressed in the scrapie group compared to the control group in the LS data, the findings are of limited value, as long as the peaks are not identified as specific proteins which can elucidate specific pathological pathways of processes. It is also uncertain whether these individual peaks are separate proteins, several peaks can represent the same protein with different charges or modifications. We also noticed that there were large differences between the different time points, even though all the samples included in the LS were run randomly at the same time. This could be due to introduction of variables during handling and pre-processing of samples, especially from the initial fractionation step. The difference in number of peaks detected in each group could be due to suspected variation in quality and quantity in the FT fraction. As pointed out also by Van Gorp et al., many promising studies on discriminating SELDI peaks have been published, but few follow-up papers on peak identification and validation have been published [46]. Barr et al. actually proposed a protein fingerprint for TSE infection in blood [47].
To create a proteomic profile able to detect sheep infected with scrapie during the incubation period with high sensitivity and specificity, rigorous testing of a large number of animals would be necessary, in addition to eliminating variability through sample handling and analytical procedures. In addition to scrapie, other neurological diseases would have to be similarly mapped. The reproducibility and validity of discriminating proteomic profiles would need to be confirmed across different laboratories and animal groups, including different genotypes, scrapie strains and age groups. One of the major limiting factors of SELDI proteomic profiles is the lack of direct comparisons of SELDI peaks based solely on m/z. Differences in experimental set-up from animal model to data analysis result in poor reproducibility in number of peaks detected, peak height and m/z, making the resultant peak list incomparable [48]. Comparison of SELDI data from different sample sets, different runs on the same or across SELDI-TOF-MS instrument(s) have resulted in considerable variation in number of discriminating peaks [37]. Comparisons made across different studies may also be misleading, as one protein species can generate about ten major peaks and many minor satellite peaks due to chemical reactions that may take place during the sample preparation and analysis. Proteins with approximately the same mass will show up with overlapping peaks, and spectra obtained with different machine settings can look different [49]. Our results also confirm this problem, as the samples set for LS and ES were prepared and analysed on two different occasions, and we were not able to reproduce the exact same results in the end point data sets. The relatively high CVp seen for peak intensity both within and between runs, indicate that slight changes in peak intensity between groups may not indicate an actual difference between groups, and thus careful interpretation of results was necessary. This problem may be overcome by considerably increasing the number of animals in each group. Results across different age-groups were not compared, as natural changes in protein profiles related to age changes may overshadow the difference due to disease status. We worked with very similar groups to enhance differences relating to scrapie, and minimize differences related to pre-analytical factors like age, sex, production status and genotype. The variance attributed to pre-analytical factors was also minimized by one normalization step before peak selection, and not two as proposed by Poon (2007), due to the risk of introducing “false” differences between profiles by this renormalization [11, 19, 27, 50]. The difficulty in identification of proteins that correspond to the SELDI peaks is, as mentioned earlier, another major limiting factor, as also mentioned by Batxelli-Molina et al. and much effort should be made to identify these discriminating proteins, especially those which are significantly different between the groups [11].
Conclusion
In conclusion, on the basis of the experimental infection model used, including route of infection and PrP genotype of the animals, we believe that the results in this study are relevant to the study of several aspects of naturally infected classical scrapie cases. Choosing peaks/proteins in biomarker research based solely on p-values from univariate models may, however, result in a number of false markers, and latent variable methods are much more suitable for these types of data. Such methods are simple to use for non-statistical users, and interpretation is made easy as results are visually well presented. This article describes one approach, from animal model to data analysis, and the resulting selection of significant protein peaks and creation of a predictive model. The results show that it is possible to use data from SELDI-TOF-MS in combination with multivariate data analysis to discriminate scrapie affected sheep from healthy controls. We identified one peak, or one discriminating protein, to be serum amyloid A (SAA), in the scrapie affected animals at the end stage. However, the practical application of this predictive model is restricted due to the limiting factors of SELDI-TOF MS. The multiple detected differences between these groups might, therefore, have been more completely illustrated by other -omic methods. Studies on differences in proteomic profiles between healthy and scrapie infected sheep will, undoubtedly, provide novel insight into the underlying pathogenic and pathological events. However, as long as these discriminating protein peaks remain unidentified, the pathological and clinical relevance of the actual proteins in relation to scrapie remains unknown. Our conclusion is therefore that there is a need for sensitive and specific bioassays using identified biomarkers, obtained by –omic methods, which can be utilized by various research groups across experiments.
Materials and methods
Animals
A total of 19 lambs over two consecutive years (2006 and 2007) were included in this study, all having the same PrP genotype, homozygous V136R154Q171 (Table 6). Lambs were inoculated orally with 1 gram homogenated pooled brain material from either healthy sheep or confirmed cases of classical scrapie immediately after birth and before any ingestion of colostrum and then grouped (control or scrapie group) according to inoculation material. Inoculation brain material used in both groups was tested for PrPSc by WB (Figure 1). The lambs were left with their mothers in confined isolated boxes under similar conditions and feeding regimes. All the lambs used were born within a time period of 15 days. At post mortem examination, the obex area of the brain from each animal was sampled for detection of PrPSc by WB (Figure 1). Animal experiments were approved by the Norwegian Animal Research Authority.
Table 6 Overview over samples, animals, genotype and age of sampling at end stage of disease
Serum samples
Serum samples used in this work were drawn every two weeks from six weeks post infection (p.i.) until euthanasia in 2007 for the longitudinal study (LS). Serum samples at time of euthanasia from both 2006 and 2007 were used for the end-stage study (ES). Serum samples were allowed to clot at room temperature for a minimum of 30 minutes and maximum 60 minutes, and then processed. Serum was pipetted in aliquots and frozen at minus 80 degrees within two hours of sampling. All the samples were subjected to the same handling procedures throughout the experiment.
Serum fractionation
Serum samples were fractionated prior to SELDI-TOF MS analysis, using strong anion exchange fractionation kit, ProteinChip® Q Spin Columns (Bio-Rad), containing Q ceramic HyperD F sorbent. Before application to columns, proteins were denatured by addition of 150 μl 9 M Urea 2% Chapters 50 mM Tris–HCl pH 9 (U9) buffer to each of the 100 μl of serum samples, this followed by an additional 250 μl 1 M Urea 0,2% Chapters 50 mM Tris–HCl pH 9 (U1) buffer. The 500 μl serum mixture was added to the columns, and incubation time was set to 30 minutes at 4 degrees on a rotator to ensure complete mixing of serum mixture and column sorbent. Each sample was fractionated into six fractions (FT/F1, F2, F3, F4, F5 and F6). Flow through (FT) fraction was captured directly after sample incubation, and the consecutive fractions were captured after adding washing buffers with decreasing pH, starting at pH 9 and ending at pH 3 when capturing F5. The last fraction, F6, was captured after a wash with an organic buffer. The different fractions were aliquoted, and stored at – 80°C soon after capture until further analysis.
SELDI-TOF MS analysis
A Weak cation exchange array (ProteinChip® CM10 Array, Bio-Rad) in combination with high stringency buffer, 50 mM HEPES pH 7.0 as binding and washing buffer was used to analyse the flow through (FT) fraction in this work. Each FT fraction was diluted 1:10 with binding buffer before application to array, and each individual LS and ES sample was applied randomly onto the array in three and five replicates, respectively. The matrix, ProteinChip® Sinapinic Acid (SPA) Energy Absorbing Molecules (EAM), was applied before the SELDI-TOF-MS analysis. The arrays were prepared and handled according to manufacturer’s instructions. The arrays were analysed on the Protein Biology System II (PBS-IIc) with autoloader (Bio-Rad Laboratories) using Ciphergen ProteinChip® Software Version 3.2.1. (ProteinChip® Software) with the integrated Biomarker WizardTM (BW) cluster analyses software [51]. Each chip was analysed with a spot protocol optimized for the low mass area (LM) between 2 and 25 kDa, and spectra were collected using an average of 130 laser shots. ES and LS samples were prepared and analysed separately. The BW feature of the ProteinChip® Software was used for peak clustering in the range of interest (2 kDa – 25 kDa).
Data processing
Spectral data was processed to reduce instrumental and handling artefacts, minimize variation within groups and maximize variation between groups, and improve peak detection. Spectra were named and organised into groups according to age at sampling and group belonging (control and scrapie). Data were processed using ProteinChip® Software [51]. This process involved four steps; calibration, baseline subtraction, filtering and noise reduction and normalization (TIC). Finally, peak selection was performed by BW. Data processing was performed following recommendations described by Bio-Rad [36]. The collected peak data was exported into Microsoft® Office Excel 2003 and Sirius Version 8.1 (Pattern Recognition System AS, Bergen, Norway) for further data analyses. The spectra were evaluated for intra-cassette and inter-cassette reproducibility by calculation of the coefficient of variation (CV) for both peak intensity and peak mass (m/z). The CV for ES data set was calculated for each of the samples based on peak information in each of the five replicates, and CV for LS data set was calculated from peak information in a quality control (QC) sample that was repeatedly run with the samples.
A calibration equation was created using the calibration feature in the ProteinChip® Software and standards containing peptides and proteins of known mass (ProteinChip All-In-One Peptide/Protein Standard, Bio-Rad), which were run parallel to the samples. One equation for each data set, ES and LS, was calculated and applied to all the spectra in each of the respective study.
The shape of the baseline of each spectrum was examined and the baseline feature was used to subtract baseline. Fitting width was set to two times (2×) expected peak width. The noise range was set to 2 kDa to exclude matrix attenuation range from the analysis, and end was set to 100% of spectrum size.
The baseline and noise reduced spectra were normalized using the Total Ion Count (TIC) Normalization feature in the ProteinChip® Software, which normalizes each spectrum to equal sum detected signal under the curve in the region of interest. Each group, based on age and group belonging was normalized separately. The resulting normalization factor created for each spectrum was inspected and evaluated. Spectra with normalization factor above mean + 2 standard deviations were excluded from further analysis.
Peak clusters were generated using the BW function in the ProteinChip® Software to detect peaks of similar mass across the spectra. Peaks were detected using the following settings; first-pass detection with signal-to-noise ratio > 5, with cluster completion using a second-pass with signal-to-noise ratio > 2. The peaks needed to be present in at least 20% of the spectra (giving a presence in at least half of each group). A mass difference of 0.3% was allowed. Peak cluster information was exported to Excel for further analysis.
Data analysis
Univariate
The data were tested for difference in relative peak intensity between the two groups using the non-parametric Mann–Whitney U test included in the BW and Sirius software. The fold change in intensity was calculated as the mean peak intensity control/mean peak intensity scrapie for significantly down-regulated peaks, and vice-versa for up-regulated peaks. For all tests, the significance level was set to p < 0.05.
Multivariate
Latent variable projection methods (LV) were used to analyse the SELDI-TOF-MS data. Both ES and LS data was analysed by principal component analysis (PCA) to visually evaluate the distribution of the data irrespectively of group belonging. Only ES data were further analysed using other LV methods. A group membership variable was defined, assigning “0” to all the samples in the control group, and “1” to all the members in the scrapie group. Partial least squares – Discriminant Analysis (PLS-DA) and target projection method (TP) were then used to evaluate the data distribution according to group membership. For all analyses, the spectral variables were standardized to unit variance, thereby preventing variables with high variance to dominate the data analysis. A non-parametric Discriminating Variable test (DIVA) was used to connect Selectivity Ratio (SR) value to the discriminatory ability of the variables, quantified as the probability of correct classification. Each variable got a correct classification rate (CR), i.e. how well each variable separated the two groups in question. The SR value was plotted against the Mean Wilcoxon Rank Sum Rate to obtain the DIVA plot.
Cross validation was used for ES data to optimize the LV models with respect to predictive performance. Different procedures for cross validation have been developed [52]. The ES data were split into four groups, constructing one PLS model for each group, one group was used as validation set and the others as training sets. The number of PLS components was chosen as the one giving the first minimum in prediction error.
Protein identification
One ES sample from each of the groups was prepared and processed for protein identification. Thirteen μl of the FT fraction were mixed with 6 μl 4× LDS, 2.5 μl 10× DTT. The sample mixture was heated to 60°C for 15 minutes. 2.5 μl IAA (60 mM) was added to the mix and let to incubate for 15 minutes at room temperature and in the dark before loading on a 16% ClearPAGE gel (C.B.S. Scientific, USA). The gel was run at 150 V for 85 minutes. After electrophoresis the gel was stained with Gelcode Blue Safe Stain (Pierce, USA) for 1 hour and de-stained overnight with ultrapure water. Three protein bands in the region of 9 and 14 kDa bands on the gel were excised and subjected to tryptic digestion using OMX tube devices (OMX, Germany) following the manufacturer’s protocol.
Tryptic peptide samples were sent to International Research Institute in Stavanger (IRIS), Mekjarvik, Norway, and protein identification was done according their standard operating procedure. The protein identification was performed by LC-MS/MS analysis using an UltiMate 3000 dual pump nanoflow HPLC system (Dionex, Sunnyvale, CA, USA) connected to a linear ion trap-Orbitrap mass spectrometer (LTQ-Orbitrap XL, Thermo Fisher Scientific, Waltham, MA, USA). A sample volume of 5 μl from each sample was loaded onto a trapping column (Acclaim PepMap100 C18, 5 μm, 300 μm I.D. × 5 mm length, Dionex) at a flow rate of 2 μl/min in 0.1% formic acid (VWR) in MilliQ water (Elga) for clean-up and pre-concentration. Peptides were separated in the analytical column (Acclaim PepMap100 C18, 3 μm, 75 μm I.D. × 15 cm length, Dionex). The mobile phases for the analytical separation consisted of 0.1% formic acid in 2.5%/97.5% acetonitrile/water (A) and 0.1% formic acid in 80%/20% acetonitrile/water (B) and were pumped with a flow of 300 nL/min. The peptides were separated on the analytical column using a linear gradient from 5 to 60% B in 165 min after a 10 min delay post injection. The gradient was then run to 100% B in 10 min and held there for 30 min to wash the columns. A total run time of 256 min was used, including the washing step and 30 min re-equilibration of the columns. A PicoTip emitter (SilicaTip, New Objective) with a 10 μm tip and without coating was used as an ESI interface. The electrospray voltage was set to 1 kV, and no sheath gas was used. The mass spectrometer was used in positive mode. Full scans were performed in the Orbitrap in the m/z range from 200 to 2000, and data-dependent MS/MS scans performed in the linear ion trap for the five most abundant masses with z ≥ 2 and intensity ≥10000 counts. Dynamic exclusion was used with 3 min of exclusion after fragmentation of a given m/z value four times. Collision-induced dissociation (CID) was used with a collision energy of 35% and with activation Q setting of 0.400 and activation time of 30 ms for MS2. The mass spectrometer was tuned daily and calibrated weekly using the calibration solution recommended by Thermo Scientific.
Each LTQ-Orbitrap raw file was analysed using the Proteome Discoverer 1.0 (Thermo Fisher Scientific). Protein identifications were performed with the SEQUEST algorithm searching against even toed ungulate database available at NCBI with trypsin as digestion enzyme, and allowing for maximum two missed cleavage sites. Carbamidomethyl (C) was set as a static modification, and oxidation (M) as a dynamic modification. Precursor ion and fragment ion mass tolerances were set to 10 ppm and 0.8 Da, respectively. Results were filtered for minimum 2 peptides and using a high and medium significance XCorr Score adjusted for peptide charges (z), Table 7.
Table 7 High and medium confidence peptide filter settings
Abbreviations
TSEs:
Transmissible spongiform encephalopathies
PrPC:
Normal cellular prion protein
PrPSc:
Scrapie prion protein
SELDI-TOF-MS:
Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry
PCA:
Principal component analysis
PLS-DA:
Partial least square discriminant analysis
TP:
Target projection
SR:
Selectivity ratio
LC-MS/MS:
Liquid chromatography tandem mass spectrometry
TIC:
Total ion current
CV:
Coefficient of variation
Da:
Dalton
BW:
Biomarker wizard
PC:
Principal component
MWCR:
Mean Wilcoxon classification rate
DIVA:
Discriminating variable
z:
Charge
LDS:
Lithium dodecyl sulphate
DTT:
Dithiothreitol
IAA:
Iodine acetamide
LV:
Latent variable
WB:
Western blot
wpi:
Weeks post inoculation.
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Acknowledgements
We are grateful to Eli Brundtland for excellent help with the serum samples, and to Mari Mæland, Kai-Erik Uleberg and Eivind Larsen for sharing their knowledge and expertise on SELDI-TOF-MS analysis. This study was supported by grant NRC 178268 (2006–2010) funded by the Research Council of Norway.
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The authors declare that they have no competing interests.
Authors’ contributions
SM carried out the proteomic studies, statistical data analysis, participated in protein identification and drafted the manuscript. OMK participated in the design of the study, statistical data analysis and helped to draft the manuscript. RA participated in the statistical data analysis. KB participated in the design of the study, carried out parts of the protein identification and helped to draft the manuscript. AH participated in the design and performance of the proteomic studies. MJU participated in its design and coordination and helped to draft the manuscript. All authors have read and approved the final manuscript.
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Meling, S., Kvalheim, O.M., Arneberg, R. et al. Investigation of serum protein profiles in scrapie infected sheep by means of SELDI-TOF-MS and multivariate data analysis. BMC Res Notes 6, 466 (2013). https://doi.org/10.1186/1756-0500-6-466
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Keywords
• Scrapie
• SELDI-TOF-MS
• PCA
• PLS-DA
• Target projection
• LC-MS/MS
• Serum amyloid A
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8,869,404,840,491,241,000 | ASTHMA
Chiropractic is not a treatment for asthma
However, many who suffer from asthma report improvement by receiving chiropractic care.
Drugs may temporarily reduce symptoms but ignore any underlying nerve disturbance.
There is research that suggests a link between the spinal column, the nervous system and the respiratory system. This may be why many have mentioned improved breathing by consulting our practice.
Countless causes
Asthma cases seem to be rising at an alarming rate. Some think it’s due to a combination of factors, especially the increase of chemicals in our environment.
These days, airtight, super-insulated homes can trap chemicals, molds, formaldehyde and other irritants. Even the increasing use of cesarean births, antibiotics and our fascination with germ killing have been cited.
If these factors were the only issue, why wouldn’t allchildren living in the same house and breathing the same air, suffer equally?
Chiropractic connection
Your diaphragm is the primary muscle used for breathing. Nerves that control each breath leave your brain and exit the spinal cord in the mid-neck (C3, C4 and C5) area. Spinal problems in this area can have a profound affect on the nerve supply to the diaphragm.
Reducing subluxations in the spine may help restore proper nervous system control of the lungs and improved function can begin.
More research is needed
In fact, research published in the Journal of Vertebral Subluxation Research documented the results experienced by 81 children with asthma who received chiropractic care. The two-month study revealed that those under care saw a 45% decrease in the number of “attacks” and that 31% of the subjects voluntarily chose to decrease their medication.
All this from improved nervous system control of the lungs!
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371,227,605,684,962,400 | All Title Author
Keywords Abstract
Parameters in panoramic radiography for differentiation of radiolucent lesions
DOI: 10.1590/S1678-77572009000500006
Keywords: image interpretation, jaw diseases, differential diagnosis, education, radiologic parameters, radiolucent lesions.
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Abstract:
objective: the aims of this study were to establish parameters in panoramic radiography for interpretation of unilocular radiolucent lesions, and to compare the accuracy of diagnoses given by examiners before and after using these parameters. material and methods: in part i, 12 specialists analyzed 24 images and the diagnostic criteria used by each examiner to make correct diagnoses were used to build a list of basic radiographic parameters for each pathology (ameloblastoma, keratocystic odontogenic tumor, dentigerous cyst, and idiopathic bone cavity). in part ii, this list was used by 6 undergraduate students (un), 8 recently graduated dentists (d), 3 oral pathologists, 3 stomatologists, 3 oral radiologists, and 3 oral surgeons to diagnose the corresponding pathologies in the other set of 24 panoramic radiographs (t2). the same analysis occurred without using this list (t1). the method of generalized estimating equations (gee) was used in order to estimate the probability of making a correct diagnosis depending on the specialty of the examiner, type of lesion, and moment of the evaluation, t1 or t2 (before or after they had access to the list of parameters, respectively). results: higher values were obtained for the probability (gee) of making a correct diagnosis on t2; the group un presented the highest improvement (14.6 %); no differences between the probabilities were observed either between un and d, or among the different groups of specialists. conclusions: the use of panoramic radiographic parameters did allow improving the diagnostic accuracy for all groups of examiners.
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7,674,397,747,790,190,000 | Genetics and Genomics Cancer Biology
scientificprotocols authored almost 4 years ago
Author: Molecular Profiling Initiative, NCI
This method was successful in our lab using prostate tissue and for our specific objectives. Investigators must be aware that they will need to tailor the following protocol for their own research objectives and tissue under study.
This method is used to detect genomic DNA deletions in tumor cells. For a more detailed discussion of applying this approach to microdissected samples, see Allelic Loss Studies in Prostate MP at NCI.
Reagents
1. DNA sample (see Processing of Microdissected Tissue - DNA-based Analysis)
2. Proteinase K (Sigma)
3. Proteinase K buffer (0.05 M tris-HCL, 0.001 M EDTA, 1% Tween 20, 0.1 mg/ml proteinase K, pH 8.0)
4. Ampli Taq Gold Buffer (Perkin Elmer)
5. dNTP mixture (Perkin Elmer)
6. Primers
7. DEPC-treated H2O
8. Ampli Taq Gold Polymerase (Perkin Elmer)
9. a-32P dCTP, 6000 Ci/mmol (NEN Dupont)
10. Formamide, 99% (Fluka)
11. Bromophenol blue-Xylene cyanole (Sigma), reconstituted as directed
12. Gel Mix-6 sequencing gel solution (Life Technologies)
13. Ammonium persulfate (Biorad)
14. 10X TBE buffer (0.89 M Tris Base, 0.89 M Boric Acid 0.02M Disodium EDTA ) (Advanced Biotechnologies)
15. Acrylease (Stratagene)
16. Glass cleaner (e.g., Windex, Glass Plus)
17. 95% ethanol
Equipment
1. Thermal cycler (MJ Research)
2. Sequencing gel electrophoresis apparatus (Gibco BRL)
3. High voltage power supply
4. Gel dryer (Life Technologies)
5. Glass plates, 31.0 x 38.5 cm (Life Technologies)
6. 0.4 mm spacers (Life Technologies)
7. Casting boot (Life Technologies)
8. Shark tooth comb (Life Technologies)
9. Small clamps
10. Whatman blotting paper, 3 mm thickness
11. Kodak Biomax MR or AR film
12. Film cassette (Amersham Life Science)
13. Film processor
Time Requirements
1. Gel preparation: 1.5 - 2 hours. Polymerization requires 1 hour, but may stand overnight.
2. LOH reactions: 2 .5 hours (approximately 1 hour for set-up, 1.5 for PCR)
3. High-resolution denaturing polyacrylamide gel electrophoresis: 1-3 hours. Twenty minutes for set-up. Electrophoresis time varies according to product size.
4. Gel drying: 1 hour
5. Autoradiography: 1 hour-2 days
Methods
TIP: Investigators must be especially careful when using this methodology to analyze archival tissue specimens. Formalin fixation in particular results in DNA that is difficult to amplify and often produces inconsistent PCR results, including artifactual allelic loss and poor amplification of large products. Therefore, when this technique is used to analyze archival samples, it is highly recommended that replicate experiments (multiple independent dissections, triplicate PCR reactions, etc.) be used to verify results.
A: LCM and Proteinase K Treatment
1. Obtain microdissected cells using the LCM procedure.
• TIP: The number of cells needed to successfully perform the assay varies depending on the quality and processing conditions of the tissue samples. One thousand cells is recommended as a good starting point.- Suspend approximately 1000 microdissected cells in 20 µl proteinase K buffer.
2. Incubate overnight at 37°C.
B: Prepare the Glass Plates
TIP: Use Accuwipes for cleaning purposes, as they will not leave lint behind and are non-abrasive.
1. Clean glass plates twice with glass cleaner.
2. Repeat using 95% EtOH.
3. Spray small plate with Acrylease.
4. Spread Acrylease evenly using a circular motion.
5. Buff dry.
6. Quickly assemble the plates without touching the clean surface.
7. Place 0.4 mm spacers on the edges of the larger plate.
8. Place the smaller glass plate on top of the larger plate and spacers.
9. Secure the plates with a casting boot (tape or clamps may be substituted for the casting boot).
C: Polymerize the Gel
TIP: Acrylamide is a neurotoxin. Be sure to wear gloves and a labcoat when working with this substance.
1. Add 480 µl of 10% ammonium persulfate to 75 ml of Gel-mix-6.
2. Mix by inversion.
3. Hold the nozzle of the bottle at the corner of the gel cast.
4. Hold the gel cast at a 45o angle to the bench and pour the gel between the plates. If bubbles get trapped between the plates, remove them by tapping the outside of the plates or by tipping the plates upright.
5. Insert the straight side of the comb approximately 1 cm into the gel. If bubbles are introduced at this point, remove the comb and use the teeth of the comb to sweep out small bubbles.
6. Clamp the top of the plates together.
7. Allow the gel to polymerize for at least one hour.
• TIP: The gel can be left to polymerize overnight. However, if bubbles appear, the gel has begun to separate from the plates.To minimize separation, wrap the gel in plastic film and store at 4°C until use.
D: PCR Reaction
TIP: Investigators must be especially careful when using this methodology to analyze archival tissue specimens. Formalin fixation in particular results in DNA that is difficult to amplify and often produces inconsistent PCR results, including artifactual allelic loss and poor amplification of large products. If this technique is to be utilized for analysis of archival samples, we highly recommend that replicate experiments (multiple independent dissections, triplicate PCR reactions, etc.) be used to verify results.
1. Remove reagents from the freezer before beginning the procedure.
• Thaw thoroughly before use.
• Prepare all reactions on ice.
• Prepare the reduced cytosine mixture prior to beginning the LOH reaction setup.
• Vortex all reagents, with the exception of Taq Gold Polymerase before beginning the PCR reaction setup.
2. Prepare 320 µl reduced nucleotide mixture:
Table 1
3.Aliquot 1 µl of each DNA sample into a separate PCR tube and set aside.
• TIP: DNA that is recovered from microdissected samples and "semi-purified" using a one-step proteinase K buffer will sometimes produce "non-specific" PCR products in addition to the true alleles. Moreover, larger alleles will sometimes amplify much less well than smaller alleles. Thus, normal-cell DNA recovered from the same tissue section as the tumor DNA serves as the best control for determining the presence or absence of allelic loss.
4.Prepare sufficient volume of the reaction mixture in a separate tube for all reaction tubes:
Table 2
5.Thoroughly mix the reaction mixture by pipetting and dispense 9 µl of the reaction mixture into each tube containing DNA sample.
• TIP: Be sure to mix the LOH reaction mixture with the DNA sample by pipetting. This is especially critical for DNA from microdissected samples that has been processed through a one-step proteinase K-based "purification."
6.Cap the reaction tubes and place them in a thermal cycler.
7.Cycle the reactions according to Tm of the specific primer set.
8.After PCR, remove the samples from the thermal cycler and dispense 2 µl of formamide/dye solution (95% formamide, 20 mM EDTA, 0.05% bromophenol blue, 0.05% xylenecyanole) into each reaction tube.
9.Store reactions at 4°C until the gel is ready for loading.
• TIP: Investigators may want to consider the "touchdown" procedure for PCR by Don RH, Cox PT, Wainwright BJ, Baker K, Mattick JS: "Touchdown" PCR to circumvent spurious priming during gene amplification. Nucl Acids Res 19:4008, 1991. Advantages include:
• Much cleaner bands, since by starting with a high annealing temperature of 66 degrees and lowering 1 degree every cycle, the first PCR products are the most specific ones.
• The exact same protocol can be used for all primers.
E: Finalize Gel Preparation 1. Remove the gel from the casting boot. - Push the spacers into the gel until they are flush with the smaller glass plate to prevent the buffer from leaking during electrophoresis (spacers tend to get pushed out of the gel during polymerization). - Place the gel in the sequencing apparatus and close the buffer release valve. - Pour 500 ml of 0.5X TBE buffer in the upper chamber and 500 ml of 1X TBE buffer in the lower chamber. - Remove the comb and clear bubbles from the loading area with a pipette. - Insert the teeth of the comb approximately 1 mm into the gel. - Pre-heat the gel at 1700 volts for 15-20 minutes.
F: Gel Loading
1. Remove the samples from the freezer.
2. Denature the samples in a thermal cycler at 95°C for 5 mins.
3. Remove samples from the thermal cycler and immediately place on ice, with an ice pack on top of the samples, for 1 min.
4. Turn off the power supply.
5. Adjust comb if it has been pushed out of the gel during pre-heating.
6. Load 4 µl of each sample per well.
• TIP: It is best to skip lanes to avoid contamination caused by leaking between the wells.
7. Run the gel at 1700 volts for 1-2 hours (running time based on PCR product size).
G: Separate the Gel
1. Turn off the power supply.
2. Drain buffer chambers (buffer must be disposed of in a liquid radioactive waste carboy).
3. Remove the gel from the sequencing apparatus.
4. Separate the plates by removing the spacers and inserting the tips of two thin spatulas in their place.
5. Gently lift the spatulas until the top plate separates from the lower plate and gel.
6. Place Whatman paper on the gel.
7. Slowly peel the Whatman paper and gel off the glass plate.
8. Cover the gel with plastic wrap and dry on a gel dryer for 1 hour.
H: Autoradiography
1. Remove the plastic wrap from the gel.
2. Place the gel in an autoradiography cassette.
3. Expose film 1 hour-2 days using Kodak BioMax MR or AR film.
• TIP: Use MR film for maximum resolution of bands. An intensifying screen is useful when analyzing PCR products from small numbers of microdissected cells.
References
1. Debelenko LV, Brambilla E, Agarwal SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Chandrasekharappa SC, Crabtree JS, Kim YS, Heppner C, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Collins FS, Travis WD, Emmert-Buck MR. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 6(13):2285-90, 1997.
2. Emmert-Buck, MR, Lubensky, IA, Dong, Q, Chandrasekharappa, C, Guru, SC, Manickam, P, Keseter, M, Olufemi, S-E, Agarwal, S, Burns, AL, Spiegel, AM, Collins, FS, Marx, SJ, Zhuang, Z, Liotta, LA, Debelenko, LV. Localization of the multiple endocrine neoplasia Type I (MEN1) gene based on tumor deletion mapping. Cancer Res 57:1855-8, 1997.
3. Emmert-Buck M R, Vocke C D, Pozzatti R O, Duray P H, Jennings S B, Florence C D, Zhengping Z, Bostwick D G, Liotta L, and Linehan WM. Allelic loss on chromosome 8p12-21 in microdissected prostatic intraepithelial neoplasia. Cancer Res 55: 2959-62, 1995.
DOI
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518,422,029,442,535,200 | English
ThisisClinicalSkillscontent
May.24.2023
Download checklist
Blood Specimen Collection: Venipuncture Vacuum-Extraction Method (Home Health Care) - CE
ALERT
Strictly adhere to guidelines for hand hygiene, standard precautions, and site preparation to minimize the risk for a health care–associated infection.undefined#ref12">12
Don appropriate personal protective equipment (PPE) based on the patient’s signs and symptoms and indications for isolation precautions.
OVERVIEW
Infection control standards must be followed when obtaining a blood specimen. Appropriate safety devices should always be used and standards should be followed to minimize the risk of exposure to blood-borne pathogens.13 The use of safer needleless devices such as those with a reliable integrated safety feature is recommended.13 Venipuncture requires an aseptic no-touch technique and sterile gloves if contact with the skin is required after the skin preparation with an antiseptic.6 Veins used for venipuncture should be repeatedly assessed for infiltration, extravasation, infection, or phlebitis using standardized scales.8,9,10 Pain, burning, stinging, erythema, warmth, and subcutaneous swelling should be reported to the practitioner.
The correct amount of blood required by the laboratory must be drawn into each blood collection tube (Table 1)Table 1 to ensure accurate laboratory test results and decrease the patient’s risk of anemia.7 Some blood collection tubes contain additives that require an exact amount of blood in the collection tube. Blood collection tubes without additives allow variable amounts of blood. Some laboratory tests require less blood than others; the minimum amount of blood needed for a required test should be confirmed with the organization’s laboratory and the manufacturer’s instructions for use.7 Some additives are more likely to contaminate other blood specimens when blood collection tubes are sequentially engaged in the rubber-sheathed needle. Knowing the correct laboratory order of the blood specimens to be obtained into the blood collection tubes is essential.14 Blood specimens should be delivered to the laboratory immediately after collection per the organization’s practice. Some blood specimens may require special storage or handling, such as being placed on ice, refrigerated, or frozen.14
Because limited venous access may be a life-threatening complication of venipuncture, maintaining the patient’s vein’s integrity is essential. A patient with veins that may collapse or become injured from the vacuum pressure may require an alternative method of blood specimen collection. In addition, a patient whose veins may be difficult to locate because of unusual anatomy, trauma from repeated phlebotomy, or edema may also require an alternative method of blood specimen collection.2
The patient’s anatomy should be assessed for sites contraindicated for venipuncture, such as:3
• Current IV access site, a site with a hematoma, or signs of phlebitis or previous infiltration on the same extremity
• History of a mastectomy on the same side as proposed site
• History of trauma or other lymphatic system compromise to the same extremity
• Extremity site affected by radiation, tissue injury, stroke, or infection
• Dialysis access site on the same extremity
• Nerve injury or other complication on the same extremity
Venipuncture can be painful, and the patient may experience anxiety or fear before the procedure. A calm approach and skilled technique may help limit a patient’s aversion to venipuncture. To reduce pain during venipuncture, an appropriate pain management strategy for the patient should be determined based on the patient’s condition, developmental level, and engagement of the patient and family.4 Anxiety may be assuaged by communicating with the patient about how to help relieve the patient’s concerns.
Appropriate laboratory tubes should be obtained before the home visit. If needed, the laboratory should be called so that the proper tubes and the volume required to process the specimens can be confirmed.
SUPPLIES
See Supplies tab at the top of the page.
EDUCATION
• Provide developmentally and culturally appropriate education based on the desire for knowledge, readiness to learn, and overall neurologic and psychosocial state.
• Explain the purpose of collecting the blood specimen and the method to be used.
• Explain how a tourniquet, antiseptic swab, and venipuncture may feel.
• Explain that pressure is applied to the venipuncture site briefly after the needle is withdrawn, without bending the patient’s arm.
• Explain that the patient may apply pressure if able.
• For a patient who has a bleeding disorder or is undergoing anticoagulant therapy, explain that pressure may have to be applied for a longer period of time to achieve clotting.
• Teach the patient the signs and symptoms of venipuncture complications (e.g., hematoma, nerve pain, extravasation, excessive bleeding, arterial puncture, infection, phlebitis) and provide instructions on when to seek additional care.
• Encourage questions and answer them as they arise.
PROCEDURE
1. Perform hand hygiene. Don appropriate PPE based on the patient’s need for isolation precautions or the risk of exposure to bodily fluids.
2. Introduce yourself to the patient, family, and caregivers.
3. Verify the correct patient using two identifiers.
4. Explain the procedure to the patient, family, and caregivers and ensure that the patient agrees to treatment.
5. Verify the practitioner’s order and assess the patient for pain.
6. Prepare an area in a clean, convenient location and assemble the necessary supplies.
7. Consult with the practitioner to minimize venipuncture and conserve blood by substituting point-of-care testing for venipuncture, using low-volume collection tubes, performing all daily tests during one venipuncture, and eliminating routine testing.7
8. Review the patient’s history for risks associated with venipuncture, such as anemia, anticoagulant therapy, low platelet count, bleeding disorder (e.g., history of hemophilia), venous collapse, traumatic venipuncture, or phlebitis.
9. Review the patient’s personal history with blood specimen collection (e.g., anxiety or fear related to venipuncture), ask about signs of adverse responses to previous venipunctures (e.g., vagal response), and determine the patient’s ability to cooperate with the procedure.
10. Review the patient’s history for an allergy or sensitivity to antiseptic solutions,5 adhesives, and dressings.11
11. Review the patient’s anatomy for sites contraindicated for venipuncture, such as:
1. Current IV access site, a site with a hematoma, or signs of phlebitis or previous infiltration on the same extremity
2. History of a mastectomy on the same side as proposed site
3. History of trauma or other lymphatic system compromise to the same extremity
4. Extremity site affected by radiation, tissue injury, stroke, or infection
5. Dialysis access site on the same extremity
6. Nerve injury or other complications on the same extremity
Rationale: Drawing blood specimens from contraindicated sites can result in false blood test results or may injure the patient.
12. Ensure that the patient has not exercised for 24 hours7 before blood sampling.
Rationale: Exercise and changes from supine to upright positions can alter plasma volume because of the force of gravity on venous hydrostatic changes and distribution of bodily fluids, which can change the values of hemoglobin, hematocrit, and other blood cell counts.7
13. Determine the need for appropriate pain management strategies to reduce the patient’s pain from the venipuncture per the organization’s practice.4
14. Review the anatomy of the patient’s venous system and the organization’s practice for the preferred veins for venipuncture.
15. Identify whether cautions or preconditions must be met before the blood specimen can be collected. Blood specimen collection can be related to medication administration (e.g., medication peak and trough levels), nutritional intake (e.g., fasting), procedures, or diagnostic testing (e.g., timed endocrine hormone levels).7
16. Identify the appropriate laboratory blood collection tubes and validate the order in which the specimens are to be transferred into the collection tubes (if multiple specimens are required) and the volume required for each test per the laboratory’s practice and the manufacturer’s instructions for use (Table 1)Table 1.
17. Review the laboratory’s requirements for labeling and handling the blood specimens.
18. Gather supplies and equipment, including specimen labels, blood collection tubes, and vascular visualization devices, if required, and bring them to the patient’s side. Replace latex equipment with nonlatex equipment if the patient has a latex allergy.
1. Ensure that all equipment has been cleaned and disinfected using an Environmental Protection Agency (EPA)-registered disinfectant per the organization’s practice.
2. Ensure that all work surfaces used to hold blood specimen collection equipment, including chair arm extensions and tables, have been disinfected to protect the patient and the blood specimen from contamination.
3. Ensure that the blood collection tubes’ expiration dates have not passed and that all equipment and tubes are intact and free from defects or compromises.14
4. Ensure that the blood collection tubes have been stored upright and at the correct temperature (e.g., some additives require refrigeration).14
5. Do not preassemble devices before patient identification.14
6. Ensure that devices for the blood specimen collection process are from the same manufacturer.
7. Review the manufacturer’s instructions for using blood collection tubes and transfer devices.
19. Provide privacy for the patient.
20. Ensure proper lighting to aid observation of vein contours and colors.
21. Assist the patient to a comfortable position.
22. Perform hand hygiene and don gloves.
23. Identify the patient’s best sites for venipuncture.
Avoid contraindicated sites.3
1. If IV fluid is being administered in one arm, choose a site on the opposite arm for blood specimen collection.
Rationale: Obtaining a blood specimen from an arm with an existing peripheral access device may interfere with laboratory analysis of the specimen.14
2. If unable to locate a site in the arm opposite an IV infusion site, look for a venipuncture site distal to the IV infusion site.14
Consult with the practitioner about stopping the IV infusion for a minimum of 2 minutes14 before obtaining the blood specimen, as applicable.
Rationale: Stopping an IV infusion allows the medication to clear before obtaining the blood specimen, as the medication may interfere with laboratory analysis of the specimen.14
3. Ask the patient to make a fist for 10 seconds to distend the veins for venipuncture.14
4. If the selected vein cannot be palpated or viewed easily, apply a warm compress over the arm for several minutes per the organization’s practice.
Rationale: Warming enhances blood flow, making veins more prominent.
24. Choose a vein that is straight and does not divert into another branch; that is easily palpable; that has no swelling, hematoma, phlebitis, infection, or infiltration; and that has not had recent venous access or venipuncture. The basilic, cephalic, and median cubital veins are the most commonly used sites for venipuncture (Figure 1)Figure 1.14
Rationale: Avoiding venipuncture in a location where a vein branches reduces the risk of a hematoma.7
25. Apply a single-use tourniquet proximal to the insertion site.7
1. Avoid using a tourniquet for a patient who has a history of bleeding, is easily bruised, has fragile skin, or has diminished circulation; however, if a tourniquet must be used, apply it loosely.6
2. Do not keep the tourniquet on the patient longer than 1 minute6 before the procedure is performed.
Rationale: Prolonged tourniquet application causes stasis, hemolysis, and hemoconcentration because of changes in the vascular epithelium from increased venous pressure and hypoxia.6
3. Release the tourniquet before preparing the site for venipuncture.
26. Apply a topical anesthetic as prescribed or per the organization’s practice to reduce pain, as needed.4 Remove the anesthetic completely from the skin after the prescribed dwell time.4
27. Remove gloves, perform hand hygiene, and don clean gloves.
28. Prepare the blood collection equipment using blood collection tubes, holders, and needles from the same system and manufacturer to prevent equipment incompatibility.
1. Choose the smallest needle that will fit into the vein but will also accommodate the prescribed blood tests without contributing to hemolysis.
2. Ensure that a double-ended straight or winged-butterfly venipuncture with tubing and a safety device is securely attached to the vacuum-extraction system collection barrel. Alternatively, and if required, remove the sterile cap from the rubber-sheathed end of the double-ended straight or winged-butterfly needle and attach the needle to the collection barrel (Figure 2)Figure 2. If a single-ended straight or winged-butterfly needle is used, attach the needle securely to a collection barrel housing a sheathed needle.
29. Prepare the venipuncture site.
1. Cleanse the site with an organization-approved antiseptic solution (e.g., alcohol-based chlorhexidine, 70% isopropyl alcohol or povidone-iodine solution) per the organization’s practice and the manufacturer’s instructions for use.5,14
2. Use a disposable sterile applicator containing sterile solution.5
3. Allow the area to air-dry.
Do not touch the site after preparation unless sterile gloves are worn.1
30. Perform the venipuncture.
1. Reapply the tourniquet and relocate the vein.
Do not fasten the tourniquet for longer than 1 minute.14
Rationale: Prolonged tourniquet application can cause stasis, localized acidemia, and hemoconcentration.14
2. Remove the cap from the venipuncture needle, maintaining the needle’s sterility. Warn the patient to expect to feel a stick.
If contamination occurs, discard the needle and the collection barrel in a sharps container and prepare a new venipuncture needle.
3. Place the thumb or forefinger of the nondominant hand distal to the venipuncture site and gently pull and stretch the patient’s skin until it is taut and the vein is stabilized.
Rationale: Gently pulling and stretching the patient’s skin helps stabilize the vein and prevent rolling during needle insertion.
4. Hold a butterfly needle (if used) by its wings; hold a straight needle (if used) at the hub. Insert the needle at a 15-degree angle14 slowly into the patient’s skin with the needle bevel facing upward (Figure 3)Figure 3.
5. Observe the patient’s response.
Signs of nerve injury include severe, unusual, or shooting pain, tingling or numbness, or a tremor in the arm. If the patient complains of any of these symptoms during venipuncture, withdraw the needle immediately and notify the practitioner.6
31. Obtain a blood specimen.
1. Observe for a blood return (Figure 4)Figure 4.
Rationale: If blood does not appear, the needle is not in the vein.
2. Hold the collection barrel securely and advance the first blood collection tube into the sheathed needle inside the barrel so that the needle pierces the rubber top of the blood collection tube.
Rationale: Pushing the sheathed needle through the rubber top breaks the vacuum, pulling blood into the tube.
Do not advance the needle farther into the patient’s vein.
Rationale: If the needle advances too far, it may transverse the vein through the opposite wall into the subcutaneous tissue.
3. Obtain the required amount of blood for all of the ordered laboratory tests, keeping the needle stabilized in the patient’s vein.
Rationale: Laboratory results are more accurate when the required amount of blood is obtained.
4. After the blood collection tube is filled to the correct level for the ordered test(s) (indicated by the marking on the tube or per the laboratory’s practice), grasp the collection barrel firmly and remove the blood collection tube, using caution not to disrupt the venipuncture needle’s location in the patient’s vein.
Rationale: Grasping the collection barrel prevents the venipuncture needle from advancing or dislodging. The blood collection tubes should be filled to the correct level because additives in certain tubes are measured in proportion to the filled tube.
5. Insert and remove additional blood specimen tubes per the laboratory’s and manufacturer’s instructions for use, as needed.
Collect blood specimen coagulation studies before collecting other blood specimens that require a tube that contains a clot activator or other additive. If using a butterfly needle with tubing, use a nonadditive tube to collect the air from the tubing before engaging a blood collection tube for a coagulation study.7,14
6. Gently invert each blood collection tube back and forth immediately after it is filled with blood if the tube contains additives. Follow the manufacturer’s instructions for the number of inversions.14
Rationale: Inverting the tube gently ensures the additives are properly mixed to prevent erroneous test results.
Do not shake the blood collection tube.7,14
Rationale: Shaking the blood collection tube may cause lysis of the blood cells, resulting in inaccurate test results.
7. If the blood is flowing sufficiently into the blood collection tubes and a tourniquet was used, release the tourniquet just before filling the last blood collection tube. If blood flow is slow, wait to release the tourniquet until the last tube is almost full. Fill the last tube and remove it from the collection barrel.
Rationale: Releasing the tourniquet before filling the last specimen tube reduces bleeding at the site when the needle is withdrawn.
32. After the required amount of blood is collected, apply a 2 × 2-inch sterile gauze pad to the venipuncture site (without applying pressure). After the last collection tube is removed, quickly but carefully withdraw the needle from the patient’s vein, activating the safety mechanism to prevent an accidental needlestick injury.13
Rationale: Direct pressure minimizes bleeding and prevents hematoma formation. A hematoma may cause compression and nerve injury.
For a patient who has a bleeding disorder or who is undergoing anticoagulant therapy, hold pressure for several minutes, as needed, until the bleeding stops.
33. Immediately discard the collection barrel, needle, and tubing in an appropriate sharps container.
Do not recap needles or attempt to remove the needle from the collection barrel.13
34. Check the blood collection tubes for any sign of external contamination with blood. Decontaminate the blood collection tubes, if necessary, per the laboratory’s and organization’s practice.
Rationale: Decontamination prevents cross-contamination and reduces the risk of exposure to pathogens present in the blood specimen.
35. Assist the patient to a comfortable position for several minutes.
36. In the presence of the patient, label the specimen per the organization’s practice.12
37. Place the labeled specimen in a biohazard bag and transport it to the laboratory immediately per the organization’s practice.
38. Reassess the venipuncture site to determine whether bleeding has stopped or a hematoma has formed.
39. Report adverse events in an organization-approved occurrence reporting system.
40. Assess pain, treat if necessary, and reassess.
41. Discard supplies, remove PPE, and perform hand hygiene.
42. Document the procedure in the patient’s record.
EXPECTED OUTCOMES
• Vein is accessed successfully without nerve or adjacent tissue injury.
• Aseptic technique is maintained.
• Venipuncture site shows no evidence of continued bleeding or hematoma after specimen collection.
• Blood specimen is appropriately labeled and transported immediately after home visit.
• Patient tolerates procedure with minimal anxiety, fear, or discomfort.
• All required laboratory blood specimens are collected accurately for testing.
• No needlestick injury occurs to the patient or health care team member.
UNEXPECTED OUTCOMES
• Hematoma forms at venipuncture site.
• Needle is inserted through the vein.
• Patient has vasovagal response, including dizziness, fainting, or loss of consciousness.
• Infection or phlebitis develops at the venipuncture site.
• Nerve or adjacent tissue injury occurs after venipuncture.
• Hemostasis is not achieved.
• Laboratory specimen is inadequate for testing or hemolyzed and cannot be processed.
• Aseptic technique is not maintained.
• Blood specimen is not obtained.
• Needlestick injury occurs to the patient or health care team member.
DOCUMENTATION
• Date and time of venipuncture, number and location of attempts, and name and credentials of person performing procedure
• Blood specimens obtained and disposition of specimens
• Location and description of venipuncture site
• Volume of blood drawn for a patient undergoing frequent blood specimens or a patient with anemia
• Laboratory to which the specimen was delivered and any information required by the laboratory
• Inability to obtain sample, if unsuccessful
• Patient’s tolerance of venipuncture
• Education
• Patient’s progress toward goals
• Unexpected outcomes and related interventions
• Assessment of pain, treatment if necessary, and reassessment
OLDER ADULT CONSIDERATIONS
• Older adults have fragile veins that are easily traumatized during venipuncture. Applying a warm compress may help with obtaining a blood sample. Using a small-gauge needle may also be beneficial.
REFERENCES
1. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 18: Aseptic non touch technique (ANTT). Journal of Infusion Nursing, 44(Suppl. 1), S56-S58. (Level I)
2. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 22: Vascular visualization. Journal of Infusion Nursing, 44(Suppl. 1), S63-S65. (Level I)
3. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 27: Site selection. Journal of Infusion Nursing, 44(Suppl. 1), S81-S86. (Level I)
4. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 32: Pain management for venipuncture and vascular access procedures. Journal of Infusion Nursing, 44(Suppl. 1), S94-S95. (Level I)
5. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 33: Vascular access site preparation and skin antisepsis. Journal of Infusion Nursing, 44(Suppl. 1), S96. (Level I)
6. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 34: Vascular access device placement. Journal of Infusion Nursing, 44(Suppl. 1), S97-S101. (Level I)
7. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 44: Blood sampling. Journal of Infusion Nursing, 44(Suppl. 1), S125-S133. (Level I)
8. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 46: Phlebitis. Journal of Infusion Nursing, 44(Suppl. 1), S138-S141. (Level I)
9. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 47: Infiltration and extravasation. Journal of Infusion Nursing, 44(Suppl. 1), S142-S147. (Level I)
10. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 50: Infection. Journal of Infusion Nursing, 44(Suppl. 1), S153-S157. (Level I)
11. Infusion Nurses Society (INS). (2021). Infusion therapy standards of practice. Standard 55: Catheter-associated skin injury. Journal of Infusion Nursing, 44(Suppl. 1), S168-S170. (Level I)
12. Joint Commission, The. (2023). National Patient Safety Goals for the home care program. Retrieved March 30, 2023, from https://www.jointcommission.org/-/media/tjc/documents/standards/national-patient-safety-goals/2023/npsg_chapter_ome_jan2023.pdf (Level VII)
13. Occupational Safety and Health Administration (OSHA). (n.d.). Hospitals etool. Patient care unit: Needlesticks/sharps injuries. Retrieved March 30, 2023, from https://www.osha.gov/etools/hospitals/patient-care-unit/needlestick-sharps-injuries (Level VII)
14. Pagana, K.D., Pagana, T.J., Pagana, T.N. (2022). Chapter 2. Blood studies. In Mosby’s manual of diagnostic and laboratory tests (7th ed., pp. 11-497). St. Louis: Elsevier.
ADDITIONAL READINGS
O’Grady, N.P. and others. (2011, updated 2017). Guidelines for the prevention of intravascular catheter-related infections, 2011. Centers for Disease Control and Prevention. Retrieved March 30, 2023, from https://www.cdc.gov/infectioncontrol/pdf/guidelines/bsi-guidelines-H.pdf (classic reference)*
World Health Organization (WHO). (2010). WHO guidelines on drawing blood: Best practices in phlebotomy. Retrieved March 30, 2023, from https://apps.who.int/iris/bitstream/handle/10665/44294/9789241599221_eng.pdf?sequence=1&isAllowed=y (classic reference)* (Level VII)
*In these skills, a "classic" reference is a widely cited, standard work of established excellence that significantly affects current practice and may also represent the foundational research for practice.
Elsevier Skills Levels of Evidence
• Level I - Systematic review of all relevant randomized controlled trials
• Level II - At least one well-designed randomized controlled trial
• Level III - Well-designed controlled trials without randomization
• Level IV - Well-designed case-controlled or cohort studies
• Level V - Descriptive or qualitative studies
• Level VI - Single descriptive or qualitative study
• Level VII - Authority opinion or expert committee reports
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