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Ventilation
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Ventilation
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High Yield Notes
7 pages
Flashcards
Ventilation
9 flashcards
Transcript
Content Reviewers:
Rishi Desai, MD, MPH
Contributors:
The main job of the lungs is gas exchange, pulling oxygen into the body and getting rid of carbon dioxide.
Normally, during an inhale - the diaphragm and chest muscles contract to pull open the chest and suck in air like a vacuum cleaner, and then during an exhale - the muscles relax, allowing the lungs to spring back to their normal size pushing that air out.
Ventilation rates measure the volumes of air moving in and out of the lungs, over a period of time.
During normal quiet breathing, each breath of air that enters and leaves the lungs is about half a liter, which is called the tidal volume.
The respiratory rate is the number breath a person takes per minute. In an adult this is normally around 15 breath per minute at rest.
So the minute ventilation is the amount of air moved in and out of the lungs in a minute. So minute ventilation is given by
Minute Ventilation = (Tidal Volume) X (Respiratory Rate)
In a normal healthy adult, this means 500 ml per breath times 15 breaths per minute, or about 7.5 litres per minute.
However, not all the air that we breathe in reaches the alveoli, where gas exchange actually takes place.
Some air is trapped in the airways - an area called the anatomical dead space.
Also, some of the alveoli may be defective and can’t even participate in gas exchange.
When you add the volume of air lost in these malfunctioning alveoli to the anatomical dead space, you get the physiological dead space.
So to calculate alveolar ventilation, it’s the tidal volume minus the physiologic dead space and that volume gets multiplied by the respiratory rate:
Alveolar ventilation = [(Tidal volume) - (Physiological dead space)] X (Respiratory Rate)
In a normal healthy person, almost all the alveoli are functioning properly, and the physiological dead space is about equal to the anatomic dead space which is about 150 ml.
So the alveolar ventilation comes to about (500 - 150) ml or 350 ml per breath, times 15 breaths per minute or about 5.2 litres per minute.
A way of measuring the alveolar ventilation without actually measuring the dead spaces is by knowing inspired air contains almost zero carbon dioxide and all the carbon dioxide in the expired air comes from the functioning alveoli.
If we call the alveolar ventilation, VA. That’s the amount of air going in and out of the alveoli in a minute.
A fraction of this volume is carbon dioxide, so let’s call that fraction FCO2. So, the volume of carbon dioxide, VCO2, is:
VCO2 = VA X FCO2
Or, VA = (VCO2) / (FCO2)
Summary
Ventilation describes the volume of air that flows into and out of the lungs per unit time. There are different ways of describing ventilation. For example, the total volume of air that flows into and out of the lungs per minute is minute ventilation. The volume of air that is exchanging oxygen and carbon dioxide at the alveolar level is called the alveolar ventilation. It is important to understand that ventilation rates will affect gas partial pressures in the blood, particularly carbon dioxide. A mismatch in the ventilation of alveoli and either the production or removal of carbon dioxide in the blood would develop a mismatch that has physiological consequences.
Sources
1. "Medical Physiology" Elsevier (2016)
2. "Physiology" Elsevier (2017)
3. "Human Anatomy & Physiology" Pearson (2018)
4. "Principles of Anatomy and Physiology" Wiley (2014)
5. "The physiology and pathophysiology of human breath-hold diving" Journal of Applied Physiology (2009)
6. "Minute ventilation of cyclists, car and bus passengers: an experimental study" Environmental Health (2009) | {
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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet
Progressive strength training to prevent LYmphoedema in the first year after breast CAncer - the LYCA feasibility study
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Vis graf over relationer
BACKGROUND: Lymphoedema is a common late effect after breast cancer (BC) that has no effective cure once chronic. Accumulating evidence supports progressive strength training (PRT) as a safe exercise modality in relation to the onset and exacerbation of lymphoedema. In the 'preventive intervention against LYmphoedema after breast CAncer' (LYCA) feasibility study we examined the feasibility of a program of PRT in the first year after BC to inform a planned randomised controlled trial (RCT).
MATERIAL AND METHODS: LYCA was a one-group prospective pilot trial inviting women operated with axillary lymph node dissection for unilateral primary BC. Participants exercised three times a week for 50 weeks (20 weeks supervised followed by 30 weeks home-based exercise). The program ensured slow individualised progression during the exercise program. The primary outcome was feasibility measured by eligibility and recruitment rates, as well as questionnaire-assessed satisfaction and adherence to exercise. Furthermore, we assessed arm interlimb volume difference by water displacement, muscle strength by dynamic and isometric muscle testing and range of movement in the shoulder by goniometry.
RESULTS: In August 2015, eight of 11 eligible patients accepted participation. Two of them dropped out early due to other health issues. The remaining six participants had high exercise adherence through the supervised period, but only three maintained this through the home exercise period. Program satisfaction was high and no serious adverse events from testing or exercising were reported. One participant presented with lymphoedema at 50-week follow-up. Muscle strength markedly increased with supervised exercise, but was not fully maintained through the home exercise period. Range of shoulder movement was not negatively affected by the program.
CONCLUSION: Recruitment, testing, and exercise in LYCA was safe and feasible. At the 50-week follow-up, there was one case of lymphoedema. The LYCA program will be further tested in a full-scale RCT.
OriginalsprogEngelsk
TidsskriftActa oncologica
Vol/bind56
Udgave nummer2
Sider (fra-til)360-366
Antal sider7
ISSN0284-186X
DOI
StatusUdgivet - 1 feb. 2017
ID: 49687421 | {
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Open Access
Gene expression analysis on small numbers of invasive cells collected by chemotaxis from primary mammary tumors of the mouse
• Weigang Wang1Email author,
• Jeffrey B Wyckoff1,
• Yarong Wang1,
• Erwin P Bottinger2,
• Jeffrey E Segall1 and
• John S Condeelis1
BMC Biotechnology20033:13
https://doi.org/10.1186/1472-6750-3-13
Received: 18 June 2003
Accepted: 12 August 2003
Published: 12 August 2003
Abstract
Background
cDNA microarrays have the potential to identify the genes involved in invasion and metastasis. However, when used with whole tumor tissue, the results average the expression patterns of different cell types. We have combined chemotaxis-based cell collection of the invasive subpopulation of cells within the primary tumor with array-based gene expression analysis to identify the genes necessary for the process of carcinoma cell invasion.
Results
Invasive cells were collected from live primary tumors using microneedles containing chemotactic growth factors to mimic chemotactic signals thought to be present in the primary tumor. When used with mammary tumors of rats and mice, carcinoma cells and macrophages constitute the invasive cell population. Microbeads conjugated with monoclonal anti-CD11b (Mac-1α) antibodies were used to separate macrophages from carcinoma cells. We utilized PCR-based cDNA amplification from small number of cells and compared it to the quality and complexity of conventionally generated cDNA to determine if amplified cDNA could be used with fidelity for array analysis of this cell population. These techniques showed a very high level of correlation indicating that the PCR based amplification technique yields a cDNA population that resembles, with high fidelity, the original template population present in the small number of cells used to prepare the cDNA for use with the chip.
Conclusions
The specific collection of invasive cells from a primary tumor and the analysis of gene expression in these cells are is now possible. By further comparing the gene expression patterns of cells collected by invasion into microneedles with that of carcinoma cells obtained from the whole primary tumor, the blood, and whole metastatic tumors, genes that contribute to the invasive process in carcinoma cells may be identified.
Keywords
Invasive CellGene Expression PatternTumor Associate MacrophageCell CollectionNeedle Content
Background
In spite of advances in screening and adjuvant therapy, breast cancer continues to be a major health problem. Once cancer cells have spread and formed metastases, breast cancers are largely incurable even with state-of-the-art medicine. Understanding how cancer cells spread to other parts of the body can provide important insights and will ultimately translate into improved diagnostic, prognostic and therapeutic approaches that allow control of cancer metastasis. Recently, emphasis has been on the development of molecular arrays to identify new genes and proteins that contribute to specific steps in metastasis [1, 2]. Large-scale nucleic acid arrays have become very useful tools for investigators exploring differences in gene expression between cell types, stages of differentiation, and cellular responses to stimuli [3]. Such approaches are crucial in the analysis of cancer as a genetic disease and in the identification of key genes that might be used in diagnosis and therapy. So far, most gene expression studies have been done using whole tumor tissue. However, human primary tumors show extensive variation in all properties ranging from growth and morphology of the tumor, and formation and growth of metastases, and the application of tissue homogenates results inevitably in averaging of the expression of different cell types. The expression profile of tumor cells essential for invasion may be masked or even lost due to the contributions of surrounding cells. It is important to develop a technology to separate pure populations of invasive cancer cells for gene expression studies. The use of Laser Capture Microdissection as a front end for array-based gene discovery is such an approach. However, some of the cell behaviors that are believed to be essential for metastasis, such as adhesion and motility, cannot be used as criteria in the selection of cells for analysis from fixed material because the behavior and history of individual cells cannot be inferred from fixed material. Methods for the collection of cells from living tumors in which key cell behaviors can be observed and used as the criteria for cell collection need to be developed. An important approach in determining the cellular mechanisms that contribute to metastasis is to collect live cells from the primary tumor based on properties believed necessary for successful metastasis. We have shown previously that one of the properties correlated with metastasis is chemotaxis to blood vessels [4]. This cell behavior allows cells to orient and move toward blood vessels facilitating their intravasation. We have developed a method to selectively collect invasive cells from live primary tumors in intact rats using a microneedle containing a chemoattractant to mimic chemotactic signals from blood vessels and/or surrounding tissue [5].
For the study of the invasive subpopulation of cells within the primary tumor, the combination of chemotaxis-based cell collection in microneedles with array-based gene expression analysis has the potential to identify the genes necessary for the individual steps of invasion at the cellular level, and for the rational interpretation of gene expression patterns in metastatic tumors. One drawback to the array technique is the need to isolate and purify microgram amounts of total RNA [6] to generate the appropriate amounts of probe needed for conventional microarrays. However, the number of cells collected from mammary tumors with microneedles in vivo is currently limited to fewer than 1000 per needle. This number of cells typically contains 20–50 ng of total RNA [7, 8], well below the amounts needed for conventional array protocols. In order to combine the collection of invasive cells from live animals with cDNA arrays technology, we have experimented with a number of methods that have been used to amplify the starting RNA in other applications [9]. We have found that the SMART PCR cDNA amplification method (ClonTech Laboratories) can be used in gene expression profiling experiments to produce cDNA libraries from total RNA that are representative of the starting mRNA. This has the potential to allow the routine analysis of differential gene expression in very small tissue samples [1012]. Key to this alternative approach is the reproducible and representative synthesis of cDNA probes that retain faithfully the complexity of the mRNA population present in the original sample [9]. In this study we compared two approaches for synthesizing cDNA probes from total RNA for use with subsequent hybridization to high-density cDNA microarrays: 1) the conventional approach of reverse transcription (RT) of 100 μg of total RNA from cultures of carcinoma cells and 2) amplification of ~30 ng of total RNA from 1000 carcinoma cells using the PCR based cDNA amplification system. The results reported here demonstrate that, for situations with limited RNA, the RT-PCR based probe synthesis method retains the original mRNA message profile, and is suitable for gene expression profiling of invasive cells collected in microneedles.
The efficiency of separation of the pure population of invasive carcinoma cells and the quality of RNA isolated from microneedles were also tested in this study.
Results
Separation of carcinoma cells and macrophages for use in microarray analysis
As shown by our group elsewhere [13], the invasive cells that enter microneedles in the primary tumor are a mixture of macrophages and carcinoma cells. This conclusion is based on both cell type-specific antibody staining and real time PCR using cell type-specific primers. In order to analyze the gene expression pattern of only a single cell type at a time, we have investigated the efficiency of separating these two cell types using standard techniques. As shown in Figure 1A and 1B based on cell type-specific antibody staining, the use of MAC 1 antibody-coated magnetic beads can be used to selectively remove the macrophage sub-population of cells from the carcinoma cells collected in a single microneedle. The separation allows removal 80% of the macrophage contribution. The ability to separate the macrophages is further demonstrated by comparing quantitative real time PCR using cell type-specific primers to the results of real time PCR on samples after removal of the macrophages by the use of magnetic beads (Fig 1C). Again, real time PCR demonstrates the extensive removal of the macrophage-specific marker, yielding a purer carcinoma cell population for further analysis.
Figure 1
Figure 1
1A and 1B: Macrophages can be separated from carcinoma cells after microneedle collection. Cells collected from a MMTV-PyMTprimary tumor in a microneedle filled with matrigel and 25 nM EGF were magnetically separated using Mac-1 coated iron beads. Approximately 80% of the macrophages were removed from the sample, leaving only a 6% contamination of the carcinoma cell population by macrophages after a single separation step.
Figure 1C: Quantitative real-time PCR shows a decrease in the amount of Mac-1 mRNA in cells separated after collection from the primary tumor. Cells were collected and separated as described in Materials and Methods. After RNA purification from cells before and after separation, real-time PCR was run for the Mac-1 (macrophage marker) and keratin 18 (carcinoma cell marker) primers. Normalization was done using β-actin as reference gene. A decrease in expression of Mac-1 is seen in the cell-separated sample compared to that of the sample containing both cell types. This further confirms our ability to reduce the contaminating cells from our collected sample, so as to have a pure carcinoma cell population for gene discovery. The level of Keratin 18 expression shows a slight increase after separation.
Characterization of cDNA amplification techniques
We have adopted a SMART (Switch Mechanism At the 5' end of RNA Transcript) amplification method [14, 15] to amplify cDNA from our needle collection cells. Key to this alternative approach is the reproducible and representative synthesis of cDNA probes that retain faithfully the complexity of the mRNA population present in the original sample [9]. In this study we compared two approaches for synthesizing cDNA probes from total RNA for use with subsequent hybridization to high-density cDNA microarrays: 1) the conventional approach of reverse transcription (RT) of 100 μg of total RNA from cultures of carcinoma cells and 2) amplification of ~30 ng of total RNA from 1000 carcinoma cells using the PCR based cDNA amplification system.
Selection of the number of cycles for the exponential PCR amplification of the cDNA is the crucial point of the technique. 10 μl aliquots from the amplification reactions after 17, 20, 23 cycles were analyzed in a 1% agarose gel. Overcycled reactions can be identified by the disappearance of the distinct bands corresponding cDNAs and the increased smear molecular weight. In this study, preparative amplifications were subsequently performed at 20 cycles for cells from culture and microneedle.
As shown in Figure 2, comparison of the relative expression level of six genes in a metastatic cell line (MTLn3) and the non-metastatic cell line (MTC) was done using real time PCR. The amplified RNA shows the similar relative level of expression as unamplified RNA indicating that the PCR based cDNA amplification technique does not give rise to a misrepresentation of the original template complexity of RNA isolated from small numbers of cells.
Figure 2
Figure 2
Relative abundance of genes is maintained during cDNA amplification as verified by Quantitative real-time PCR. cDNA from 1000 MTLn3 (a metastatic cell line) or 1000 MTC cells (non-metastatic cell line) was diluted (1:10) after 20 cycles of SMART PCR amplification, and the expression of selected genes was compared with cDNA from 3 μg unamplified total RNA from MTLn3 or MTC cells by real-time PCR.
By comparing the distribution of ratios of gene expression in a metastatic cell line (MTLn3) and the non-metastatic cell line (MTC), it was possible to establish the relatedness of the expression patterns of the two cell types on a 9000 gene chip. As shown in Figure 3, the correlation of the expression ratios allows one to establish the reproducibility and relatedness of the preparations of cDNA. In Figure 3A, RNA isolated from ten million cells of each cell line was used to prepare the cDNA probe for use in the array. As shown in Fig 3A, comparison of two separate chips probed with unamplified sample shows a correlation coefficient of greater than 0.91. We then evaluated amplification of RNA from 1000 cells, followed by hybridization to two microarrays (Figure 3B). The amplified RNA samples showed a correlation coefficient in excess of 0.93 indicating that this technique generates a highly reproducible cDNA product. Finally, the average ratio of expression patterns for each gene in 3A and 3B are plotted in Figure 3C and show a correlation in excess of 0.9. This indicates that the PCR based amplification technique yields a cDNA population that resembles with high fidelity the original template population present in the small number of cells used.
Figure 3
Figure 3
The correlation coefficient demonstrates that amplified cDNA is comparable to that of conventionally isolated RNA from large numbers of cells. A) By comparing the distribution of ratios of gene expression in MTLn3 and MTC, the relatedness of the expression patterns of the two cell types is establish on a 9000 gene chip. Log base 2 ratios from 2 chips were plotted for unamplified probes from MTLn3 and MTC cells. B) Log base 2 ratios from 2 chips using PCR amplified probes of MTLn3 and MTC cells shows a higher correlation coefficient. C) The mean of the log base 2 ratios in A and B shows a correlation coefficient within the accepted range for conventional RNA methods.
This conclusion is supported by the data in Figure 4, in which the level of expression of a select number of overexpressed genes identified initially in unamplified RNA was also found to be over-expressed in chips probed with amplified cDNA. All of these results indicate that the PCR based cDNA amplification technique is eminently suitable for use with small numbers of cells as those obtained using needle collection.
Figure 4
Figure 4
Cancer metastasis genes overexpressed in MTLn3 cells are detected by both probe synthesis techniques. Amplified cDNA probe from MTLn3 cells and MTC cells were hybridized to a 9000 gene cDNA microarray. When compared to a chip hybridized with probes generated from unamplified RNA, the level of expression for selected metastasis genes are seen to show similar levels of expression on the amplified cDNA probe chip.
Use of PCR based cDNA amplification with cells collected in microneedles from the primary tumor
RNA quality is an important issue for gene expression analysis. As shown in Fig 5A, total RNA isolated from microneedle collected cells was checked using the Agilent Bioanalyzer and the RNA 6000 Pico kit. The RNA 6000 Pico kit used here allows the determination of the integrity of very low amount of RNA as well as an estimation of the amount of the isolated RNA. The size distribution and rRNA ratio (28S/18S = 2.7) indicates good intactness of RNA sample. Furthermore, validation of the RNA quality using the relative abundance of the marker template, beta-actin mRNA, demonstrates that the amount of the mRNA template isolated from cells in the collection needle was identical to that of RNA isolated conventionally from cells obtained from the whole primary tumor (Figure 5B).
Figure 5
Figure 5
The RNA from 200 and 400 cells is of equal amount and quality of RNA purified by conventional methods. Figure 5A: Total RNA isolated from microneedle collected cells was checked using Agilent Bioanalyzer and RNA 6000 Pico kit. The size distribution and rRNA ratio (28S/18S = 2.7) indicates good intactness of RNA sample. Figure 5B: A standard curve was generated for the CT value of a known quantity of RNA from a specific cell number using the β-actin primers for real-time PCR. The RNA from 200 and 400 cells were amplified by the SMART PCR method and run identically by real-time PCR. The CT values for the amplified RNA fall on the curve showing that the appropriate amount of the house keeping gene is present in the amplified sample. The CT values for the amplified samples are designated by the red asterisks.
In order to study the gene expression patterns of invasive cells collected from the primary tumor using microneedles, we amplified RNA from the cells collected in a single microneedle in the primary tumor. Amplification of the RNA from 800 cells collected in a microneedle yielded a pattern of PCR products with a size complexity that was very similar to the size complexity of the PCR product obtained from one thousand cultured carcinoma cells (Fig 6A). Figure 6B demonstrates the use of the cDNA amplified from cells collected in a microneedle from the primary tumor in probing a high-density cDNA microarray. More than 91% of the spots showed a good hybridization signal. Finally, as shown in Figure 6C, the distribution diagram shows a similar distribution of gene expression patterns for amplified samples indicating the cDNA prepared from the small number of cells is of sufficient quality and complexity to be useful in probing the nine thousand genes present in this high-density array.
Figure 6
Figure 6
The RNA from microneedle collected cells was extracted and amplification was performed using SMART PCR. Separately, 1μg of Universal Mouse Reference RNA (Stratagene) were used to generate reference cDNA. Fig 6A shows a gel picture of amplified cDNA from microneedle collected cells. The numbers indicate the PCR cycle number. The generated PCR product from the needle sample as well as the Universal Mouse Reference cDNA were labeled with Cy5 or Cy3. The two resulting cDNA probes were then mixed together and hybridized to a microarray slide containing 9700 genes. Fig 6B shows a part of the entire array (4 out of 16 blocks) generated using PCR amplified probe. Fig 6C is a histogram of the distribution of gene expression (CY5/Cy3) ratios for the array elements for hybridizations comparing gene expression.
Discussion
Microneedle collection
In our previous study [5], we reported that needles containing chemoattractants can be used to collect the subpopulation of motile and chemotactic tumor cells from a primary tumor in vivo as a population suitable for further analysis. It suggests that needles filled with growth factors and matrigel, when inserted into the primary tumor, can faithfully mimic the environment that supports invasion and intravasation in vivo, and that the same cell behaviors that contribute to chemotaxis in vitro also contribute to invasion in vivo.
An advantage of using the needle collection technique described here for the collection of cells for genomic/proteomic analysis is that the cell behavior can be characterized during the collection process. This can be done by varying the conditions required for cell collection such as the extracellular matrix composition and/or cytokines used as chemoattractants, determining how these changes affect efficiency of cell collection, and then relating these observations to the gene expression and protein composition patterns subsequently obtained from array analysis of the collected cells. Furthermore, cells can also be characterized by intravital imaging during collection to directly visualize the cell-cell and cell-extracellular matrix interactions that contribute to the invasion of the needle under these different conditions [16]. In addition, cells could be cultured and transplanted into other host animals to determine whether they stably retain differential characteristics that contribute to metastatic potential. Finally, by comparing the gene expression patterns of cells collected by invasion into needles with that of cells obtained from the whole primary tumor, the blood, and whole metastatic tumors, genes that contribute to the invasive process uniquely may be identified.
Separation of macrophages from the microneedle collection samples also makes it possible to analyze the gene expression pattern of Tumor Associated Macrophages
The tumor microenvironment contains stromal cells that influence the behavior of the tumor. Of these, there is increasing evidence that macrophages play an important role in modulating the metastatic capacity of the tumor. This includes clinical evidence showing a strong correlation between TAM (Tumor Associated Macrophages) [17, 18] and poor prognosis, and genetic studies in mice where removal of macrophages from the tumor bed leads to severely reduced rates of metastasis [19, 20]. Macrophages may contribute factors that affect tumor progression by altering the microenvironment including angiogenic and proteolytic factors [19]. These cells are also capable of producing many growth factors, including members of the EGF-family, which directly influence the behavior of tumor cells. In wound healing or at sites of infection, macrophages synthesize chemotactic factors that recruit other blood cells. The unique ability of macrophages to localize to specific sites and perform such tasks suggests that they could also provide chemotactic cues in tumors promoting the egress of the carcinoma cells from the tumor core. The collection of macrophages with carcinoma cells into microneedles in response to EGF is consistent with a role for macrophages in cancer cell invasion.
The methods described here allow for the collection of invasive tumor cells and Tumor Associated Macrophages and their separation into two cell types. These techniques will allow us to analyze the gene expression pattern not only for tumor cells but also for macrophages. It will make possible the identification of paracrine and other microenvironment-dependent interactions that contribute to the invasive process.
RNA quality of microneedle collected cells
Integrity of RNA samples is essential in the context of doing gene expression analysis on the microneedle collected cells. The matrigel in the needle makes it difficult to extract the RNA due to the abundance of proteins and collagen. In order to remove these proteins, which can interfere with the procedure, the standard RNeasy Mini Protocol from animal tissue has been adapted to include a proteinase K digest. After dilution of the lysate, the sample is treated with proteinase K. Debris is pelleted by centrifugation. Ethanol is then added to the cleared lysate and RNA is bound to the RNeasy membrane. This protocol has been used successfully for RNA isolation from microneedle collection samples and ensured high-quality RNA. As shown in our result, total cellular RNA prepared from microneedle collection samples remains intact after isolation, increasing confidence in subsequent molecular analyses.
PCR based cDNA amplification for use in microarray analysis of invasive carcinoma cells
PCR based cDNA amplification results in a cDNA product that resembles the starting template in size hetero-dispersion and complexity. Amplified cDNA is of a quality sufficient for use with high-density cDNA microarrays.
The specific collection of invasive cells from the primary tumor and the analysis of gene expression in these cells is now possible. We have demonstrated that RNA obtained from as few as 400 cells collected in a microneedle from the primary tumor, when amplified as cDNA using the PCR based protocol, can be used for microarray expression analysis. We have further documented that calibration of the number of PCR cycles used in this method allows amplification without loss of either relative mRNA copy abundance or complexity of the amplified product. This technology will allow the characterization of gene expression patterns of invasive tumor cells within the primary tumor during invasion and in response to varying genetic backgrounds. It will also make possible the identification of paracrine and other microenvironment-dependent interactions that contribute to the invasive process.
Conclusions
The specific collection of invasive cells from the primary tumor and the analysis of gene expression in these cells are now possible. By further comparing the gene expression patterns of cells collected by invasion into microneedles with that of carcinoma cells obtained from the whole primary tumor, the blood, and whole metastatic tumors, genes that contribute to the invasive process in carcinoma cells may be identified.
Methods
Mice
All mice were created in the FVB-C3H/B6 background and remained in a consistent background throughout breeding. The origin and identification of MMTV-PyMT has been described previously [20]. MMTV-GFP mice were described previously [21] and crossed with the MMTV-PyMT mice to produce GFP labeled tumors. Tumors were allowed to grow for 16–18 weeks prior to cell collection to ensure late stage carcinomas and increased metastasis.
Preparation and handling of collection needles
We have combined needle collection of invasive cells with multiphoton-based intravital imaging in mice with mammary tumors produced by the expression of the polyomavirus middle T oncogene. Expression of the polyomavirus middle T antigen in the mammary gland (MMTV-PyMT) results in transformation of the mammary epithelium and the rapid production of multifocal mammary adenocarcinomas [22]. MMTV-MiddleT transgenic mice crossed with MMTV-GFP transgenics were allowed to grow tumors for 16 weeks. On the day of the experiment 33-gauge needles were prepared by filling them with 1:10 matrigel and L15-BSA (the isotonic equivalent of 5% FBS), or L15-BSA with a final concentration of 25nM EGF. All needles contained 0.01 mM EDTA (pH 7.4) to sequester heavy metals that might be released from the needle. A mouse was anesthetized using 5% isoflurane and laid on its back. The isoflurane was reduced to 2 %, and a small patch of skin was removed to expose the tumor. Three 25-gauge needles, with inserted blocking wires, were positioned with the needle holder held in a micromanipulator for stability, into the tumor. The guide wires were removed and the matrigel containing needles were inserted. The animal was kept under monitored anesthesia for 4 hours. Afterwards, the needle contents were expelled onto a cover slip, mixed 1:1 with DAPI and counted immediately.
Macrophage separation from cultured cells
As described in our previous work [13], carcinoma cells comprised approximately 73% of the total cell population, while macrophages comprised 26%, together accounting for over 99% of the cells collected in response to EGF. To test the possibility of removing the macrophages from this total cell population, the following experiment was performed. BAC-1.25 macrophages and MTLn3-GFP adenocarcinoma cells grown in culture were removed with PBS/ 2 mM EDTA, pH 7.5. After counting cells, approximately 1000 carcinoma cells were mixed with 350 macrophages in 90 μl of PBS/0.5% BSA/ 2 mMEDTA in a 500 μl eppendorf tube. Cells were then mixed with 10 μl of MACS CD11b Microbeads (Miltenyi Biotec). These microbeads are colloidal super-paramagnetic beads conjugated with monoclonal anti-mouse CD11b (Mac-1α) antibodies. The cells were placed at 4°C for 15 min and then placed in a magnetic separator (LifeSep HGS-1.5; Dexter Magnetic Technologies) for 15 min at 4°C. The supernatant was removed while still in the magnetic separator and the cells were stained with DAPI and counted immediately. Different cells types were identified by their expression or lack of expression of GFP.
Macrophage separation from microneedle collected cells
Cells were collected from MMTV-PyMT mice. The needle contents were extruded into a 500 μl eppendorf tube with PBS/BSA/EDTA and diluted to 100 μl in the same buffer. 10 μl was removed and stained with DAPI to get an approximate cell count. The other 90 μl was treated with the microbeads as described above. After cell separation, cells were mixed 1:1 with 10% buffered Formalin on a poly-l-lysine coated Mattek dish and stained for anti-pankeratin and anti-F480.
Real Time PCR was performed on mRNA isolated from the collected cells before and after microbead separation using macrophage (MAC-1) and carcinoma cell (keratin) specific primers.
Conventional total RNA extraction and microarray hybridization
For isolation of RNA from large numbers of cultured cells, standard RNA extraction and microarrays hybridization we followed standard protocols as described elsewhere [6, 16].
RNA Extraction and cDNA amplification from small numbers of cells and microneedle collection samples
Cell collection was performed using needles with 25 nM EGF [5], followed by microbead separation. Cells collected from each needle were divided into 1/10 of the collection volume for counting. The remaining 9/10 of cells from the microneedle were placed into a 1.5-ml microcentrifuge tube containing 350 μl of guanidine thiocyanate buffer, homogenized by passing the lysate through a 20-G needle, attached to a sterile plastic syringe, at least 5–10 times. 500 μl of double-distilled water and 10 μl of Qiagen Proteinase K solution was added to the homogenate and mixed thoroughly by pipeting and incubated at 55°C for 10 minutes. Extraction was continued using the RNeasy kit (QIAGEN), and RNA molecules selectively bound to the silica gel base were eluted with 30 μl RNase-free water. The RNA was then concentrated by ethanol precipitation and re-dissolved in 3.5 ul DEPC water.
The total RNA was reverse-transcribed directly using the SMART PCR cDNA synthesis kit (Clontech, Palo Alto, CA) according to the manufacturer's protocol. Annealing was conducted using a modified oligo(dT) at 70°C for 2 minutes in the presence of the SMART II oligonucleotide in a total volume of 5.5 μl. The reaction was followed by the addition of Superscript II (200 units) RNase H- reverse transcriptase (RT) (Gibco-BRL, Gaithersburg, MD) and incubated at 42°C for 1 hour. The reaction was stopped by adding 40 μl of Tris-EDTA buffer and heatingat 72°C for 7 minutes. Representative double-stranded cDNAs were then generated by exponential PCR amplification. The optimal number of cycles for each sample was determined by analyzing the PCR products of a series of PCR amplifications using different numbers of cycles by electrophoresis. Four microliters from the 50-μl single-stranded cDNA stocks were amplified in 50-μl reactions using the SMART PCR primer by the predetermined exponential number of cycles. Amplified cDNAs from the cells of the primary tumor and needle collection were diluted and used for further analysis by cDNA microarrays and real-time PCR.
Microarray hybridization and analysis
Microarray analysis was performed by using cDNA microarrays made at AECOM. About 9,700 mouse genes (Incyte Genomics) were precisely spotted onto a single glass slide. Detailed descriptions of microarray hardware and procedures are available from http://www.aecom.yu.edu/cancer/new/cores/microarray/default.htm.
After amplification, cDNAs were purified using the QIAquick PCR Purification Kit (Qiagen) and eluted with TE buffer. For each probe, labeling was conducted by incorporation of Cy5 or Cy3-dUTP (Amersham Pharmacia) during random hexamer-primered primer extention in the presence of Klenow DNA polymerase (Life Technology). Briefly, 2.5 μg dscDNA was mixed with 3 μl (0.5 μg/μl) random primer, adjusted to 23 μl, boiled at 95°C for 5 minutes, and put on ice. The above was then mixed with 3 μl reaction 2 buffer (Biolabs), 3 μl 10X dNTP (1.2 mM dCTP, dGTP and dATP, 0.6 mM dTTP), 3 μl Cy5 dUTP and 1 μl Klenow DNA polymerase and incubated at 37°C for 2 hours and stopped with EDTA. The two resulting cDNA probes were then mixed together, purified and concentrated, denatured at 94°C, and hybridized to an arrayed slide overnight at 50°C. Details of slide washing, image collection and data normalization and analysis were described in previous study [16]. In this study, comparisons of normalized data were graphed using Log2 (ch1/ch2) ratio scatter plots. The linear regression function in Excel was used to calculate R2 (the correlation coefficient).
Quantitative Real-Time PCR (QRT-PCR)
Quantitative RT-PCR analysis of the abundance of mRNA in cell and tissue samples was performed by using the iCycler apparatus (Bio-Rad) with sequence specific primer pairs for selected genes. The SYBR Green PCR Core Reagents system (Perkin-Elmer Applied Biosystems) was used for real-time monitoring of amplification. Results were evaluated with the ICYCLER IQ REAL TIME DETECTION SYSTEM software (Bio-Rad) [16].
Quality control of the RNA prepared from cells collected in microneedles
Total RNA from cells in microneedles was extracted. To verify successful RNA isolation and the intactness of the RNA samples, the RNA 6000 Pico kit and Agilent 2100 Bioanalyzer (Agilent Technologies) were used. The system automatically calculates the ratio of ribosomal bands in total RNA samples and shows the percentage of ribosomal impurities in RNA samples.
Total RNA from mammary tumors of MMTV-PyMT mice was prepared, and different amounts of RNA (correlated with the numbers of cells, 30 pg/cell) were used to generate a standard curve by real-time PCR. The abundance of β-actin mRNA was measured by the CT (threshold cycle) values of the real time PCR reaction. Cells were collected from MMTV-PyMT tumors of the mammary using the microneedle technique. One fourth of the cDNA (equivalent to that from 200 and 400 cells, in three repeats) from two independent cell collection experiments was used in real-time PCR with the same β-actin primers used to construct the standard curve. The CT values for these two samples were fit to the standard curve.
Declarations
Acknowledgements
This work was supported by grant 5R33CA089829 from NIH. We thank Dr. Jiri Zavadil and the staff of Albert Einstein Biotechnology Center for their invaluable help and expertise, Dr. Sumanta Goswami for assistance with statistical analysis.
Authors’ Affiliations
(1)
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, USA
(2)
Department of Medicine, Albert Einstein College of Medicine, Bronx, USA
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Copyright
© Wang et al; licensee BioMed Central Ltd. 2003
This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
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-709,030,168,438,355,600 | Medical questions & health advice by board certified doctors
"Why do I have a burning rash in the armpits?"
ZocdocAnswersWhy do I have a burning rash in the armpits?
Question
My armpits are covered in this itchy, bumpy red rash. I'm a 33 year old woman, over weight but in good health otherwise. It looks like poison ivy, but I haven't been in the woods in a long time. What is this?
Answer
This sounds like quite an annoying rash. Unfortunately, no rash can be diagnosed without first being evaluated by a physician. In your case, it is probably okay for you to first see you primary care physician (family doctor or internal medicine doctor) before jumping to see a specialist. The first question I would have for you is "have you changed deodorant brands lately" Changing the brand of deodorant you are using can expose you to a new chemical that you are sensitive to. If you are putting something on the skin of your armpits that you are allergic to, the rash will look very much like poison ivy. Other possibilities include atopic dermatitis (also known as eczema). This is an itchy, sometimes bumpy, red rash that can develop in those areas. Another possibility is that you have s skin fungal infection, which is common in areas of the body where there is moisture and skin comes into contact with itself. I suggest that you schedule an appointment with your primary care physician. He or she can take a more detailed history of your rash and perform a thorough physical exam of it. If the diagnosis or treatment is at all in question, then you may warrant referral to a dermatologist. Good luck.
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-5,271,217,842,787,558,000 | A nutrient-dense diet is essential to achieve optimum health, and your hair is no exception. Yet if you are going bald due to genetic influences, even the best foods will not halt the progression. So where does the truth lie? Is there a connection between diet and hair loss?
There are approximately 100,000 hairs on the head of an average adult. Even people not experiencing hair loss shed about 100 hairs a day—about 1%—or an astonishing 36,000 a year on average. The shedding is part of the natural growth (anagen) and resting (telogen) stages of the hair follicle. In our youth this hair is replaced at the same rate. In genetic hair loss the replacement is less than complete, resulting in eventual thinning or baldness.
The body needs essential nutrients daily to build those new hairs. So to answer the question, yes, there is a connection between diet and healthy hair. The foods listed below will keep the hair you have as healthy as possible.
Popeye was on to something.
Spinach is very high in iron, as well as beta-carotene, folate and vitamin C, all essential nutrients. Prolonged or extreme iron deficiency can directly lead to hair loss. To determine if this is an issue contributing to your hair loss you can check your ferritin levels. Ferritin is a protein found in your blood cells that contains iron. A ferritin test helps your doctor understand how much iron your body is storing. Lots of ferritin equals lots of iron which is essential to building healthy hair. So next time you are in the veggie aisle, remember to pick up those power-packed leafy greens.
Go nuts.
Nuts such as pecans, cashews, Brazil nuts, almonds and peanuts are great for ensuring the quality of your hair. These nuts contain high amounts of healthy oils, which contribute to the elastin in your hair. Lack of elastin can lead to hair that easily snaps and breaks. Counting calories? Reach for raw instead of roasted and salted.
Sounds fishy.
It is hard to overstate the role magnesium plays in the human body—suffice it to say that it regulates more than 300 biochemical processes, and foods rich in magnesium help hair grow. Fish is a delicious source of this essential mineral. Types of fish that are richest in magnesium include caviar, cod, salmon, mackerel and halibut.
It’s Greek to me.
Greek yogurt contains lots of vitamin B5 and vitamin D, both of which are linked to hair and follicle health. It’s also a great source of calcium and live bacteria, which is crucial to a healthy digestive system according to a growing body of research. Skip the sweetened versions that contain more calories than a candy bar. The naturally sour version may be an acquired taste for you, but once you are hooked you will understand why Greek yogurt is prized around the world.
The golden egg
A strand of hair is mostly composed of protein, and your hair therefore needs protein to grow. Eggs are a valuable—even portable—source of protein, which can also been found in many other foods such as meat, fish and dairy products. Eat the whole egg for maximum nutrition, superior taste, and to reduce food waste.
A healthy diet is important for healthy hair, but it will not prevent or reverse genetic hair loss. To find out more about the causes, prevention, and tailored solutions to your hair loss, schedule a free consultation with Dr. Harris.
Contact my clinic for a consultation or ask me a question about your unique situation and how we might treat it.
Dr. James Harris is an internationally renowned hair transplant surgeon, inventor of patented follicular unit excision technology, published author in the field of hair restoration and an advocate for patient care. He is currently at the forefront of research and development in the field of hair cloning. Learn more about Dr. Harris or read rave reviews from his patients.
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8,528,354,708,167,421,000 | Business
Do Melatonin Diffusers Help You Sleep Better — and Are They Safe?
Melatonin level is produced by your mind in reaction to the darkness. It promotes sleeping as well as the scheduling of your sleep patterns. Melatonin release can be disrupted by being subjected to light late at night. Melatonin appears to have other functions in the body besides sleep, according to studies. Such impacts, though, are not well known. Melatonin pills can be derived from wildlife or microbes, though they’re very commonly produced. You can use Melatonin Vape Pen to get several benefits from it. The following is information regarding melatonin nutritional supplements.
Is it help with sleep?
Insomniacs have difficulty falling asleep, remaining asleep, or even both. Chronic insomnia is defined as a set of problems that linger for a pretty long time. There isn’t enough good research on the efficiency or security of melatonin supplements for sleeping problems to suggest treatment, according to treatment practices from some professional institutes. As the first medication for insomnia, some institutes strongly recommend cognitive behavior therapy for sleeping problems. Some institutes also say that Melatonin helps people a lot with their sleeping problems. Read more to know how it is helpful:
How does it help with sleep?
You may wonder how this thing will help you with your sleep. This chemical will help you in several ways, and you can read the methods of its working below:
By removing stress:
Melatonin diffusers remove the stress in a person and allow that person to sleep peacefully. Stress is the main reason why many people can’t sleep properly and peacefully. There are many thoughts in our brain that make us worry about various things and don’t allow a person to sleep peacefully. You must be facing these unnecessary thoughts, too, if you often feel problems in getting good sleep. If that’s true, you must get help from Melatonin Diffusers too.
Relax the brain:
This thing relaxes the brain of a person, and you can sleep peacefully after that. When the brain of any person is relaxed, he/she can get full sleep and never face the problems like insomnia. So, Melatonin Diffusers cause some effects on the brain, which relax the person suffering from this disease, and you can never feel the restlessness that causes the sleeping problems.
Reduce pains for a small time period:
There are many people who face sleeping problems because they are suffering from some serious pains. If you can’t sleep because of some physical pains as well, Melatonin Diffusers may be helpful for you as well. Usually, people who are going through some serious diseases like cancer and other ones like that face sleeping problems, and this thing is helpful for such people.
So, in this way, Melatonin Diffusers are helpful for people who are suffering from sleep problems. You can read about all these things and boost your knowledge regarding how this thing helps people with sleep problems.
Are they safe?
Many people who learn about Melatonin Diffusers and their users often question their safety. It will be fully safe if you consider a few things before taking them.The things you should consider are:
Use a safe amount:
If you’ll use Melatonin so much and you can’t set a safety level while taking it, you may get addicted to it. It isn’t healthy to have an addiction to anything, and to stay healthy and to stay safe from the bad effects of it; you must use it less. People who start using Melatonin without getting proper information about it often make the mistake of using it without any safety concern. You must save yourself from this mistake and use a safe amount of Melatonin after taking suggestions from your doctor. It will not cause any problem if you don’t use it more than the suggested amount, but if you’ll use it more, then Melatonin isn’t safe for you to use.
Consult with your doctor:
You need to consult with your doctor, too, before using Melatonin to treat your sleeping problems. There are many people who have some other disorders, and they are using medicines to treat them. If you use it without consulting with your doctor, you may end up making the biggest mistake. Whenever your doctor says that it is safe for you to use Melatonin for treating your insomnia, then you can use it without any problem, but if your doctor recommends you to stay away from it as it can cause some bad effects on you after reacting with your medicine or any other health-related problem, then you need to avoid taking Melatonin.
Is there any chance of getting addicted to it?
If you’ll use too much amount of Melatonin for treating your sleeping problems, there is an option that you may get addicted to it. When people take too much amount of Melatonin and start taking that high amount on a daily basis, then there are chances of getting addicted to it. But if the amount is under control, then you can easily get rid of it once the sleeping problems are solved. You can reduce the amount of it that you take on a daily basis, and then after that, you can slowly get rid of it, and you’ll not feel any kind of addiction. So, there isn’t any chance of getting addicted to Melatonin if the amount you are taking is under control.
Conclusion:
So many people want to know whether Melatonin Diffusers help with making sleep better or not, and the answer is yes. It will be helpful for you if you are using it safely and consuming an overdose of it. There are several people who want to get rid of insomnia, and they can do so by consuming Melatonin Diffusers. They’ll be safe for you if you’ll take a secure amount and if you’ll consume it after consulting with your doctor. Be careful before using Melatonin Diffusers for sleeping problems and collect full information about them before consuming them as they can cause harm in some cases too.
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} | 6e3c8d3593f3f69280bb5502b214ab8e |
-7,877,284,315,308,544,000 | Rated 5.0/5 based on 14 votes
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Doctor insights on: Calf Pain
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Calf Pain (Overview)
Means a pain in the calf. This can be from muscle strain, a clot in a vein, a torn tendon, infection or a host of several other problems, including referred pain from someplace higher up, like the lower back. The best starting place for calf pain is your primary medical doctor, who can then make an appropriate referral depending on what he or she feels it might be.
Dr. Warren Strudwick
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24 years in practice
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Calf Pain (Overview)
Means a pain in the calf. This can be from muscle strain, a clot in a vein, a torn tendon, infection or a host of several other problems, including referred pain from someplace higher up, like the lower back. The best starting place for calf pain is your primary medical doctor, who can then make an appropriate referral depending on what he or she feels it might be.
Dr. Warren Strudwick
Board Certified
24 years in practice
279K people helped
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3
3
Back pain (Tip)
Back pain
When pain is radiating or "shooting down" down your leg, consult your physician. ...See more
4
4
How should I treat severe left calf pain?
How should I treat severe left calf pain?
Depends on the cause: Calf pain can develop from a partial tear of the calf muscle, a blood clot, a ruptured baker's cyst from behind the knee, contusion/hematoma, strain due to altered gait/limping or it can be referred pain, often from nerve irritation from the lumbar spine. How you treat calf pain differs depending on the diagnosis. Until you see a physician, pain meds, limiting your weight-bearing & icing can help. ...Read more
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Dr. Warren Strudwick
Board Certified
24 years in practice
279K people helped
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5
5
What kind of pills or treatment can somebody get for calf pain?
What kind of pills or treatment can somebody get for calf pain?
It depend: Calf pain could be a muscular strain or could be a sign of blood colt in the leg especially with female contraceptives, I am recommending to check out with your doctor. ...Read more
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7
7
How can I get rid of calf pain when I walk fast and far?
How can I get rid of calf pain when I walk fast and far?
could be circulatio: Calf pain could be due to circulation problems but can also be do to a tight achilles. Try mild stretching...But if continues please have someone look at it. ...Read more
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8
8
Can you die from calf pain?
Can you die from calf pain?
Yes: I agree with dr. Rosen. Need to rule out blood clots on the legs as the clots can break off and travel to lung. People can die from blood clots in the lung. Now, other causes of calf pain- will also include restless leg syndrome; related to iron deficiency ; muscle problems ( inflammation or sprain etc) and many more. Need to know what the cause is- that is important. Please see your doctor. ...Read more
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Dr. Alan Ali Dr. Ali
1 other doctor agreed:
9
9
Living with Ongoing Pain (Tip)
Living with Ongoing Pain
Live with the pain instead of for the pain. ...See more
10
10
How much should I worry about calf pain?
Depends: It depends on the severity, frequency as well as the when and how. What makes it better or worse. One leg, both legs. Is it associated with swelling? Are there general health issues? Are you at risk for peripheral vascular disease? Do you have low spinal problems. Or does this come on only after vigorous exercise? ...Read more
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Dr. Warren Strudwick
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-6,420,859,582,590,282,000 | Health
Olfactory Neuroblastoma
When a cancer starts specifically in the nerves that affect your sense of smell, it is known as olfactory neuroblastoma. (Esthesioneuroblastoma is another name for this type of cancer.) An olfactory neuroblastoma often happens on the roof of the nasal cavity. It involves the cribriform plate, which is a bone between the eyes and located deep in the skull. Olfactory neuroblastoma is a rare form of cancer.
Symptoms
A number of symptoms and warning signs can indicate olfactory neuroblastoma:
• Pain around the eyes
• Stuffiness or congestion that worsens or doesn't improve
• Blockage of the nose
• Nasal drainage in the throat (postnasal drip)
• Watery eyes
• Nosebleeds
• Pus from the nose
• Face or tooth numbness
• Loose teeth
• Decreased sense of smell
• Loss of or change in vision
• Ear pain or pressure
• Trouble opening the mouth
• Enlarged lymph nodes in the neck
Diagnosis
A variety of different scanning techniques are helpful in examining the nasal cavity. These include X-rays, CT scans, and MRI. To gain additional information, your doctor may perform a biopsy. This is done by obtaining a tissue sample and examining it under a microscope to determine what kind of cancer is present.
Treatment
In most cases, the first treatment involved in a nasal cavity cancer, such as olfactory neuroblastoma, is surgery to remove the tumor. Often, this treatment is used to remove a wide swath of tissue around the cancer, as well, to help ensure that all the cancer has been removed. Wide local excision and medial maxillectomy are 2 procedures that are commonly done. These are invasive procedures that may require the reconstruction of part of the face, but these offer the best chance of long-term survival. In some instances, less invasive surgeries, such as endoscopic surgery using a thin flexible, lighted tube, might be possible.
Radiation therapy is also usually part of the treatment plan for olfactory neuroblastoma. This may be the primary treatment or it might be used after surgery to reduce the chances of the cancer returning. In some cases, chemotherapy may also be used to treat olfactory neuroblastoma.
You may need a combination of treatments involving radiation and chemotherapy after surgery to give you the best chance of survival.
Prevention
Research has found that people who are exposed to harmful chemicals and particles through work or other means have an increased risk of developing nasal cavity cancers. Some possible culprits include wood dust, flour, nickel and cadmium dust, glues, and formaldehyde and other solvents. Tobacco smoke may also be a contributing factor in developing an olfactory neuroblastoma. To protect yourself, avoid these substances as much as possible.
Managing olfactory neuroblastoma
Any cancer diagnosis is stressful, but there is hope for those with a diagnosis of olfactory neuroblastoma. The best thing you can do is be vigilant about your health and have a positive outlook about your treatments. Following a healthy diet and living as healthy a lifestyle as possible may play a role in your recovery, as well as preventing a recurrence of the cancer.
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-8,341,986,677,791,459,000 | How to Get Rid Of Nausea from Drinking, Pregnancy Fast
0
642
how to get rid of nausea
Having a nausea during pregnancy or menstrual period, from drinking too much alcohol, coffee, taking antibiotics, name it is one of the worst mood killers. It can also get too severe that it kills your productivity at work if not make you unable to report at work. This article will not all discuss common causes but also highlight how to get rid of nausea at home.
Why Do I Feel Nauseous? – What Causes Nausea
Nausea is the result of physiological changes in the body associated with the following factors:
1. Sun poisoning
2. Sinus drainage
3. Anxiety
4. Alcohol: After a night of drinking it is common to get a hangover that is often characterized by a nauseate feeling.
5. Drinking excess or very strong coffee
6. Side-effects of certain medications e.g. NSAIDs (painkillers), antibiotics etc.
7. Birth control pills
8. Pregnancy: It is common to get morning sickness while pregnant.
9. Menstruation periods: This is the result of hormonal fluctuations.
10. Infections: Nausea may be the result of viral e.g. stomach flu as well as bacterial infections.
11. Some perfume fragrances.
12. Medical conditions such as gastritis, kidney stones, acid reflux
13. Jet lag: If you have ever felt nauseated after travelling on a plane, then you might have experienced a jet lag. Related to jet lag, motion sickness can also lead to a nauseous feeling.
14. Use of certain herbal remedies such as kratom
15. Quitting smoking
16. Riding a roller coaster
17. Vigorous activities and exercises such as running, weight lifting etc.
18. Taking high doses of zinc supplements
How to Get Rid Of Nausea after Drinking Too Much Alcohol
how to get rid of nausea from drinking too much alcoholYou drank a few too many and now you have a killer nausea and other symptoms of hangover such as dizziness, splitting headaches, stomach upset etc. You are not alone. Many people go through this after a night of drinking.
According to the NHS Choices, alcohol is a diuretic. This means that when consumed, it deprives your body of its fluids leading to dehydration. Nausea and other symptoms associated with drinking too much alcohol are caused by the dehydration.
According to Columbia University, alcohol irritates the stomach lining, simulate higher secretion of gastric acids in the stomach, and lead to triglycerides buildup in the liver. These factors contribute to the nauseous feeling from drinking too much.
If you are looking to know how to cure nausea the morning after drinking excess alcohol, there is one fact that you need to know. There is truly no cure for hangover but you can control the nausea and other symptoms using the following home remedies:
Rehydrate and Rehydrate, Then Rehydrate Some More
Rehydrating the body is the best way to stop the nauseous feeling and other symptoms of hangover after a night of drinking.
This not only helps to restore the fluids lost from your body but also dilute natural chemicals (congeners) often added in alcoholic beverages. These impurities can worsen the hangover symptoms.
It is in fact advisable to drink at least half a liter of water before you go to bed, then continue sipping water throughout the night.
If you forgot to drink water the previous night – and while drinking – and now have terrible nausea and other symptoms of hangover to show for it, it is still not too late to gulp down water. It will take your hangover treatment efforts a long way.
Other than water, juice and other non-fizzy drinks can also help to return the lost body fluids and thus get rid of nausea faster after drinking too much alcohol. Bland drinks the likes of soda water, isotonic drinks (e.g. lucozade) etc. can also help to restore body fluids.
Avoid Caffeinated Beverages
Since coffee is a stimulant, some people claim that it can help you get started after a hangover. According to the Health Line website however, caffeine will only dehydrate you more and make your body tremble more as well as increase the nausea.
Choose Your Painkillers Wisely
Taking some painkiller medications is recommended for alleviation of the splitting headaches that usually develop after drinking overnight. Most people however make one grave mistake when buying the painkillers; they go for aspirin.
Aspirin can irritate the stomach even more not to mention worsen the nauseated, sickly feeling, says the NHS Choices website. The Health Line website also suggests staying away from acetaminophen (Tylenol) since it slows the rate of alcohol metabolism in your body. It can also cause damage to your liver.
Instead, the NHS Choice recommends taking Paracetamol-based medications. According to the Health Line website, ibuprofen also make a good choice for pain relieving medications. They are easily available in most pharmacies.
Break Some Eggs
Eggs are among the best foods to get rid of hangover symptoms such as nausea. They are rich in cysteine, an amino acid that helps to break down the harmful toxins built up in your system after a night of drinking. That way you will feel less nauseated and more energized.
Going overboard with fat or grease when preparing the eggs can however be counterproductive and make the nausea worse.
Eat a Banana, Pretzels, or Kiwi Fruits
When drinking, you lose lots of potassium and other essential salts and minerals from the body. When the body is low in potassium, you get nausea and tiredness among other symptoms.
Bananas are rich in potassium and will thus help replenish and rejuvenate your body. They also help to soothe the stomach while providing you with essential energy in the form of carbohydrates.
Kiwi fruits are also a great source of potassium. As for pretzels, they are rich in salt and taking bananas alongside bananas is particularly helpful.
Sip a Cup of Ginger Tea
Ginger is another great home remedy for nausea, vomiting, and stomach disturbances associated with excess drinking and other factors. Below are two guidelines on how to stop feeling nauseous after drinking too much alcohol:
1. Chop a fresh ginger root into thin slices.
2. Add them to 4 cups of water and then bring it to a boil for 10 minutes.
3. Strain the ginger out, then mix the juice with ½ cup of honey and the juice from half a lemon and half an orange.
4. Sip the resulting sweet mixture right away.
5. Repeat several times for the best post-drinking nausea relieving action.
Chewing small pieces of ginger throughout the day can also help to get rid of nausea.
Peppermint
Studies have also shown peppermint to be an effective remedy for nausea due to drinking too much alcohol and other causative factors. It can also relieve the often accompanying stomach upset. Peppermint is touted to help fasten the detoxification process while aiding in faster digestion. Below is how treat nausea naturally using this herbal remedy:
1. Get some fresh peppermint leaves and chew them gradually in the course of the day.
2. You can also steep 1 teaspoon dried peppermint leaves for 15 minutes and then strain to make a cup of tea. Enjoy the cup and prepare and take some more as necessary in the course of the day.
3. You may also find peppermint flavored gums such as Tic-Tacs helpful for nausea and other symptoms of hangover. Avoid taking too much of these since they are sugary and can make things worse if not taken in moderation.
Avoid Very Hot Showers
You wake up in the morning getting late for work or class, hit the shower, and after a quick hot shower, you end up feeling more nauseous than you did before. Why is it so?
According to savethestudent.org, although a long shower goes a long way in rejuvenating your energy-devoid body, very hot showers will only do the opposite. The excess heat will go to your head and increase nausea. So take a cold or warm shower, and if you can open the windows for some fresh air.
Other Tips to Get Rid Of Nausea and Other Symptoms from Drinking Too Much Alcohol
• Take a bowl of bouillon soup. This comes in handy in replacing the lost vitamins and minerals while getting you rejuvenated. It is especially helpful if your stomach s very irritated and you don’t feel like taking anything solid. A bowl of whole grain cereals is also helpful. Some people will also wear to the effectiveness of honey sandwiches.
• Don’t go back to drinking. “Hair of the dog”, “kutoa lock”. These are just of the terms used to refer to the habit of waking up to some alcohol as a way to relieve nausea and other symptoms. If thinking about it, don’t. It doesn’t actually help matters. It is like postponing a problem at the risk of getting it later, probably stronger.
How to Get Rid Of Nausea during Pregnancy
how to get rid of nausea while pregnantNausea and vomiting are common problems during pregnancy especially the first trimester. The collective term “morning sickness” is typically used to refer to them.
For pregnant women whether or not they will get nauseated is not as much relevant as the question, “when does nausea start during pregnancy?” Nausea and other symptoms of pregnancy begin at about week six. The symptoms last up to about 14 weeks. This can however vary from one person to another.
According to the American Pregnancy Association, up to 70 percent of women experience nausea and other pregnancy symptoms when pregnant.
Nausea and vomiting tend to strike early morning since you have had a chance to eat something, hence the term morning sickness, but you can get the nauseated feeling at any time of the day. This may be triggered by certain smells.
Nausea is indicative of a healthy pregnancy and is nothing to worry about, but can be relieved with the following home remedies:
Take Ginger
Ginger is among the best home remedies to get rid of nausea while pregnant. Also according to the NHS choices website, there has not been any reported cases of adverse effects of ginger to pregnant women.
As regards how to treat nausea with ginger, there are several options to consider:
• Ginger supplements: As the NHS Choices website reports, some preliminary studies have shown ginger supplements to be effective in making nausea and vomiting go away. Some pharmacies and supermarkets stock ginger supplements; start your search there.
• Ginger biscuits can also help to relieve nausea and vomiting during pregnancy.
• Ginger ale is another great home remedy for nauseous felling during pregnancy but the Baby Center suggests paying special attention to ensure that the ginger ale product of your choice is manufactured using real ginger.
• Ginger tea is also a nice natural way to go about combating pregnancy nausea. Grate a small piece of fresh ginger root and then boil it in a cup of water. Drink a cup every now and then and that nauseous feeling will so be cleared.
Stop the Nausea with Peppermint
Like ginger, peppermint has a strong aroma that helps to fight the nauseated feel and vomiting associated with early pregnancy. You can either make peppermint tea by steeping dry peppermint leaves or take some peppermint-flavored candies or gums.
Watch Your Eating Habits
An empty stomach worsens nausea and other pregnancy symptoms. It is not just about what you eat but also the intervals at which you eat. Here are useful dietary tips to observe when pregnant:
• Eat small meals frequently throughout the day as opposed to three large meals most people are used to.
• Avoid of fatty, sweet, and spicy foods and instead eat foods that are loaded with proteins and complex carbohydrates e.g. bread, pasta, rice. Fresh vegetables are also recommended. Eat your meals slowly as you are likely to feel nauseated when your stomach gets full quickly.
• Start your day with a cracker. The Baby Center recommends having them by your bedside and nibbling one or a few 30 minutes or so before you rise up in the morning. If you as well feel nauseous at night, take one and it will help you get the much needed relief.
• The NHS Choices recommends eating cold as opposed to hot meals since the latter tends to give out more of their aroma which can then trigger nausea.
• If you suspect any particular food or smell makes you nauseated, do away with it.
• Sip lots of fluids gradually in between meals including water, carbonated beverages, lemonades, sports drinks, etc.
Pay Attention to Your Body Movements
How you treat your body during pregnancy will determine whether you help stop nausea and vomiting or worsen them. Here are some beneficial considerations:
• Don’t go to sleep or lie down immediately – more so on your left side of your body – after you are through eating. This slows down the rate of digestion, which may then make nausea more severe.
• Rather than shoot out of bed in the morning or after a midday rest, rise up slowly, taking a couple minutes to sit down by the bedside.
• Avoid tight clothes, especially those that tighten you around the waist.
Make Yourself Forget About It
This sounds like a bizarre suggestion for a pregnancy nausea remedy but when it comes to nausea, nothing makes it more powerful than thinking about it. Think of any way to distract yourself from paying attention to the sickly feeling e.g. chatting with friends, playing a game, etc. and you will notice a huge difference.
Ace Your Dental Hygiene
When it comes to pregnancy, dental hygiene becomes ever more important. Nothing will dilute your nausea-fighting effort more than uncared for teeth and gum. Brush your teeth every time you are done eating. You should also floss and rinse your mouth with a mouthwash frequently.
Get Lots of Fresh Air
When it comes to pregnancy and vomiting during nausea, lack of fresh air is a big no-no. Keep the windows open and ensure that your house is well ventilated. If you have a fan, consider running it often. It also helps to walk about in fresh air outside.
Give Yourself Adequate Rest
Lying down frequently as your body needs is one of the easiest yet most effective natural remedies for morning sickness.
Turn to the Medication Cabinet for Solution
If none of the above home remedies for nausea during pregnancy are helping to keep the problem at bay, you may want to talk to your doctor or health care provider about taking some nausea medications.
It is also possible that too much iron is responsible for increasing nausea. Your doctor or healthcare provider may consider switching to another prenatal vitamin supplements.
According to the American Pregnancy Association, vitamin B-6 supplements have been shown to reduce nausea when pregnant. Talk to your healthcare provider about this option.
References
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3,715,657,675,884,893,700 | complement
complement
complementer, n.
n. /kom"pleuh meuhnt/; v. /kom"pleuh ment'/, n.
1. something that completes or makes perfect: A good wine is a complement to a good meal.
2. the quantity or amount that completes anything: We now have a full complement of packers.
3. either of two parts or things needed to complete the whole; counterpart.
4. full quantity or amount; complete allowance.
5. the full number of officers and crew required on a ship.
6. Gram.
a. a word or group of words that completes a grammatical construction in the predicate and that describes or is identified with the subject or object, as small in The house is small or president in They elected her president. Cf. object complement, subject complement.
b. any word or group of words used to complete a grammatical construction, esp. in the predicate, including adverbials, as on the table in He put it on the table, infinitives, as to go in They are ready to go, and sometimes objects, as ball in He caught the ball.
7. Geom. the quantity by which an angle or an arc falls short of 90° or a quarter of a circle. Cf. supplement (def. 4).
8. Also called absolute complement. Math. the set of all the elements of a universal set not included in a given set.
9. Music. the interval that completes an octave when added to a given interval.
10. Immunol.
a. a system in vertebrate blood of 12 or more proteins that react in a cascade to a cell displaying immune complexes or foreign surfaces, acting in various combinations to coat the cell and promote phagocytosis, make holes in the cell wall, or enhance the inflammatory response.
b. any of the proteins in the complement system, designated C1, C2, etc.
v.t.
12. to complete; form a complement to: This belt complements the dress better than that one.
13. Obs. to compliment.
v.i.
14. Obs. to compliment.
[1350-1400; ME < L complementum something that completes, equiv. to comple(re) to fill up (see COMPLETE) + -mentum -MENT]
Syn. 12. COMPLEMENT, SUPPLEMENT both mean to make additions to something. To COMPLEMENT is to provide something felt to be lacking or needed; it is often applied to putting together two things, each of which supplies what is lacking in the other, to make a complete whole: Two statements from different points of view may complement each other. To SUPPLEMENT is merely to add to: Some additional remarks may supplement his address.
Usage. COMPLEMENT and COMPLIMENT, which are pronounced alike and originally shared some meanings, have become separate words with entirely different meanings. As a noun, COMPLEMENT means "something that completes or makes perfect": The rare old brandy was a perfect complement to the delicious meal. As a verb, COMPLEMENT means "to complete": A bright scarf complements a dark suit. The noun COMPLIMENT means "an expression of praise, commendation, or admiration": The members paid her the compliment of a standing ovation. The verb COMPLIMENT means "to pay a compliment to": Everyone complimented him after the recital.
* * *
In physiology, a complex system of at least 20 proteins (complement components) in normal blood serum.
The binding of one component to an antigen-antibody complex begins a chemical chain reaction important in many immunological processes, including breakdown of foreign and infected cells, ingestion of foreign particles and cell debris, and inflammation of surrounding tissue. Complement components and antibodies are the substances in human serum responsible for killing bacteria.
* * *
▪ immune system component
in immunology, a complex system of more than 30 proteins that act in concert to help eliminate infectious microorganisms. Specifically, the complement system causes the lysis (bursting) of foreign and infected cells, the phagocytosis (ingestion) of foreign particles and cell debris, and the inflammation of surrounding tissue.
The interacting proteins of the complement system, which are produced mainly by the liver, circulate in the blood and extracellular fluid, primarily in an inactivated state. Not until the system receives an appropriate signal are they activated. The signal sets off a chemical chain reaction in which one activated complement protein triggers the activation of the next complement protein in the sequence.
Complement activation occurs by two routes, called the classical pathway and the alternative pathway, or properdin system. A different type of signal activates each pathway. The classical pathway is triggered by groups of antibodies (antibody) bound to the surfaces of a microorganism, while the alternative pathway is spurred into action by molecules embedded in the surface membranes of invading microorganisms and does not require the presence of antibodies. Both pathways converge to activate the pivotal protein of the complement system, called C3.
The activation of C3 fragments the protein into two pieces—a smaller piece, called C3a, which promotes an inflammatory reaction, and a larger piece, called C3b, which binds to the surface of a microbial cell. C3b helps bring about the elimination of the microbial invader in two ways:
● Bound C3b activates the formation of membrane attack complexes, structures composed of other complement proteins that poke holes into the membrane of the invading microorganism and allow the contents of the cell to leak out and the cell to die.
● The C3b-coated microorganism attracts white blood cells called macrophages and neutrophils and enhances their ability to ingest the microorganism or transport it to the liver or spleen for further processing.
Complement was identified in the late 19th century as one of two soluble proteins in human blood serum responsible for killing bacteria, the other substance being antibody. The original complement protein was called alexin, but its name was eventually changed to indicate how the protein “complemented” the action of antibody in carrying out bacterial lysis. The classical pathway was characterized in the early part of the 20th century, prior to the discovery of the alternative pathway, which was described in the 1940s but not fully appreciated until the 1970s. Because antibodies are not needed to activate the alternative pathway—but are required to set off the classical cascade—the alternative pathway serves as a first defense against infection and is part of the nonspecific, innate immune response, which occurs before a specific, acquired immune response can be mounted. The alternative pathway appears to be the more primitive of the two systems, and the nomenclature, therefore, indicates the sequence of discovery of the two pathways and not their evolutionary history.
* * *
Universalium. 2010.
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• complément — [ kɔ̃plemɑ̃ ] n. m. • 1308; de l a. fr. complir « remplir »; repris 1690; lat. complementum, de complere « remplir » 1 ♦ Ce qui s ajoute ou doit s ajouter à une chose pour qu elle soit complète. ⇒ achèvement, couronnement. Le complément est… … Encyclopédie Universelle
• complement — COMPLEMÉNT, complemente, s.n. 1. Ceea ce se adaugă la ceva spre a l întregi; complinire. 2. Parte secundară a propoziţiei care determină un verb, un adjectiv sau un adverb. 3. Substanţă de natură proteică prezentă în serul normal şi care… … Dicționar Român
• Complement — Complément Cette page d’homonymie répertorie les différents sujets et articles partageant un même nom … Wikipédia en Français
• Complément à 2 — Complément à deux Le complément à deux est une représentation binaire des entiers relatifs qui permet d effectuer les opérations arithmétiques usuelles naturellement. bit de signe 0 1 1 … Wikipédia en Français
• complement — COMPLEMENT. s. m. Ce qui s ajoute à une chose pour lui donner sa perfection. On dit en Théologie, Complément de béatitude, pour exprimer Le comble de la beatitude. La résurrection des corps sera le complément de la béatitude des Saints.Complément … Dictionnaire de l'Académie Française 1798
• complement — n Complement, supplement are comparable both as nouns meaning one thing that makes up for a want or deficiency in another thing and as verbs meaning to supply what is needed to make up for such a want or deficiency. Complement implies a… … New Dictionary of Synonyms
• Complement — Com ple*ment, n. [L. complementun: cf. F. compl[ e]ment. See {Complete}, v. t., and cf. {Compliment}.] 1. That which fills up or completes; the quantity or number required to fill a thing or make it complete. [1913 Webster] 2. That which is… … The Collaborative International Dictionary of English
• complement — complement, compliment, complementary, complimentary 1. Complement and compliment each function as noun and verb; in pronunciation they are largely indistinguishable except that in the verbal function compliment has a fuller i sound in its second … Modern English usage
• Complement — (v. lat. Complementum), 1) Ergänzung; 2) (Math.), C. einer Größe ist im Allgemeinen das, was zu dieser addirt werden muß, um ein gewisses Ganze zu erhalten. Complement eines Winkels od. Kreisbogens ist beziehungsweise derjenige Winkel od. Bogen,… … Pierer's Universal-Lexikon
• complement — ► NOUN 1) a thing that contributes extra features to something else so as to enhance or improve it. 2) the number or quantity that makes something complete. 3) a word or words used with a verb to complete the meaning of the predicate (e.g. happy… … English terms dictionary
• Complement a un — Complément à un Le complément à un est l opération qui inverse la valeur de chacun des bits d un nombre binaire. Il est la première étape du complément à deux. Exemple Ce document provient de « Compl%C3%A9ment %C3%A0 un ». Catégorie :… … Wikipédia en Français
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What is megaloblastic (pernicious) anemia?
Megaloblastic anemia, also called pernicious anemia, is a blood disorder in which there is anemia with red blood cells that are larger than normal. In addition to the cells being large, the inner contents of each cell are not completely developed. This malformation causes the bone marrow to produce fewer cells that die earlier than the 120-day life expectancy. Instead of being round or disc-shaped, the red blood cells can be oval. Megaloblastic anemia usually results from a deficiency of folic acid or of vitamin B-12.
What’re causes of megaloblastic (pernicious) anemia?
Deficiencies of vitamin B12 and folic acid are the most common causes of megaloblastic anemia. Other causes include:
Digestive diseases. Megaloblastic anemia is caused by certain diseases of the lower digestive tract ( include celiac disease, chronic infectious enteritis, and enteroenteric fistulas). Pernicious anemia is a type of megaloblastic anemia caused by an inability to absorb Vitamin B-12 due to a lack of intrinsic factor in gastric secretions.
Malabsorption. Inherited congenital folate malabsorption, a genetic problem in which infants cannot absorb folic acid in their intestines, can lead to megaloblastic anemia.
Drugs that affect DNA synthesis such as chemotherapy drugs, include phenytoin, primidone, and phenobarbital, can impair the absorption of folic acid.
Other causes are leukemia, myelodysplastic syndrome, myelofibrosis, alcohol abuse.
What’re symptoms of megaloblastic (pernicious) anemia?
The following are the most common symptoms of megaloblastic anemia:
Change in skin color
Diarrhea
Headaches
Loss of appetite
Pale skin color
Sore mouth and tongue
Tingling and numbness of hands and feet
Tiredness
How is diagnosis of megaloblastic (pernicious) anemia?
Megaloblastic (pernicious) anemia is usually discovered during a medical examination through a routine blood test. Diagnostic procedures for megaloblastic (pernicious) anemia may include:
Complete blood count (shows anemia with large red blood cells)
Bone marrow examination (can help show whether your bone marrow is healthy and making enough red blood cells)
Serum B12 (can help show vitamin B12 blood level)
Schilling test (detect vitamin B12 absorption)
Serum folate (can help show whether you have pernicious anemia or another type of anemia)
How is treatment of megaloblastic (pernicious) anemia?
The goal of treatment for megaloblastic (pernicious) anemia include preventing or treating the anemia and its signs and symptoms ; controlling complications, such as heart and nerve damage. The treatment depends on the cause. If the disorder is caused by an absorption problem in the digestive tract, this may need to be treated first. Usually treatment may include vitamin B12 injections and folic acid supplement.
Monthly vitamin B12 injections are prescribed to correct the vitamin B12 deficiency. This therapy corrects the anemia and may correct the neurological complications if taken soon enough. For less severe megaloblastic (pernicious) anemia, you should take large doses of vitamin B12 pills. A vitamin B12 nose gel and spray also are available. A well-balanced diet is essential to provide other elements for healthy blood cell development, such as folic acid, iron, and vitamin b12.
Which foods are contain rich folic acid and vitamin B12:
eggs
meat
poultry
milk
shellfish
fortified cereals
How is prevention of megaloblastic (pernicious) anemia?
If pernicious anemia is caused by a lack of intrinsic factor, you can’t prevent. If megaloblastic (pernicious) anemia is caused by not get enough vitamin B12 and folic acid in their diets, adequate intake of vitamin B-12 and folic acid is helpful.
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-6,957,924,362,758,393,000 | 3and and Fig
3and and Fig
3and and Fig. Bafilomycin A1 identification with the T-cell receptor (TCR) drives na?ve Compact disc4+ T cells to differentiate into effector T helper (Th) cell subsets, such as for example Th1, Th2, and Th17 cells, that afterwards become Bafilomycin A1 storage T helper type 1 (mTh1), mTh2, and mTh17 cells that orchestrate long-term antigen-specific immune system responses (1C3). Lately, predicated on disparate cytokine creation patterns, many distinctive mTh2 subpopulations have already been discovered functionally; Th2 + 1 cells, IL-17Cmaking Th2 cells, and high IL-5Cproducing pathogenic T helper type 2 (Tpath2) cells (4C7). Th2 + 1 cells generate IFN- furthermore to Th2 cytokines, IL-17Cmaking Th2 cells generate IL-17 and Th2 cytokines, as well as the high IL-5Cproducing memory-type Tpath2 cells exhibit ST2, an element from the IL-33 receptor. Tpath2 cells generate huge amounts of IL-5 after TCR arousal (7, 8). A number of these Th cell subpopulations have effector features that play essential assignments in the pathogenesis of Th1, Th2, and Th17 cell-mediated inflammatory illnesses (3). In comparison to models where in fact the stability of typical Th cell subsets Bafilomycin A1 (Th1, Th2, and Th17) establishes certain disease expresses, we’ve suggested a pathogenic Th people disease induction model, where the minority existence of unconventional Th cell subsets establishes disease (3). IL-33, a known person in the IL-1 family members, is certainly released from Bafilomycin A1 several cells, including epithelial cells, in response to mobile irritation or harm (9, 10). and so are genes well-known to become from the intensity of asthma symptoms (11). IL-33 arousal exacerbates allergic airway irritation and is connected with infiltration of eosinophils in to the mucosa (12). The IL-33 receptor comprising IL-1 and ST2 receptor accessories protein is certainly portrayed on several inflammatory cells, including type 2 innate lymphoid cells (ILC2s) and Tpath2 cells (8, 13). IL-33 is certainly essential in ILC2 cells for triggering creation of IL-13 and IL-5 and in addition, in Tpath2 cells for chromatin redecorating from the gene locus and up-regulation of ST2 appearance (8). It’s been reported a subset of Treg cells expresses ST2 (14). Treg cells suppress immune-mediated irritation (15, 16). ST2+ Treg cells are produced by TCR arousal in the current presence of IL-33 in an activity managed by IRF4, BATF, and PPAR (17). Helminth infections may induce the era of Th2 cells and Treg cells (18, 19). In this scholarly study, we utilized the nematode helminth (Nb). Nb goes by through the lungs before achieving the gut and it is expelled within 10 d in mice. Mice acquire and keep maintaining immunity against Nb for over 1 con. Nb induces deposition of Th2 cells in the lungs that peaked 10 d after infections (18). Helminth-induced Th2 cells generate IL-4, IL-5, and IL-13, which leads to raised serum IgE, eosinophilia, goblet cell hyperplasia, and eventually, helminth expulsion (20). The sort 2 inflammatory immune system response induced by helminth attacks is comparable to that IKK2 seen in allergic asthma (21). Helminth infections increased IL-33 amounts in the lungs (22), such as for example takes place during asthma pathogenesis, and IL-33 insufficiency impairs the expulsion and inhibition of maturation of worms (23). Nevertheless, the functionally vital subpopulation of mTh2 cells that induces immune system replies against helminth continues to be unknown. Within this research, we discovered CXCR6+ST2+ mTh2 cells that lessen the fecundity from the helminth, Nb, via the deposition of eosinophils expressing high degrees of main simple protein (MBP) in the lung (24). Notably, the reduced amount of fecundity induced by CXCR6+ST2+ mTh2 cells was suppressed with the ST2+ however, not the ST2? Treg cells elicited in Nb infections. We showed a molecular and cellular system fundamental the immune system response against helminth. Results Helminth Infections Induces IL-5CProducing ST2+ mTh Cells. We lately.
Categories: MT Receptors
Categories | {
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5,062,971,252,788,017,000 | The Immune System – What An individual Should Realize
The body is choose a defense system called the immune system and it is the response to problems from outside the particular body. When typically the immune system turns into bogged down that affects the wellness of the entire body. To help obtain optimal health, a dietary supplement developed especially for the immune system is needed. Sport nutrition that will certainly help the system during times of stress plus frustration, when it is at it is lowest and typically the body is a lot more susceptible to outside the house diseases.
The defense system consists involving cells, tissues plus soluble molecules that will provide your body’s security against pathogens plus tumor cells. More than thousands of years immune system has created a means regarding identifying and countering specific viruses and other agents attempting to be able to attack the body. Becoming tired or worn out is a form of pressure to some healthy immune system. Over these intervals, disease carrying brokers attempt to attack the body. The proof system requires big amounts of strength to fight off these agents that will are obtained via a healthy diet, exercise and dietary dietary supplements.
Ikaria lean Belly Juice requires a variety of vitamins, minerals and vitamins to do at their best, and when the particular system is fit and strong is the key to be able to a healthy human body. Common signs of an unhealthy system could be fatigue, allergies, colds and flu’s, slow healing and inflammation. Causes of these symptoms may be poor diet, excessive tension and not sufficient exercise.
The resistant systems function is always to identify invaders to the body and retain them out, or to seek all of them out and ruin them before these people can do ruin. The system will go through a number of methods before it attacks and destroys these types of organisms and elements trying to invade the body and create a disease. Parts of the system are antigen particular and have memory space. These parts allow the system to be able to act against particular invaders and enable it to recognize invaders that this has encountered before.
Typically the system needs to be supported throughout the entire 12 months, especially during the particular cold and flu seasons. It need to be strong enough to defend the entire body against germs and microorganisms which are seeking to cause problems each and every day. A dietary supplement containing several herbal products can support the machine by establishing free of cost radicals that can prevent damage to be able to healthy cells.
A way to ensure your immune method stays healthy and active is by using Resistant Support Capsules. These types of capsules contain a great array of elements that are regarding those fighting away attacks from international invaders to typically the body. They can be the must for methods that are compromised or for system’s that tend to be able to have lower immune system systems. it’s the must for preventing off those colds, flu’s and also other health problems.
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316,431,070,084,723,400 | What Does Pnf Stretching Stand For? (Best solution)
Proprioceptive Neuromuscular Facilitation (PNF) is a more advanced form of flexibility training. PNF involves both stretching and contracting (activation) of the muscle group being targeted in order to achieve maximum static flexibility.
What is PNF stretching and how should you use it?
• Proprioceptive Neuromuscular Facilitation (PNF) is a more advanced form of flexibility training, which involves both the stretching and contracting of the muscle group being targeted. PNF stretching is one of the most effective forms of stretching for improving flexibility and increasing range of motion. Oct 17 2019
What are the 3 types of PNF stretching?
The three main PNF techniques are hold-relax, contract-relax, and hold-relax with agonist contraction. If you’re unfamiliar with how these partner stretching techniques work, it’s best to consult a physical therapist or personal trainer.
What type of stretching is PNF?
PNF is an acronym for proprioceptive neuromuscular facilitation. It is not really a type of stretching but is a technique of combining passive stretching (see section Passive Stretching) and isometric stretching (see section Isometric Stretching) in order to achieve maximum static flexibility.
You might be interested: What Is The Purpose Of Static Stretching? (Solved)
What is PNF stretching best for?
PNF stretching is one of the most effective forms of stretching for improving flexibility and increasing range of motion. PNF stretching was originally developed as a form of rehabilitation, and to that effect it is very effective.
When is PNF stretching used?
Proprioceptive neuromuscular facilitation (PNF) is a stretching technique that can improve your range of motion. Many therapists use PNF to help people regain their range of motion after injury or surgery. However, it can also be used by athletes and dancers to improve their flexibility.
What is PNF stretching a level PE?
Proprioceptive Neuromuscular Facilitation (PNF) stretching PNF refers to a stretching techniques in which a muscle group is passively stretched, then contracts isometrically against resistance while in the stretched position, and then is passively stretched again through the resulting increased range of motion.
What is the concept of PNF?
Medical Definition of proprioceptive neuromuscular facilitation.: a method of stretching muscles to maximize their flexibility that is often performed with a partner or trainer and that involves a series of contractions and relaxations with enforced stretching during the relaxation phase —abbreviation PNF.
How does PNF assist rehabilitation?
PNF is a form of stretching designed to increase flexibility of muscles and increase range of movement. PNF is a progressive stretch involving muscle contraction and relaxation. Your physiotherapist will gently stretch the muscle and you will resist the stretch by contracting the muscle for about 5 seconds.
What does proprioceptive neuromuscular facilitation mean?
Proprioceptive Neuromuscular Facilitation (PNF) is a more advanced form of flexibility training. PNF involves both stretching and contracting (activation) of the muscle group being targeted in order to achieve maximum static flexibility.
You might be interested: Why Does Stretching Make Muscles Tight? (Solution found)
What is the difference between static and PNF stretching?
Two common methods of stretching in clinical practice are static stretching and proprioceptive neuromuscular facilitation (PNF) stretching. It is generally believed that PNF stretching will result in increased ROM compared with static stretching due to increased inhibition of the targeted muscle.
What is PNF used for?
Proprioceptive Neuromuscular Facilitation (PNF) is a stretching technique utilized to improve muscle elasticity and has been shown to have a positive effect on active and passive range of motions (Funk et al., 2003; Lucas and Koslow, 1984; Wallin et al., 1985).
What are some examples of PNF stretches?
PNF Stretching An example would be biceps and triceps in the arm and hamstrings and quadriceps in the leg. You should only do this form of stretching with the help of a qualified fitness specialist.
Why do we use PNF patterns?
Many times, PNF is used to increase flexibility, strength and coordination when there are deficiencies in the respective areas. It is thought that the education and reinforcement of repeated PNF patterns increases coordination while promoting joint stability and neuromuscular control.
What athletes would use PNF stretching?
This method of training is most suited to sports where the athlete’s joint may be forcefully taken beyond the active ROM. These sports include: rugby, Australian Rules Football, Ice-Hockey, and American Football.
How does PNF stretching assist active and passive range of motion?
PNF stretching, in particular, is all about activating certain muscle groups and lengthening them out until they’re at peak flexing position, then gently pushing back on them. This provides a level of resistance which enhances the muscle action.
You might be interested: What Mussle Needs Stretching Before Exercises? (TOP 5 Tips)
What type of stretching is also known as PNF quizlet?
commonly called proprioceptive neuromuscular facilitation,or PNF involves taking the muscle to its end ROM (point of joint compensation), actively contracting the muscle to be stretched for 7 -15 seconds, then passively moving the joint to a new end ROM and holding this position for 20-30 seconds.
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835,871,490,517,959,300 | Info
4 Steps of Aerobic Respiration
Aerobic respiration is a physiological process that takes place in your body to generate an energy molecule called adenosine-5'-triphosphate, or simply ATP. All of your body's cells rely on ATP for normal functioning. This is especially true as it relates to your musculoskeletal system, which requires a large amount of this molecule to allow for normal movement. There are four main steps during aerobic respiration, each of which contributes to the production of ATP.
Glycolysis
The first step in aerobic respiration is glycolysis, which literally means the breakdown of glucose. This process takes place in the cytoplasm, which is a jelly-like substance in your cells. During glycolysis, molecules of glucose are broken down to yield four molecules of ATP, two three-carbon molecules called pyruvate and two molecules of nicotinamide adenine dinucleotide, or NADH. Although four ATP molecules are created here, the net result is only two molecules of ATP. This is because glycolysis actually uses two ATPs during the first phase of the process to generate glyceraldehyde-3-phosphate.
Acetyl-CoA
The next step in aerobic respiration is the formation of acetyl-coenzyme A. This occurs in the mitochondria, which are small energy organelles within your cells. The pyruvate that was created during glycolysis is converted to a two-carbon acetyl group, which then combines with coenzyme A to produce acetyl-coA.
Krebs Cycle
The third step in aerobic respiration also takes place in your mitochondria. The acetyl-coA that was produced from pyruvate combines during the Krebs cycle to produce oxaloacetate, thus forming citrate. This citrate then undergoes several conversion steps to form the following compounds, in order: isocitrate, alpha ketoglutarate, succinyl-CoA, succinate, fumarate and malate. Along the way, one molecule of guanosine triphosphate (GTP), three molecules of NADH and one molecule of flavin adenine dinucleotide (FADH2), are produced. The GTP is then converted into a molecule of ATP.
Electron Transport Chain
The final step of aerobic respiration is the electron transport chain, or ETC. This last step uses the NADH and FADH2 that were created in previous steps to generate ATP. A lot of ATP, actually -- 34 molecules of ATP to be exact. The ETC accomplishes this large production of ATP by pumping out the hydrogens from the NADH and FADH2 to the inner membrane of your mitochondria, thus creating an electrochemical proton (H+) gradient. Chemical energy is therefore generated, and this energy is used to create energy in the form of ATP via the ATP synthase enzyme. | {
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3,105,076,050,276,162,600 | Self-Diagnosed Autism: Is It a Valid Diagnosis?
From Autism Parenting Magazine
By Yolande Loftus, BA, LLB, December 5, 2023
You’ve researched and pored over every reputable autism resource to check symptoms and characteristics of the neurodevelopmental condition. So many things finally make sense. But is self-diagnosed autism a valid diagnosis?
Self-diagnosed autism is controversial. Some in the autism community feel it’s a slippery slope to misdiagnosis, dilution of resources, and silencing of the “true” autistic voice.
There are actually many valid reasons to seek a medical diagnosis for autism spectrum disorder. Still, there may also be a case for self-diagnosis, especially for those who simply cannot afford a formal medical one.
The Challenges of Diagnosing Autism
Mental health professionals or pediatric neurologists often diagnose autism spectrum disorder in children. They use specific criteria, like that found in The Diagnostic and Statistical Manual of Mental Disorders.
The DSM–5 criteria for autism are concentrated in two core areas:
• Persistent deficits in social interactions and communication
• Restricted and/or repetitive behaviors (and sensory interests)
These impairments must be clinically significant and present early — although they may manifest later due to masking and other coping strategies, especially in so-called “high-functioning” individuals.
There are many challenges in diagnosing autism in adults, including:
• Recalling early memories and potential symptoms may be difficult for adults and their aging parents.
• It can be difficult to find a doctor with the training and knowledge to diagnose autism spectrum disorder outside the pediatric population.
• There are no widely accepted (or specific) diagnostic criteria for diagnosing autism in adults, and it’s easy to see how it may be difficult to obtain a diagnosis.
• Although there are tests available to determine if an adult is on the spectrum, they can be expensive and with a long waiting list.
These are just some practical realities that may be challenging to overcome when seeking a formal autism diagnosis. The emotional toll may be equally taxing.
From the neurodivergent perspective, phone calls, appointments, meetings, and conversing with various healthcare practitioners may be daunting. Parents with kids on the spectrum often tell us the hell of getting their child diagnosed.
Such parents often have the broad autism phenotype (BAP) and possess autistic traits, which may make the social interaction aspect of health appointments challenging.
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“I Think I Know More Than My Doctor…”
Few things are as maddening as describing certain characteristics and assuming everyone on the spectrum possesses them to a degree. While everyone is different, it does seem like a shared love of research is commonly found in adults seeking a diagnosis.
Before seeing a doctor or psychologist, many adults who think they might have autism already know a lot about it. If they meet with a practitioner who doesn’t understand the details of autism, like masking and camouflaging, they might feel disappointed if they know more than the mental health professional.
In a perfect scenario, an adult, like a parent who suspects they are on the autism spectrum after their child’s diagnosis, could easily schedule a comfortable appointment. A specialist would assess them in a location that meets their sensory needs.
Does this sound like wishful thinking? This is likely why many people feel that autism self-diagnosis is a better and safer choice.
In a 2019 study on psychiatrists’ understanding and views on autism, nearly half of the participants shared personal experiences with autism. This included parenting an autistic child, being on the spectrum themselves, or having connections with someone affected by autism.
This is not to say adults seeking a diagnosis should only seek out doctors with a personal connection to autism. However, in addition to specialized training, experience, and empathy, this could facilitate formal adult diagnosis.
Because even armed with research and hours of studying symptoms, self-diagnosing autism may still be incorrect and sometimes even dangerous.
The Risks of Self-Diagnosed Autism
Understanding yourself well can be a good reason for self-diagnosis. However, autism often comes with complex conditions such as neurodevelopmental and mental disorders, like schizophrenia and bipolar disorder. Simply knowing yourself may not be enough.
Even if autism was self-diagnosed accurately, a healthcare practitioner may view all symptoms objectively and holistically. Sometimes, they may diagnose comorbid conditions like anxiety and depression alongside autism.
Treatment or intervention for mental health issues needs specialist care. When self-diagnosing autism, there is a risk of missing co-occurring conditions or misdiagnosing as one condition masks or overlaps with another.
Self-diagnosing autism sometimes leads to self-treatment. Obtaining appropriate medication may be difficult without a formal medical diagnosis.
While adopting a healthy lifestyle and obtaining appropriate support may improve the lives of autistic people, many on the spectrum also need prescription medication and the services of therapists.
Being Different Is Not a Diagnosis
Advocates raising awareness and acceptance of neurodivergence did not expect that some would want to be on the spectrum just to stand out. The autistic community is often annoyed by those who self-diagnose autism because of seemingly superficial traits.
Their irritation is obvious. It stems from repeatedly pointing out the obvious: just because someone is a bit socially awkward and has strong interests doesn’t mean they’re autistic.
Treating the condition with glib fascination takes away from the struggle and pride of those who feel their identity and neurodivergence are interwoven.
Is There a Middle Ground?
The difficulty of obtaining a formal diagnosis of autism in adulthood means many will self-diagnose. In some cases, self-diagnosis will be accurate. But the case against self-diagnosis is strong, leading to many asking if there is a middle ground.
Perhaps the groundwork of self-diagnosis could be presented to an open-minded doctor. Many adults merely seek confirmation. For them, a lifetime of living with a differently wired brain leaves little doubt of being autistic.
Some adults seek such confirmation from a pediatrician, especially when the same specialist is diagnosing their child. Confirmation could mean appropriate treatment becomes available for these adults, and comorbid mood or anxiety disorders may be identified and treated.
Seeking out healthcare practitioners with experience and specialist knowledge of the presentation of autism in adults is the first step. While each individual on the spectrum is different, certain characteristics are commonly found in adults on the spectrum.
If autism was not diagnosed in childhood, it often indicates the adult may possess normal or high intellectual capabilities and the ability to mask symptoms for social acceptance.
In certain situations, social communication and sensory processing differences may, however, be obvious:
• Eye contact, for example, may not feel natural, but some adults on the spectrum force themselves to “look someone in the eye,” causing strain and discomfort.
• Non-verbal cues, small talk, and banter may be challenging for adults on the spectrum.
• In written communication, adults on the spectrum may not see the need for niceties, preferring to get to the point of the communication.
• Many adults on the spectrum feel safe when routines and structures are firmly in place.
• Being able to control sensory input helps self-regulation, which is why many adults feel safe at home, where they are in control.
• Special interests may be one of the greatest sources of pleasure for the autistic adult. Some manage to launch a successful career based on such interests.
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The Importance of Autism Diagnosis in Adults
A 2021 research article reveals the challenging nature of adult autism diagnosis. But studies also tell us about the enormous emotional impact of finally feeling validated by a diagnosis of autism in adulthood.
A different study notes that adults who have self-diagnosed autism also report feelings of understanding themselves better, relief, and joy in finding online communities.
Except for a few individuals who might seek attention, self-diagnosing autism is usually not about suppressing the real voice of autistic individuals or trying to represent neurodivergence without understanding its history.
Many adults who self-diagnose have struggled for years, never feeling like they fit in and hiding symptoms to be socially accepted.
Discovering an identity on the autism spectrum may lead to expressing feelings similar to those described in a study titled: Suddenly the first fifty years of my life made sense’: Experiences of older people with autism.
FAQs
Q: Is it common to self-diagnose autism?
A: Approximately one-third of individuals in the United States self-diagnose using online information, but diagnosing autism can be challenging. It is advisable to consult medical professionals to prevent misdiagnosis, as autism symptoms may resemble those of anxiety, depression, trauma, ADHD, bipolar disorder, and other conditions.
Q: Can you detect autism later in life?
A: A late diagnosis, defined as 12 years or older, is associated with increased mental health challenges. A recent study revealed that adults diagnosed with autism are nearly three times more likely than those diagnosed in childhood to report psychiatric conditions.
Q: Is there a autism self-diagnosis test?
A: Although there are some tests online, an accurate diagnosis can only be made through clinical evaluation. Autism self-diagnosis tests are only for personal use.
Q: What is autism sometimes mistaken for?
A: Some brain disorders, such as ADHD and anxiety disorders, share symptoms with autism. It’s possible for autism to be misdiagnosed as another disorder due to these overlapping symptoms.
Q: How do I confirm I have autism?
A: To obtain a precise adult autism diagnosis, it’s necessary to consult with a mental health professional. They will inquire, conduct evaluations, and observe your behavior, speech, and interactions during the assessment process.
References:
“Masking Is Life”: Experiences of Masking in Autistic and Nonautistic Adults
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8992921/
Exploring the Experience of Seeking an Autism Diagnosis as an Adult
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645668/
Understanding psychiatrists’ knowledge, attitudes and experiences in identifying and supporting their patients on the autism spectrum: online survey
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469236/
Medication Treatment for Autism
https://www.nichd.nih.gov/health/topics/autism/conditioninfo/treatments/medication-treatment
Comorbid autism spectrum disorder and anxiety disorders: a brief review
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772195/
Realizing a diagnosis of autism spectrum disorder as an adult
https://www.researchgate.net/publication/297616098_Realizing_a_diagnosis_of_autism_spectrum_disorder_as_an_adult
Real-World Experiences in Autistic Adult Diagnostic Services and Post-diagnostic Support and Alignment with Services Guidelines: Results from the ASDEU Study
https://link.springer.com/article/10.1007/s10803-021-04873-5
Diagnosis of autism in adulthood: A scoping review
https://pubmed.ncbi.nlm.nih.gov/32106698/
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4,836,454,042,234,958,000 | Xanax cause high blood pressure - Reliable Drugstore You May Rely on
Xanax cause high blood pressure
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-8,223,097,954,374,610,000 | You are here:
Massage therapy
Massage therapy is the treatment of the muscles and soft tissues in your body. It can help lower stress, ease tension in your muscles and make you feel more relaxed. Massage therapy is one of the most popular complementary therapies used by people living with cancer.
When having massage therapy, you usually lie on a table. You can wear either loose-fitting clothing or you can be undressed (with a sheet covering your body). Massage on your neck, arms and shoulders can be done while sitting in a chair. Sometimes the therapy rooms have low lighting and quiet music to help you relax during your treatment.
Massage therapy methods
There are many different types of massage therapy methods. A massage therapist may use just one type of massage or may combine different types during a treatment session.
Swedish massage is the most common type of massage therapy in Canada. The massage therapist uses long strokes, pressure, stretches and friction to loosen tight muscles.
Deep tissue massage is done with stroking and finger pressure on deep layers of muscle tissue, where muscles are tight or knotted.
Myotherapy may also be called trigger point or pressure point massage therapy. It is done with a variety of strokes and focused pressure to ease or release trigger points. Trigger points are knots of tight muscle tissue that may cause pain or limit range of motion. They can be painful when pressed during massage.
Lymphatic massage may also be called lymphatic drainage. It uses slow, light, rhythmic touch and pressure to help the body move lymph fluid throughout the lymphatic system. It is most often used to decrease lymphedema.
Reflexology is based on the theory that every part of our body is represented by a different area on our feet. Pressing on specific reflex points on the feet can treat the area of the body where there are blockages in energy flow. Sometimes the therapist may also use reflex points on the hands or ears. Reflexology is often used in relaxation therapy to encourage the body to function better under stress.
Oncology massage is a specialty where massage techniques are changed to meet the needs of people with cancer and undergoing cancer treatments.
Massage as a complementary therapy
There is no evidence at this time that massage therapy can treat cancer itself. There is evidence that massage therapy helps people with cancer physically and emotionally, and it can improve their quality of life.
People often use massage therapy to help reduce muscle soreness and stiffness. It can also help reduce pain (such as headaches and low back pain), anxiety and stress. It improves circulation and promotes relaxation and a sense of well-being. Studies have shown that massage therapy can help reduce stress, anxiety, pain, fatigue and depression. It can also help with problems sleeping (insomnia), improve sleep quality and reduce nausea.
A type of lymphatic massage called manual lymph drainage (MLD) can reduce the swelling from lymphedema in women with breast cancer.
Side effects and risks of massage therapy
Talk to your healthcare team if you’re thinking about trying massage therapy. Be sure to tell your massage therapist that you have cancer, any treatments that you have had or are having, and any medicines that you’re taking. Depending on your overall health and the conventional cancer treatments you are receiving, you may need to avoid certain types of massage.
If you have damaged blood vessels or a bleeding disorder, such as easy bruising and bleeding or blood clots, you should not have a massage. If you are taking blood thinners, you should avoid massage or only have very gentle, light touch massage to prevent bruising and bleeding.
If you have osteoporosis or a cancer that has spread to the bone (called bone metastasis), having physical manipulation or deep pressure massage may lead to a bone breaking (fracture).
If you have had radiation therapy, you may find it uncomfortable to have the treatment area touched, even lightly. If you do find massage comfortable but are still having radiation treatment, don’t use lotion or oil on the area that receives radiation.
Don’t have a massage if you have a fever or infection. If you have an open wound or sore, the therapist will not treat that area.
Some people have minor bruising or swelling or notice that their muscles feel even more sore shortly after a massage.
Allergic reactions are possible if aromatherapy oils are used during the massage.
Some people might worry that massage in the area of a tumour can increase the flow of blood and lymph fluid, causing cancer cells to break away and travel to other parts of the body. Recent evidence suggests that the speed of blood or lymph fluid circulation has nothing to do with the spread of cancer cells. Massage therapy is safe for people with cancer.
Finding a therapist
Massage therapy is a recognized healthcare profession. It’s important to have massage done by a registered massage therapist (RMT). Some provinces and territories have professional massage therapy associations that make sure that therapists are properly trained and follow professional standards. Private healthcare plans may require a doctor’s prescription for massage therapy and will only cover massage given by an RMT.
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-5,042,822,420,023,995,000 | Dr. Alex Jimenez, El Paso's Chiropractor
I hope you have enjoyed our blog posts on various health, nutritional and injury related topics. Please don't hesitate in calling us or myself if you have questions when the need to seek care arises. Call the office or myself. Office 915-850-0900 - Cell 915-540-8444 Great Regards. Dr. J
Doctor of Chiropractic, Dr. Alexander Jimenez breaks down how pinched nerves cause back and neck pain.
You hear people say it a lot:
“I have a pinched nerve, and wow, it hurts.”
But what exactly is a pinched nerve? How does it cause back pain or neck pain? What are the symptoms of a pinched nerve—beyond pain? And most importantly, what can you do about a pinched nerve? Learn the basics of pinched nerves here.
Pinched Nerves: A Common Cause of Back & Neck Pain
What Is A Nerve?
Nerves are your body’s messengers. They transport signals to and from your brain—messages like “Move this toe” or “Ouch, that cactus needle really is sharp.” You have a central nervous system, which is made up of your brain and spinal cord. You also have a peripheral nervous system, which is the system of nerves that branches off the brain and spinal cord.
What Do Nerves Look Like?
If it helps, think of nerves like a garden hose (except they aren’t green). They have an outside membrane that transports those electrical messages. Inside nerves, there’s a fluid that nourishes and replenishes the outer membrane.
You’re Getting on My Nerves
When a nerve gets pinched, the messages and the nourishing fluid don’t flow quite as well as they should (still helpful to think of a garden hose here). A pinched nerve can start sending the “Ow, pain” message to the brain, and it can also have trouble communicating clear messages, possibly leading to weakness, numbness, or tingling.
What Can Pinch a Nerve?
As a nerve exits the spinal canal, it can be pinched by a herniated disc or a bone spur. Bone spurs, also known as osteophytes, are bony bumps that can develop on a spinal joint over time. They can push into the spinal nerve, as you can see in this illustration (red = pain generator, of course).
What Does a Pinched Nerve Feel Like?
A pinched nerve mostly feels like pain. If you have a pinched nerve in your low back, it can cause pain to travel (or radiate, in doctor-speak) down your leg. You may also know that as sciatica. A pinched nerve in the neck can create pain that shoots down your arm. Other symptoms of pinched nerves include muscle spasms, burning, tingling, and a hot/cold sensation.
Now the Good Stuff: Pinched Nerve Treatments
Pinched nerve treatments fall into two categories: what you can do at home (self-care) and what your doctor may prescribe for you.
Pinched Nerve Self-care #1: Heat and Ice
Heat and ice can work wonders on a pinched nerve. Switch between 20 minutes of heat and 20 minutes of ice—and remember that you shouldn’t put the heat and ice packs directly on your skin.
Pinched Nerve Self-care #2: Get a Massage
The muscles around a pinched nerve can become tight, so having a professional massage therapist work the painful area can bring pain relief. You may also consider a handheld massager.
Pinched Nerve Self-care #3: Take a Walk
Let’s say it’s your low back—a pinched nerve in your low back—that’s hurting you. A nice, easy stroll is a good way to stay active and address your pain. Gone are the days of extended bed rest for back pain: doctors now are more likely to recommend you exercise and stretch to help relieve your pain.
When Should You Call a Doctor?
If you try the self-care thing and yet your pinched nerve pain persists, you should consider calling the doctor. If you’ve been in pain for more than a couple of days, schedule an appointment. You should also call the doctor if you experience a very sudden onset of weakness, or if you experience profound numbness. Losing bowel and/or bladder control is also a good reason to call the doctor.
How a Doctor Treats a Pinched Nerve
The doctor will try to diagnose the cause of your pinched nerve, and then the doctor will be able to develop a treatment plan. That plan may include prescription pain medications, physical therapy, or cortisone injections. But keep this in mind: the treatment plan will be specifically tailored for you, and it’s in your best interest to follow it closely.
Dr. Alexander Jimenez ♛
Advanced Chiropractic & Wellness Authority ⚕ Healthcare Educator • Injury, Sciatica Specialist • 915-850-0900 📞
We Welcome You 👊🏻.
Purpose & Passions: I am a Doctor of Chiropractic specializing in progressive, cutting-edge therapies and functional rehabilitation procedures focused on clinical physiology, total health, practical strength training, and complete conditioning. We focus on restoring normal body functions after neck, back, spinal and soft tissue injuries.
We use Specialized Chiropractic Protocols, Wellness Programs, Functional & Integrative Nutrition, Agility & Mobility Fitness Training and Cross-Fit Rehabilitation Systems for all ages.
As an extension to effective rehabilitation, we too offer our patients, disabled veterans, athletes, young and elder a diverse portfolio of strength equipment, high-performance exercises and advanced agility treatment options. We have teamed up with the cities premier doctors, therapist and trainers to provide high-level competitive athletes the possibilities to push themselves to their highest abilities within our facilities.
We’ve been blessed to use our methods with thousands of El Pasoans over the last three decades allowing us to restore our patients’ health and fitness while implementing researched non-surgical methods and functional wellness programs.
Our programs are natural and use the body’s ability to achieve specific measured goals, rather than introducing harmful chemicals, controversial hormone replacement, un-wanted surgeries, or addictive drugs. We want you to live a functional life that is fulfilled with more energy, a positive attitude, better sleep, and less pain. Our goal is to ultimately empower our patients to maintain the healthiest way of living.
With a bit of work, we can achieve optimal health together, no matter the age or disability.
Join us in improving your health for you and your family.
It’s all about: LIVING, LOVING & MATTERING! 🍎
Welcome & God Bless
EL PASO LOCATIONS
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6440 Gateway East, Ste B
Phone: 915-850-0900
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8,885,615,317,385,399,000 | Angiogenesis and vascular permeability occur following endothelium activation by vascular endothelial
Angiogenesis and vascular permeability occur following endothelium activation by vascular endothelial growth element (VEGF). and vascular permeability. Pharmacological inhibition of PI3K (α/β) suppressed both Ras- or VEGF-mediated vascular response endothelial cell morphogenesis assay using human being umbilical vein endothelial cells (HUVEC) expressing RasV12 RasV12S35 and RasV12C40 was performed. Representative photographs are demonstrated in Fig. 1A top and the total tube size (mm) in three independent (10×) fields is definitely demonstrated in Fig. 1A bottom. Compared with VEGF RasV12 and RasV12S35 induced a significant increase in formation of capillary-like tubular constructions AR-C155858 that are sustained for up to 120h vs. 72h for VEGF. This is sustained by constitutive activation of the Erk/PI3K from the selective Ras mutations. In the VEGF treatment an immediate activation of ERK/PI3K is definitely induced by VEGF followed by depletion/inactivation of the VEGF from your serum at 37°C with time (Supplemental Fig. S1 A). Significantly HUVEC expressing RasV12 and RasV12S35 induced related levels of branching morphogenesis while RasV12C40 failed to induce tube formation. Further treatment of HUVEC expressing RasV12S35 or RasV12C40 with VEGF generates little increase in morphogenesis without a synergistic effect (Supplemental Fig. S1 B). These findings reveal that Ras-induced activation of the ERK/MAPK pathway in cultured HUVEC is sufficient to induce tube formation while activation of PI3K is not. Number 1 Selective activation of the ERK/MAPK pathway by AdRasV12S35 is sufficient to AR-C155858 produce angiogenesis and was assessed by ectopic manifestation of Ras mutations in the chick chorioallantoic membrane (CAM). Filter disks saturated with AdRasV12 AdRasV12S35 or AdRasV12C40 were placed on the CAM of 10-day-old chick embryos (N=24 for each treatment) and the angiogenic response was assessed 5 days post-infection (Materials and Methods). Representative images of the angiogenic response to treatments are demonstrated in Fig. 1B. Lysates of the transduced CAMs were evaluated for Ras manifestation ERK- and PI3K-activity by immunoblotting specific antibodies to Ras P-Erk and P-Akt [Ser473] (Fig 1C). A designated angiogenic response associated with triggered Erk was recognized in the CAMs treated with VEGF or those expressing RasV12 and RasV12S35 compared with settings (Fig. 1C D). CAMs expressing RasV12C40 showed no angiogenic response or Erk activation (Fig. 1C D) even though phosphorylation of Akt in these cells is observed (Fig. 1C). Ectopic manifestation of RasN17 a dominating bad Ras [S17→N17] disrupted the angiogenic response to VEGF in CAMs (Fig. 1D) indicating that Ras activation is required for the angiogenic response downstream of VEGF. Detergent lysates of AR-C155858 these CAMs (15 min after VEGF treatment) were evaluated for Ras manifestation ERK and PI3K-activity as AR-C155858 above (Fig 1C). Our findings show that Ras-induced selective activation of the ERK/MAPK pathway is sufficient for neovascularization both and (Fig. S3) we identify co-localization of increased P-Erk and CD31 in AdRasV12S35 treated sections (Fig. S4B) and co-localization of increased P-Akt and CD31 in AdRasV12C40 treatment (Fig. S4B b) relative to control treatment (Fig. S4B c). Control AdGFP-treated sections were stained for CD31 (Fig. S4B c) or treated with secondary antibodies alone prior to staining for P-Erk and P-Akt (Fig. S4B d). To determine if ectopic manifestation of RasV12 RasV12S35 and RasV12C40 prospects to AR-C155858 modified VEGF manifestation we isolated the total RNA form these cells and performed reverse transcription followed by Real-Time Quantitative PCR analysis PIK3C3 of VEGF-A manifestation relative to the endogenous gene cyclophilin (CPH) (Methods). We found no evidence of increased VEGF-A manifestation with RasV12 RasV12S35 and RasV12C40 over-expression in the mouse ears (Table S1). Additionally treated cells did not display altered VEGF levels by western blotting (data not demonstrated) indicating that VEGF half-life has not been modified by post-translational stabilization upon adenoviral treatment. To exclude AR-C155858 additional potential paracrine effects induced from the Ras mutations we have evaluated additionally effects of numerous autacoid inhibitors and the PI3K δ/γ inhibitor TG100-115 within the vascular permeabilitity induced by RasV12C40 (Supplemental Materials and Methods Number S5 A-F). TG100-115 clogged the transendothelial flux of FITC-fluorescent beads associated with RasV12C40 (Number S5 B) while the NO inhibitor Nω-Nitro-L-Arginine the serotonin.
History Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory discomfort however the
History Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory discomfort however the precise system implicated in these results isn’t completely elucidated. administration of comprehensive Freund’s adjuvant (CFA) we examined the antiallodynic (von Frey filaments) and antihyperalgesic (plantar check) results made by the subplantar administration of JWH-015 as well as the reversion of their results by the neighborhood co-administration with CB2R (AM630) peripheral opioid receptor (naloxone methiodide NX-ME) or CB1R (AM251) antagonists. Appearance of CB2R and NOS1 aswell as the antinociceptive results produced by a higher dosage of JWH-015 coupled with different dosages of selective L-guanylate cyclase (ODQ) or Olmesartan PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP route blocker (glibenclamide) had been also assessed. Outcomes show that the neighborhood administration of JWH-015 dose-dependently inhibited the mechanised and thermal hypersensitivity induced by CFA which results had been totally reversed by the neighborhood co-administration of AM630 or NX-ME however not AM251. Inflammatory discomfort elevated the paw appearance of CB2R as well as the dorsal main ganglia transcription of NOS1. Furthermore the antinociceptive ramifications of JWH-015 had been absent in NOS1-KO mice Olmesartan and reduced by their co-administration with ODQ Rp-8-pCPT-cGMPs or glibenclamide. Conclusions/Significance These data Mouse monoclonal to CD37 suggest which the peripheral antinociceptive ramifications of JWH-015 during chronic inflammatory discomfort are mainly made by the neighborhood activation from the nitric oxide-cGMP-PKG-KATP signaling pathway prompted by NOS1 and mediated by endogenous opioids. These results claim that the activation of the pathway may be an interesting healing target for the treating chronic inflammatory discomfort with cannabinoids. Launch The activation of both cannabinoid receptors 1 (CB1R) and 2 (CB2R) decrease nociception in various animal discomfort models [1]-[3]. Nevertheless as the analgesic potential produced from the arousal of CB1R is normally accompanied with many central site-effects the administration of selective CB2R agonists decreases nociception without leading to those results [4]. As a result the peripheral antinociceptive results made by selective CB2R agonists after regional inflammation have already been demonstrated in a number of functions [2] [5]-[7]. It really is popular that CB2R are generally situated in the peripheral anxious program but although an elevated expression of Olmesartan the receptors has been showed in the dorsal main ganglia and paw of pets with severe (inflammatory discomfort [2] [8] [20]. Our outcomes support and broaden this hypothesis within a chronic style of inflammatory discomfort at 10 times after CFA shot. The CB2R specificity from the inhibitory results induced by JWH-015 was showed by the entire reversion of their results with the neighborhood co-administration using a selective CB2R however not a CB1R antagonist. Furthermore the actual fact that the best dosage of JWH-015 didn’t generate any significant impact in the contralateral paw of CFA-injected mice denotes the peripheral site of actions of this medication. Our data also present that although persistent inflammatory discomfort didn’t alter the peripheral mRNA or proteins degrees of CB2R in the dorsal main ganglia it does increase their appearance in the paw. Olmesartan That is relative to the unchanged appearance of the receptors seen in the dorsal main ganglia of pets with bone-cancer induced chronic discomfort [3] aswell regarding the elevated expression of these seen in the paw of pets with severe inflammatory discomfort [8]. Hence our outcomes support these data and broaden theme to chronic inflammatory discomfort conditions. It really is known which the antinociceptive results produced by a particular CB2R agonist (AM1241) are mediated through the discharge of β-endorphins which may actually action at μ-opioid receptors on the terminals of Olmesartan principal afferent neurons to create peripheral antinociception during severe inflammation and bone tissue cancer discomfort [3] [17]-[18]. Our outcomes demonstrated which the antiallodynic and antihyperalgesic results made by JWH-015 had been totally reversed by their regional co-administration using a peripherally performing opioid receptor antagonist. These results uncovered that during chronic inflammatory discomfort the opioid-mediated antinociception produced from the activation of peripheral CB2R by JWH-015 can be functional. Relative to the books [21] our outcomes also showed that chronic inflammatory discomfort induced a humble upsurge in the dorsal main ganglia transcription of NOS1 which didn’t correlate with an elevated protein expression.
Chronic myeloid leukemia is certainly effectively treated with imatinib but reactivation
Chronic myeloid leukemia is certainly effectively treated with imatinib but reactivation of BCR-ABL frequently occurs through acquisition of kinase domain mutations. of the kinase domain is compromised and all ABL sequence beyond the kinase domain is eliminated. Although we speculated that BCR-ABL35INS is kinase-inactive recent reports propose this mutant contributes to ABL TKI resistance. We present cell-based and biochemical evidence establishing that BCR-ABL35INS is kinase-inactive and does not contribute to TKI resistance and we find that detection of BCR-ABL35INS does not consistently track with or explain resistance in clinical samples from chronic myeloid leukemia patients. Introduction Imatinib is an inhibitor of BCR-ABL the tyrosine kinase Rabbit Polyclonal to DNA Polymerase alpha. that causes chronic myeloid leukemia (CML). Most newly diagnosed patients achieve durable remissions on imatinib therapy 1 2 but 10%-15% fail to respond or relapse. The leading cause of imatinib resistance is reactivation of BCR-ABL because of kinase domain point mutations. Most BCR-ABL mutants are susceptible to alternative ABL tyrosine kinase inhibitor (TKI) therapies.3-8 Sequencing of the BCR-ABL kinase domain in patients exhibiting signs of TKI treatment failure has also revealed the presence of alternatively spliced variants including BCR-ABL35INS in which retention of 35 intronic nucleotides at the exon 8/9 splice junction introduces a stop codon after 10 intron-encoded residues.9-13 The result is loss of the last 653 residues of BCR-ABL including 22 native kinase domain residues.10 12 Notably the reported frequency of detection of the BCR-ABL35INS mutant in cases of imatinib resistance (including instances in which a point mutation is concurrently detected in the BCR-ABL kinase domain) as detected by direct sequencing is ～1%-2% 10 14 although more sensitive quantitative assays have reported detection of very low levels of the mutant transcript at a considerably increased prevalence.14 Although BCR-ABL truncated immediately after the ABL kinase domain is fully transforming in a murine model of CML 15 we predicted BCR-ABL35INS would lack kinase activity because the mutation eliminates the last 2 helices of the ABL kinase domain and disrupts a complex set of interactions among noncontiguous residues.10 By contrast recent reports have suggested that BCR-ABL35INS confers TKI resistance in CML9 12 14 16 and have proposed a BCR-ABL35INS tailored clinical trial 16 but they have not addressed the mechanism for this or assessed BCR-ABL35INS catalytic activity. We provide AS 602801 cell-based and biochemical studies of BCR-ABL35INS and a retrospective analysis of its detection in the context AS 602801 of treatment and response in CML patients. Methods AS 602801 IL-3 withdrawal Ba/F3 cells cultured in standard media (RPMI 1640 media 10 FBS l-glutamine penicillin-streptomycin; Invitrogen) containing IL-3 from WEHI-conditioned media were infected with retrovirus expressing BCR-ABL BCR-ABL35INS or BCR-ABLK271P/35INS (MSCV-IRES-GFP) and stable cell lines were sorted for GFP (FACSAria II; BD Biosciences). After IL-3 withdrawal cells were counted daily.17 Ba/F3 immunoblotting Ba/F3 parental cells and Ba/F3 cells expressing or coexpressing BCR-ABL BCR-ABL35INS or BCR-ABLK271P/35INS were boiled for 10 minutes in SDS-PAGE loading buffer. Lysates were separated on 4%-15% Tris-HCl gels transferred and immunoblotted with antibodies for the BCR N-terminus (3902; Cell Signaling Technology) ABL C-terminus (24-11; Santa Cruz Biotechnology) phospho-ABL (Y412 AS 602801 [1b numbering] and Y393 [1a numbering]; Cell Signaling Technology) or α-tubulin (T6074; Sigma-Aldrich). Imatinib dose response Ba/F3 BCR-ABL cells were infected with retrovirus carrying BCR-ABL35INS BCR-ABLK271P/35INS or empty vector (MSCV-IRES-GFP) and cells were sorted by FACS for GFP. Resultant cell lines were plated in escalating concentrations of imatinib in quadruplicate and proliferation was assessed after 72 hours. Analogous experiments were conducted with transfected GFP-sorted K562 cells. ABL autophosphorylation and peptide-substrate assays Autophosphorylation assays that used GST-ABL (residues 220-498) AS 602801 GST-ABL35INS (220-474 then YFDNREERTR-STOP) 10.
Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity
Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity minimizes toxicity and provides a promising new chemical entity for treatment of ocular NV. Artemisinin and they are transcriptionally activated by hypoxia-inducible factor-1 (HIF-1) (17 Artemisinin 18 Thus an alternative strategy to accomplish “combination therapy” for neovascular diseases is to develop inhibitors of HIF-1. To achieve this goal a cell-based reporter assay was developed to screen for drugs that inhibit HIF-1 Artemisinin transcriptional activity. This screen recognized digoxin and other cardiac glycosides and the anthracycline chemotherapeutic brokers doxorubicin (DXR) and daunorubicin (DNR) as potent inhibitors of HIF-1-mediated gene transcription (19 20 Digoxin functions by reducing HIF-1 levels while DXR and DNR have no effect on levels and exert their effect by blocking the binding of HIF-1 to DNA. In tumor xenograft models DXR and DNR suppressed the expression of multiple angiogenic factors and reduced tumor angiogenesis and tumor growth. This provides an explanation for the previous clinical observation that low-dose anthracyclines inhibit tumor angiogenesis the basis for metronomic therapy (21). We previously exhibited that digoxin prevents upregulation of several proangiogenic factors in ischemic retina and suppresses retinal and choroidal NV (22). In this study we investigated the effects Artemisinin of DXR and DNR in models of ocular NV including a nanoparticle-based controlled release strategy for delivery of DXR-polymer conjugates. 2 Methods 2.1 Animals Pathogen-free C57BL/6 mice (Charles River Wilmington MA) and Dutch belted rabbits (Robinson Services Inc Mocksville NC) were treated in accordance with the Association for Research in Artemisinin Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research and the guidelines of the Johns Hopkins University or college Animal Care and Use Committee. 2.2 Synthesis of PSA-PEG3 polymer Poly[(sebacic acid)-co-(polyethylene glycol)3] (PSA-PEG3) was synthesized by melt polycondensation. Briefly sebacic acid (Sigma-Aldrich St. Louis MO) was refluxed in acetic anhydride (Sigma-Aldrich St. Louis MO) to form sebacic acid prepolymer (Acyl-SA). Citric-polyethylene glycol (PEG3) was prepared as previously explained (41) using methoxy-poly(ethylene glycol)-amine (CH3O-PEG-NH2 ) Mn 5 0 (Rapp Polymere GmbH Tubingen Germany). CH3O-PEG-NH2 2 g citric acid (Sigma-Aldrich St. Louis MO) 26 mg dicyclohexylcarbodiimide (DCC Acros Organics Geel Belgium) 83 mg and 4-(dimethylamino)pyridine (DMAP; Acros Organics Geel Belgium) 4 mg were added to 10 mL dichloromethane (DCM) (Fisher Pittsburgh PA) stirred overnight at room heat then precipitated and washed with anhydrous ether (Fisher Pittsburgh PA) and dried under vacuum. Next Acyl-SA (90% w/w) and PEG3 (10% w/w) were placed into a flask under a nitrogen gas blanket and melted (180°C) and high vacuum was applied. Nitrogen gas was swept into the flask after 15 minutes. The reaction was allowed to proceed for 30 minutes. Polymers were cooled to ambient heat dissolved in chloroform (Sigma-Aldrich St. Louis MO) and precipitated into extra petroleum CD7 ether (Fisher Pittsburgh PA). The precipitate was collected by filtration and dried under vacuum to constant weight. Polymer structure was verified by 1H nuclear magnetic resonance (NMR) spectroscopy in CDCl3 (Bruker Avance 400 MHz FT-NMR Madison WI). The excess weight percentage of PEG estimated by 1H NMR was 10.5%. The PSA-PEG3 polymer was characterized by gel permeation chromatography (GPC) (JASCO Easton MD). The weight-average molecular excess weight (Mw) of the polymer was 26.7 kDa with a polydispersity index of 2.10. 2.3 Preparation of DXR-polymer particles DXR-PSA-PEG3 particles were prepared using an oil-in-water emulsion method. First PSA-PEG3 and DXR (NetQem Durham NC) were dissolved in DCM (Fisher Pittsburgh PA) at defined ratios and concentrations. For nanoparticles 80 mg PSA-PEG3 and 20 mg DXR were dissolved in 6 mL DCM and 2 mL dimethyl sulfoxide (DMSO) (Fisher Pittsburg PA). For microparticles 200 mg PSA-PEG3 and 40 mg DXR were dissolved in 3 mL DCM and 1.5 mL DMSO. The combination was incubated at 50°C for 2 hours before homogenizing (L4RT Silverson Machines East Longmeadow MA).
The success of gene therapy in the ocular environment is partly
The success of gene therapy in the ocular environment is partly due to the presence of hyaluronan in vitreous. PF 573228 transgene PF 573228 manifestation. Deletion of these proteolytic sites in CD44 also inhibits transgene manifestation. Expression of CD44 having a mutation to prevent phosphorylation of serine 325 inhibits the response to vitreous. Manifestation of the CD44 intracellular website enhances transgene manifestation in the absence of vitreous. CD44-mediated enhancement of gene manifestation was observed with vectors using different promoters and appears because of an increase in mRNA production not because of an increase in vector transduction as determined by quantitative RT-PCR and quantitative PCR respectively. These data match a model where the connection of hyaluronan in vitreous and CD44 modulates transgene manifestation by initiating CD44 proteolysis and launch of the cytoplasmic website resulting in PF 573228 improved transgene PF 573228 transcription. and (8). To further increase upon these observations we analyzed signaling mechanisms of CD44 CD164 and their part in the modulation of Ad transgene manifestation in the presence of vitreous. One mechanism of CD44 signaling entails sequential proteolysis and liberation of its intracellular website (CD44ICD) (9) a process studied extensively in malignancies (10) and somatic cells (11). The first step in this process is the cleavage and dropping of the extracellular website of CD44 by one of several matrix metalloproteases (MMPs) (12). The remaining CD44 peptide becomes the substrate of the γ-secretase complex. This enzymatic complex cleaves CD44 within its transmembrane website and liberates the CD44ICD into the cellular cytoplasm (13). The CD44ICD then translocates to the nucleus where it can regulate gene manifestation (14). Additionally CD44 is known to become phosphorylated at two serines in its intracellular website at residues 291 and 325. These phosphorylations have been shown to potentially regulate the connection of CD44 with cytoskeletal parts (15). Phosphorylation at serine 325 has also been shown to be necessary for facilitating the connection of CD44 with HA (16). Multiple viral gene transfer strategies could potentially benefit from understanding the mechanism of improved transgene manifestation through CD44-mediated signaling. Here we explore the potential of this approach to increase IL-12 production after gene transfer. IL-12 is definitely a proinflammatory cytokine secreted by dendritic cells that among additional functions promotes cytotoxic T cell and NK cell activity (17). The anti-tumor effects of IL-12 have been analyzed previously by administering recombinant IL-12 into a mouse model of neuroblastoma (18) PF 573228 as well as others have explored changes of cells with Ad-IL12 vectors to induce an anti-tumor immune response after infusion into animal models of neuroblastoma (19) and glioblastoma (20). Although medical software of PF 573228 IL-12 therapy offers thus far not demonstrated robust effectiveness (21) achieving higher levels of IL-12 manifestation in modified immune cells or within the tumor itself could potentially enhance tumor killing using this strategy. The studies reported here show the vitreous-mediated enhancement of Ad transgene manifestation happens under multiple promoters and is seen with Ad5 vectors that enter the cell via coxsackie and adenovirus receptor (CAR) or with Ad5F35 vectors that enter the cell via the Ad35 receptor CD46. These studies also demonstrate the connection of HA with CD44 plays a significant part in regulating vitreous-mediated enhancement of Ad transgene manifestation. This enhancement was found to result in an increase in transgene transcription without an increase in Ad vector transduction effectiveness. We further demonstrate the inhibition of MMPs or the γ-secretase complex by small molecule inhibitors significantly decreases Ad transgene manifestation for 10 min and the supernatant was aliquoted and freezing. Luciferase Assay To assay luciferase activity cells plated inside a 96-well plate (2 × 104 cells/well) were washed once with PBS and lysed in 50 μl/well reporter lysis buffer (Promega Madison WI). 5 μl of cell lysate was added to 50 μl of luciferase substrate (Promega) and combined softly by flicking. Luminescence was averaged for 12 s using a luminometer. Counts per second were converted into light models (LU) by a standard curve using.
nonionic surfactant vesicles or SPANosomes (SPs) made up of cationic lipid
nonionic surfactant vesicles or SPANosomes (SPs) made up of cationic lipid and sorbitan monooleate (Span 80) had been synthesized and examined as siRNA vectors. beacons mainly because probes for cytosolic delivery. The outcomes demonstrated efficient endosomal get away and cytosolic delivery from the siRNA cargo pursuing internalization from the SP/siRNA complexes. To conclude Period 80 CCT239065 can be a powerful helper lipid as well as the SPs are guaranteeing automobiles for siRNA delivery. software23. Today’s function explored the potential of the nonionic surfactant Period 80 co-formulated with DOTAP and TPGS like a delivery program for siRNA. The SP/siRNA formulation was proven to possess good colloidal balance (Shape 1) and high siRNA launching actually at high NA/SP percentage (1/2.5) and raised percentage of TPGS (Shape 2). Furthermore the tiny particle size and moderate surface area charge of SP/siRNA complexes (Shape 2) are appealing features that may create a prolonged blood flow period23 41 The complexes of SP with 5% TPGS although displaying a more substantial particle size than complexes of SP with 1% TPGS still continued to be under 200 nm42. The complexes of SP with 5% TPGS could possibly be good for applications by reducing plasma proteins binding and staying away from RES uptake because of increased PEGylation denseness for the particle surface area42 43 Cryo-TEM pictures from the SP/siRNA complexes demonstrated how the complexes had been mainly unilamellar core-shell contaminants and had been distinct through the multilamellar constructions from the liposome/siRNA complexes31 44 The multilamellar constructions from the liposome/siRNA complexes had been formed as the adversely charged CCT239065 siRNA substances could actually keep adjacent membranes collectively44. The specific morphology from the SP/siRNA complexes means that the Period 80 including membrane may possess completely different properties through the lipid bilayer which CCT239065 can avoid the membranes from developing multilayered constructions. Transfection experiments demonstrated how the SP/siGFP complexes with NA/SP percentage < 1/5 led to a significant reduced amount of GFP manifestation (Shape 5A). The perfect NA/SP percentage for SP/siRNA complexes was discovered to become 1/15. Further lowers in the NA/SP percentage did not lead to better knockdown from the GFP gene. An identical trend continues to be observed both in polymer-45 and liposome-46 mediated siRNA transfection previously. Set alongside the trusted cationic liposome centered transfection reagent LF SP accomplished markedly higher GFP silencing activity in the complete dosage range (5~100 nM). SP/siGFP was 5.2-fold far better in GFP silencing than LF at 40 nM. Furthermore the SP/siArom complexes had been shown to efficiently silence the endogenous aromatase gene displaying 77% knockdown in SKBr-3 cells at a siRNA focus of 40 nM (Shape 6). Furthermore the high transfection effectiveness of this book vector was followed by minimal cytotoxicity (Shape 4). For both GFP and aromatase gene silencing the actions of SP with 1 % and 5%TPGS weren't statistically significant recommending an increased percentage of TPGS in the SP formulation didn't significantly influence the transfection activity. Because adding even more PEGylated lipids to cationic liposomes offers been shown to lessen RES clearance47 and decrease their cytotoxicity7 SP with higher TPGS percentages enable you to attain optimal blood flow half-time and lower toxicity delivery of siRNA and warrants further analysis. ACKNOWLEDGMENT This ongoing function was Mmp24 support partly by NSF Give EEC-0425626 NIH Give R01 CA135243 and R21CA131832. The authors desire to say thanks to Mike Darby for offering the aromatase inhibitor 7α-APTADD and Bryant Chinung Yung for the beneficial comments CCT239065 and suggestions about the manuscript. Sources 1 Bumcrot D Manoharan M Koteliansky V Sah DW. RNAi therapeutics: a potential fresh course of pharmaceutical medicines. Nat Chem Biol. 2006;2(12):711-719. [PubMed] 2 Akinc A Zumbuehl A Goldberg M Leshchiner Sera Busini V Hossain N Bacallado SA Nguyen DN Fuller J Alvarez R Borodovsky A Borland T Constien R de Fougerolles A Dorkin JR Narayanannair Jayaprakash K Jayaraman M John M Koteliansky V Manoharan M Nechev L Qin J Racie T Raitcheva D Rajeev KG Sah DW Soutschek J Toudjarska I Vornlocher Horsepower Zimmermann TS Langer R Anderson DG. A combinatorial collection of lipid-like components for delivery of RNAi therapeutics. Nat Biotechnol. 2008;26(5):561-569. [PMC free of charge content] [PubMed] 3 Palliser D Chowdhury D Wang QY Lee SJ Bronson RT Knipe DM Lieberman J. An siRNA-based microbicide protects mice.
The mechanisms that regulate the acidification of intracellular compartments are key
The mechanisms that regulate the acidification of intracellular compartments are key to host defense against pathogens. determined the effect of imatinib on the growth of the major human pathogen in macrophages. In summary our results identify the control of phagosomal acidification as a novel function of Abl tyrosine kinase and provide evidence AKT inhibitor VIII that the regulation occurs on the level of the vacuolar-type H+-adenosine triphosphatase. Given the efficacy of imatinib in a mouse model of tuberculosis and our finding that orally administered imatinib increased the ability of human serum to trigger growth reduction of intracellular M. tuberculosis clinical evaluation of imatinib as a AKT inhibitor VIII complementary therapy of tuberculosis in particular multidrug or extremely drugresistant disease is AKT inhibitor VIII warranted. Lysosomes are subcellular organelles that function to digest cellular debris and aid in the destruction of AKT inhibitor VIII microbial pathogens. These functions in cell homeostasis and host defense are dependent on the acidification of lysosomes providing the optimal environment for the activation of degradative enzymes. Definition of the mechanisms that regulate the acidification of intracellular compartments Ctsd will provide new insights into host defense against AKT inhibitor VIII microbial pathogens. Recent studies indicate that lysosome function is regulated by the Abelson AKT inhibitor VIII (Abl) tyrosine kinase (1). The Abl kinase gene family consists of the Abl tyrosine kinase (Abl1) its paralog Arg and the oncogenic fusion protein Bcr-Abl (2). Abl tyrosine kinase is turned on in response to intracellular or extracellular stimuli. Activation causes ATP-dependent relationships with multiple mobile focuses on including cytoskeletal protein that organize actin dynamics and cell migration (2). Even more particularly Abl tyrosine kinase favorably regulates autophagy by orchestrating the localization and activity of glycosidases cathepsins and lysosomes recommending that Abl tyrosine kinase can be involved in digestive function and removal of personal- and international materials (1 3 Chromosomal translocation from the breakpoint cluster area gene towards the ABL gene generates the Bcr-Abl fusion proteins leading to constitutive Abl tyrosine kinase activity and persistent myeloid leukemia (CML) (4). This sentinel locating continues to be translated into medical recommendations and pharmacological inhibition of Abl tyrosine kinase by imatinib (STI571) may be the current regular treatment for early-stage CML (5). Imatinib neutralizes Abl tyrosine kinase activity by competitive displacement of ATP through the binding pocket. Regardless of the wide practical activity of Abl tyrosine kinase the procedure is normally well tolerated. Instead of many other tumor treatments imatinib will not increase the threat of attacks raising the interesting possibility it helps immune effector systems. as well as the sponsor cell kinase interact and influence the results of infection. Lately it was proven that silencing of ABL1 impacts the growth from the in-tracellular pathogen (7) which inhibition of Abl tyrosine kinase decreases the bacillary fill inside a mouse style of tuberculosis (8). Because limitation of mycobacterial development needs the acidification of phagosomes we hypothesized that Abl tyrosine kinase regulates the acidity in lysosomes and modulates the development of and human being macrophages. With this research we demonstrate that Abl tyrosine kinase settings phagosomal acidification by modulating the manifestation from the proton pumping enzyme vacuolar-type H+-adenosine triphosphatase (vATPase). Imatinib-added in vitro or after dental administration- strengthens the antimicrobial activity of human being macrophages against and really should be examined as an adjuvant therapy against drug-resistant tuberculosis. Components and Strategies Cell tradition reagents Cells had been cultured in RPMI 1640 moderate (Biochrom) supplemented with glutamine (2 mM; Sigma-Aldrich) 10 mM HEPES 13 mM NaHCO3 100 μg/ml streptomycin 60 μg/ml penicillin (all from Biochrom) and 5% heat-inactivated human being Abdominal serum (Cambrex) (= full moderate [CM]). For the tradition of bronchoalveolar lavage (BAL) cells streptomycin was changed by amphotericin B (5.6 μg/ml).
Rationale Deficient response inhibition is a prominent feature of many pathological
Rationale Deficient response inhibition is a prominent feature of many pathological conditions characterised by impulsive and compulsive behaviour. on various behavioural measures such as response inhibition perseveration sustained attention error monitoring and motivation. Results Blockade of α2-adrenoceptors improved sustained attention and response inhibition whereas α1 and β1/2 adrenergic receptor antagonists disrupted go performance and sustained attention respectively. No relevant effects were obtained after targeting DA D1 D2 or D4 receptors while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour though generally impairing other task measures. Conclusions Our results suggest that the use of specific pharmacological Rabbit polyclonal to beta Actin. agents targeting α2 and β noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity whereas DA D3 receptors may modulate error monitoring and perseverative behaviour. value was obtained by multiplying the number of GoRTs in the distribution by the probability of responding on stop trials at one given SSD. To obtain the SSRT the respective SSDs were subtracted from the in GoRT after a failed stop trial it is usually a negative value (see discussion). A significant change in PES in the experiments here described is interpreted as a change in the capacity of the animal to use errors to guide subsequent behaviour Adoprazine (SLV313) and/or as a Adoprazine (SLV313) variation in speed-accuracy trade-off strategy. Finally the number of nose-pokes made into the food well during TO periods (total nose-pokes divided by the total number of TO periods; NP/TO) thus when there is no programmed consequence for this action is considered as a measure Adoprazine (SLV313) of perseveration and the latency to collect the reward from the food well (RCL) is interpreted as a measure of motivation. Drugs Drug doses were adapted from available published data or chosen from previous dose-response curve experiments and published functional neurochemistry data. Solutions were freshly prepared every day. Different groups of animals were used for each drug and at least 2?days were allowed between drug injections. During the time between the administration of the compound and the beginning of the task animals where singly housed in holding cages and left undisturbed in a quiet room. All drugs were administered via intraperitoneal injections at a volume of 1?ml/kg and according to a randomized Latin square design unless otherwise stated. Atipamezole (α2 adrenoceptor antagonist) A group of 14 animals (350-400?g) were injected with the highly selective α2 antagonist atipamezole (Pertovaara et al. 2005; Antisedan Pfizer). Atipamezole (0.03 0.1 0.3 plus vehicle) Adoprazine (SLV313) was diluted in 0.9?% saline and administered 45?min before test sessions (Haapalinna et al. 1998; Scheinin et al. 1988; Sirvio et al. 1993; Virtanen et al. 1989). Three animals were excluded from the final analysis for violation of the race model assumptions (final only at doses below ~3?mg/kg when administered via intraperitoneal injection (Levant and Vansell 1997). Thus since the effects observed in the present experiment are significantly different from the control condition only at 3? mg/kg it is possible that they are partly due to the drug’s action on D2 receptors. Both nafadotride and 7-OH-PIPAT increased performance monitoring/adjustment as measured by PES which may be mediated by the mesolimbic DA system where D3 receptors are located (Sokoloff et al. 1990; Stanwood et al. 2000). Although all the behavioural effects of D3 ligands arose in a context of psychomotor depression the increase in PES cannot be readily assimilated to motor impairments for the way this variable is calculated. However for both compounds the beneficial effects on performance control or compulsive nose-poking did not translate in improved stopping. The relatively similar effects produced by administration of D3-preferring agonist and antagonist are puzzling but not surprising. For instance both agonist (Duarte et al. 2003b) and antagonist (Vorel et al. 2002) have been shown to attenuate cocaine-induced conditioned place preference. Finally the similarity of the behavioural effects elicited by nafadotride and 7-OH-PIPAT may be due to the characteristic biphasic dose-effect relationship exhibited by D3.
It has been shown previously that norbinaltorphimine (norBNI) and 5?-guanidinonaltrindole (5?-GNTI)
It has been shown previously that norbinaltorphimine (norBNI) and 5?-guanidinonaltrindole (5?-GNTI) long-acting kappa opioid receptor (KOPR) antagonists cause Mubritinib (TAK 165) frenzied scratching in mice [1;2]. The absence of KOPR in KOPR ?/? mice was confirmed with radioligand binding using [3H]U69 593 Taken together our data suggest that the presence of kappa receptors is not required for the excessive scratching caused by zyklophin. Thus zyklophin similar to the structurally different KOPR antagonist Mubritinib (TAK 165) 5?-GNTI appears to act at other targets to elicit scratching and potentially the sensation of itch. receptor binding study For confirmation of the deletion of the kappa receptor in KOPR ?/? mice both knockout mice and the wild-type counterparts were kept for two weeks after the injection of zyklophin to give sufficient time for elimination of the peptide. Mice were euthanized with CO2 gas and the brains removed. The forebrain was collected and weighed. For homogenization ice-cold 50 mM Tris-HCl and 1 mM EDTA buffer pH 7.4 was used in a 1:6 w/v ratio with a Fisher F60 Sonic Dismembrator for 20 s. Knockout and wild-type samples were run side by side. Binding was performed in 50 mM Tris-HCl buffer containing 1 mM EGTA (pH 7.4). The selective KOPR agonist [3H]U69 593 (2 nM) was used with 200 GRIN2B μl homogenate for a final volume of 1 mL. Naloxone (10 μM) was used to define nonspecific binding. The reaction mixture was incubated for 1 hr at room temperature and terminated by filtration under reduced pressure with GF/B Mubritinib (TAK 165) filters presoaked with 0.1 mg/ml BSA and 0.2% polyethyleneimine. Filters were washed three times with ice-cold 50 mM Tris-HCl buffer containing 0.15 M NaCl (pH 7.4). Radioactivity on filters was determined by liquid scintillation counting. Data analysis All data were analyzed for significance with the Student’s t-test in GraphPad Prism 6.0 (La Jolla CA). Statistical significance was defined as P ≤ 0.05. All data are expressed as values ± S.E.M. Results Zyklophin causes scratching in a dose-dependent manner Zyklophin induced scratching by 1 min after s.c. injection into the nape of the neck of male Swiss-Webster mice. The incidence of scratching was dose-related (0.1 0.3 and 1 mg/kg) over the 30 min observation period (Fig. 2). Most of the scratching occurred within 15 min of injection and was essentially over after 30 min. Figure 2 Zyklophin induced scratching in a dose-dependent manner when injected s.c. into the nape of neck in male Swiss-Webster mice. Each value represents mean ± S.E.M. (n=6-12). Mice injected with saline had < 5 bouts of scratching/30 ... Pretreatment with norBNI does not attenuate zyklophin-induced scratching Mice pretreated with norBNI (20 mg/kg i.p.) 18-20 hr before s.c. injection of 0.3 mg/kg zyklophin did not show a statistically significant (P=0.3887) decrease in scratching behavior compared with saline pretreatment (Fig. 3). This dose of norBNI given i.p. 18-20 hr before saline did not cause scratching (data not shown). Figure 3 Pretreatment of mice with norBNI (20 mg/kg i.p.) 18 hr before zyklophin (0.3 mg/kg s.c.) Mubritinib (TAK 165) did not attenuate zyklophin-induced scratching. Each value represents mean ± S.E.M. (n=6). Zyklophin-induced scratching persists in KOPR ?/? mice KOPR ?/? mice injected with zyklophin (0.3 mg/kg) did not show a statistically significant (P=0.5998) lower level of scratching behavior in comparison to wild-type C57BL6/J mice (Fig. 4). The number of scratches in C57BL6/J mice was much fewer than that observed in Swiss-Webster mice given the same dose of zyklophin. To confirm deletion of the KOPR [3H]U69 593 radioligand binding was performed on brain homogenates. There was no specific binding of [3H]U69 593 in brains of KOPR ?/? mice while there were appreciable levels of specific binding in the wild-type animals (684 ± 178 dpm/1.3 mg protein). Figure 4 Deletion of the KOPR did not attenuate zyklophin (0.3 mg/kg s.c.)-induced scratching in C57BL6/J male mice. Each Mubritinib (TAK 165) value represents mean ± S.E.M. (n=6). Discussion We found that zyklophin (0.1-1 mg/kg) a short-acting KOPR antagonist elicited Mubritinib (TAK 165) dose-dependent scratching when injected s.c. in the nape of the neck of mice. Most of.
Inflammatory bowel diseases (IBD) are seen as a chronic swelling from
Inflammatory bowel diseases (IBD) are seen as a chronic swelling from the intestinal tract connected with an imbalance from the intestinal microbiota. fusion proteins such as for example anti-TNF medicines. Notwithstanding the high price involved these natural therapies show a higher index of remission allowing a significant decrease in instances of medical procedures and hospitalization. Furthermore migration inhibitors and fresh cytokine blockers certainly are a promising alternative for treating individuals with IBD also. With this review an evaluation of books data on natural remedies for IBD can be approached with the primary focus on treatments predicated on growing recombinant biomolecules. 1 Intro The part of intestinal milieu in immune system homeostasis is apparently of higher significance than it had been previously believed. This complicated interplay of hereditary microbial and environmental elements culminates inside a suffered activation from the mucosal immune system and nonimmune reactions. Under normal circumstances the intestinal mucosa is within circumstances of “managed” swelling regulated with a sensitive stability of Th1 Th17 Th2 Th3 Th9 and Treg cells [1-6]. Inflammatory colon illnesses (IBD) are linked to an immunological imbalance from the intestinal mucosa primarily connected with cells from the adaptive disease fighting capability which react against self-antigens creating chronic inflammatory circumstances in these individuals. NVP-ADW742 Ulcerative colitis (UC) and Crohn’s disease (Compact disc) will be the most researched types of inflammatory colon diseases getting the highest prevalence in the globe human population. The pathophysiological systems of IBD aren’t fully realized although these illnesses have been found out several years ago [7-10]. In today’s work we try to review the existing approaches for dealing with IBD concentrating on the new treatments predicated on natural substances. 2 Inflammatory Colon Disease It really is well known that the amount of bacterias in the gastrointestinal tract is approximately 10 instances higher in comparison with eukaryotic cells in the torso. Also the standard enteric bacterial flora can be a complicated ecosystem of around 300-500 bacterial varieties [11 12 Furthermore the balance from the innate and adaptive immunity is crucial because of this microenvironment homeostasis. With this feeling the disease fighting capability has the essential NVP-ADW742 role of NVP-ADW742 advertising immune system tolerance thereby preventing the particular immune system response against the top mass of commensal bacterias. The neighborhood immunity in intestinal mucosa is actually guaranteed by gut connected lymphoid cells (GALT) constituted by Peyer’s areas lymphoid follicles and mesenteric lymph nodes [13]. Along with mobile environmental and hereditary elements deregulation of immune system reactions in the intestinal mucosa continues to be from the etiology of IBD. Modifications in the autophagy-a mobile process linked to the degradation of intracellular pathogens antigen digesting rules of cell signaling and T cell homeostasis-usually leads to decreased clearance of pathogens therefore adding to the starting point of inflammatory disorders in vulnerable topics [14 15 With this feeling mutations on ATG16L1 gene an associate of a family group of genes involved with autophagy were recognized in individuals with Compact disc [16]. The damage of self-antigens tolerance in the intestinal mucosa by damage or hereditary predisposition can lead to Compact disc or UC [17 18 Cells from the innate immunity such as for example macrophages and dendritic cells are specific in determining microorganism’s molecular patterns utilizing the design reputation receptors (PRR) such as for example toll-like receptors (TLR) and nucleotide-binding oligomerization domains (NOD). In this respect mutations in the caspase recruitment domain-containing proteins 15 (Cards-15) gene encoding the NOD-2 proteins were from the event of IBD specifically Compact disc. NOD2 can be an intracellular microbial sensor that works while a potent regulator and activator of swelling. Therefore deficiency with this proteins promotes essential changes for the immune system response in the lamina propria creating a chronic swelling in the cells. NVP-ADW742 Clinically it Rabbit Polyclonal to Cytochrome P450 2A6. really is of interest to look for the romantic relationship between NOD2 gene position and the effectiveness of antibiotic treatment in Compact disc [19-22]. Also the imbalance between Th1 and Th2 cytokines released from the intestinal mucosa determines the strength and duration from the inflammatory response in experimental colitis [23]. The secretion of particular cytokines such as for example tumor necrosis factor-alpha (TNF-is in charge of triggering the creation of inflammatory cytokines in cells from the innate disease fighting capability adding to the boost from the swelling. | {
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6,993,270,672,542,681,000 | COVID-19 Style Guide
Updated August 14, 2020
On this page:
Centers for Disease Control and Prevention
Use the full name on first reference. CDC may be used on second reference.
coronaviruses
The family of viruses that includes SARS-CoV-2, which causes the disease COVID-19 (coronavirus disease 2019).
The new coronavirus (using the article the) may be used in reference to the virus that causes COVID-19.
COVID-19
Short for coronavirus disease 2019, the disease caused by the SARS-CoV-2 virus. Symptoms vary and can include fever, cough, difficulty breathing and/or loss of taste or smell, but individuals with COVID-19 may experience mild or even no symptoms.
Do not use COVID-19 to refer to the virus that causes it. Never shorten to COVID unless it is used in a quotation.
current
When writing about health and safety guidelines or best practices associated with the COVID-19 pandemic, be sure to communicate that what’s being discussed reflects the most current information. COVID-19 continues to be a developing situation, and guidelines may change.
For up-to-date information about official university guidelines, visit UB’s Health and Safety Guidelines webpage. Additional information may also be found on the Centers for Disease Control and Prevention Coronavirus (COVID-19) website and the New York State Department of Health Novel Coronavirus website.
face covering
Current health and safety guidelines require all students, faculty, staff and visitors to wear a face covering over the nose and mouth at all times while on campus. Varieties include surgical masks, multilayer cloth masks or N95 masks, which are tight-fitting, cup-shaped masks that filter the air.
Face covering is more accessible than face mask and is preferred as a general term. However, face mask or mask may be used in graphic design applications, such as signs or posters, where space may be limited. Default to face covering in longer articles, documents or web copy.
face shield
A protective transparent visor secured around or over the head and covering the entire face. A face shield is a specialized type of personal protective equipment and is not expected to be worn on campus except in specific circumstances by health care professionals or as required by individual units. A face shield, though a type of face covering, is generally not a substitute for a more fitted face covering like a surgical mask, but an individual may use a face shield in lieu of a fitted face covering when there is a valid medical reason why that person cannot wear a face covering. Therefore, it is important to practice physical distancing when using a face shield alone.
isolation
The practice of separating sick people, such as those with confirmed cases of coronavirus infection, from others to contain the spread of contagious diseases.
Isolation is different from quarantine; do not use them interchangeably. Though the process of separation may be similar, isolation pertains specifically to individuals confirmed (or presumed with a high degree of certainty) to be infected, while quarantine pertains specifically to individuals who may have been exposed but have not been confirmed to be infected.
personal protective equipment
Equipment, such as face coverings or gowns, worn to reduce exposure to dangers such as contagions.
Always use personal protective equipment. Do not use PPE unless in a direct quotation, making sure to spell it out later.
physical distancing
The current health and safety guidance to individuals to maintain a minimum 6 feet of distance between themselves and others outside their home.
Preferred over social distancing.
quarantine
The precautionary practice of separating a person who might have been exposed to a contagion such as the new coronavirus from others prior to the possible development of infection. Not everyone who quarantines will necessarily develop infection. Current guidelines recommend that members of the UB community who have not returned to campus since it first closed in mid-March of 2020 quarantine for seven days before returning to campus, while those traveling from states with high rates of community spread are required to quarantine for 14 days. Quarantining individuals should stay home, monitor their health and follow additional guidelines from health experts.
Quarantine is different from isolation; do not use them interchangeably. Though the process of separation may be similar, quarantine pertains specifically to individuals who may have been exposed but have not been confirmed to be infected, while isolation pertains specifically to individuals confirmed (or presumed with a high degree of certainty) to be infected. | {
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1,289,160,690,463,647,500 | Ina May Gaskin On Giving Birth Without Fear (VIDEO)
Home Birth Guided By Midwives That Stand Behind Ina May Gaskin Giving Birth Without Fear
Ina May Gaskin, MA, CPM, Ph.D. is the director, and founder of the Farm Midwifery Center located in Tennessee. In this TED Talk, Ina speaks on "Reducing Fear Of Birth In U.S. Culture".
How Ina May Gaskin Coaches Giving Birth Without Fear
When many Americans think about giving birth, the main thing they think about is the pain involved. The fear and anxiety that the anticipation of pain that childbirth can bring often makes the last weeks of pregnancy, as well as the birth itself, a negative experience for many women.
However, Ina May Gaskin believes giving birth without fear can make the entire experience of labor and birth a more positive one.
Ina May Gaskin is one of the foremost midwives in the U.S. Her ideas about the fear of giving birth have to lead to a drastic change in the way many women and their caregivers or partners approach to birth, so that fear isn’t the primary feeling that accompanies it.
Find a Midwife
Tips To Experience Less Fear During Labor and Birth
Women in labor can take on many activities that can reduce their pain and discomfort during labor. Among these are taking short naps, eating when hungry, drinking when thirsty and getting out of bed to move around and to dance. Kissing her partner can help her to relax, and it creates a more supportive atmosphere.
When helping a woman through labor, Ina May Gaskin suggests avoiding giving her a rough examination that will only cause her to tense up. Instead, create a calm atmosphere and encourage her with the right words when she’s afraid.
How To Stay Calm and Open During Birth
Women have to open up to give birth, and allowing her to be calm and to feel secure can help this process. To help her to dilate, keep the lights low and the noise and commotion to a minimum. If the mother becomes afraid, using humor can help her to relax.
Making her laugh allows her to remain calm. Knowing her well and knowing what makes her laugh is helpful in finding what will make her laugh. When she feels love, she will make more oxytocin and endorphins, and this will help her with her pain and prevent her from feeling fear.
A doula also knows all these calming techniques. When you pair a doula with a midwife, you create a wonderful support team to aid in a fear-free labor and birth experience. When fear creeps in, your birth team will have the experience and skills to help change the mood back to a positive and hopeful one.
Find a Doula
Ina May Gaskin has been a longtime teacher of midwifery and is the author of ‘Ina May’s Guide to Childbirth,’ ‘Spiritual Midwifery,’ and ‘Birth Matters,’ among other titles. She is recognized as an authority on mother-led birth who caters to what the mother needs to have a positive and healthy birth.
To get a better understanding of giving birth without fear, we recommend reading her books on Childbirth and Breastfeeding!
Spiritual Midwifery
Ina May’s Guide to Childbirth
Birth Matters: A Midwife’s Manifesta
Ina May’s Guide to Breastfeeding: From the Nation’s Leading Midwife
Water Birth Image Credit: Jason Lander
Prenatal DNA
Anna Taylor
Nutritionist, Mother, Wellness Advocate and Founder of OrganicHealthNow.com | {
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-4,207,234,384,276,218,400 | Full Text Archive logoFull Text Archive — Free Classic E-books
A History of Science, Volume 2 by Henry Smith Williams
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A History of Science, Volume 2, by Henry Smith Williams
Scanned by Charles Keller with OmniPage Professional OCR software
A
HISTORY OF SCIENCE by HENRY SMITH WILLIAMS, M.D., LL.D.
ASSISTED BY
EDWARD H. WILLIAMS, M.D.
IN FIVE VOLUMES
VOLUME II.
CONTENTS
BOOK II
CHAPTER I. SCIENCE IN THE DARK AGE
CHAPTER II. MEDIAEVAL SCIENCE AMONG THE ARABIANS
CHAPTER III. MEDIAEVAL SCIENCE IN THE WEST
CHAPTER IV. THE NEW COSMOLOGY--COPERNICUS TO KEPLER AND GALILEO
CHAPTER V. GALILEO AND THE NEW PHYSICS
CHAPTER VI. TWO PSEUDO-SCIENCES--ALCHEMY AND ASTROLOGY
CHAPTER VII. FROM PARACELSUS TO HARVEY
CHAPTER VIII. MEDICINE IN THE SIXTEENTH AND SEVENTEENTH CENTURIES
CHAPTER IX. PHILOSOPHER-SCIENTISTS AND NEW INSTITUTIONS OF
LEARNING
CHAPTER X. THE SUCCESSORS OF GALILEO IN PHYSICAL SCIENCE
CHAPTER XI. NEWTON AND THE COMPOSITION OF LIGHT
CHAPTER XII. NEWTON AND THE LAW OF GRAVITATION
CHAPTER XIII. INSTRUMENTS OF PRECISION IN THE AGE OF NEWTON
CHAPTER XIV. PROGRESS IN ELECTRICITY FROM GILBERT AND VON
GUERICKE TO FRANKLIN
CHAPTER XV. NATURAL HISTORY TO THE TIME OF LINNAEUS
APPENDIX
A HISTORY OF SCIENCE
BOOK II
THE BEGINNINGS OF MODERN SCIENCE
The studies of the present book cover the progress of science
from the close of the Roman period in the fifth century A.D. to
about the middle of the eighteenth century. In tracing the course
of events through so long a period, a difficulty becomes
prominent which everywhere besets the historian in less degree--a
difficulty due to the conflict between the strictly chronological
and the topical method of treatment. We must hold as closely as
possible to the actual sequence of events, since, as already
pointed out, one discovery leads on to another. But, on the other
hand, progressive steps are taken contemporaneously in the
various fields of science, and if we were to attempt to introduce
these in strict chronological order we should lose all sense of
topical continuity.
Our method has been to adopt a compromise, following the course
of a single science in each great epoch to a convenient
stopping-point, and then turning back to bring forward the story
of another science. Thus, for example, we tell the story of
Copernicus and Galileo, bringing the record of cosmical and
mechanical progress down to about the middle of the seventeenth
century, before turning back to take up the physiological
progress of the fifteenth and sixteenth centuries. Once the
latter stream is entered, however, we follow it without
interruption to the time of Harvey and his contemporaries in the
middle of the seventeenth century, where we leave it to return to
the field of mechanics as exploited by the successors of Galileo,
who were also the predecessors and contemporaries of Newton.
In general, it will aid the reader to recall that, so far as
possible, we hold always to the same sequences of topical
treatment of contemporary events; as a rule we treat first the
cosmical, then the physical, then the biological sciences. The
same order of treatment will be held to in succeeding volumes.
Several of the very greatest of scientific generalizations are
developed in the period covered by the present book: for example,
the Copernican theory of the solar system, the true doctrine of
planetary motions, the laws of motion, the theory of the
circulation of the blood, and the Newtonian theory of
gravitation. The labors of the investigators of the early decades
of the eighteenth century, terminating with Franklin's discovery
of the nature of lightning and with the Linnaean classification
of plants and animals, bring us to the close of our second great
epoch; or, to put it otherwise, to the threshold of the modern
period,
I. SCIENCE IN THE DARK AGE
An obvious distinction between the classical and mediaeval epochs
may be found in the fact that the former produced, whereas the
latter failed to produce, a few great thinkers in each generation
who were imbued with that scepticism which is the foundation of
the investigating spirit; who thought for themselves and supplied
more or less rational explanations of observed phenomena. Could
we eliminate the work of some score or so of classical observers
and thinkers, the classical epoch would seem as much a dark age
as does the epoch that succeeded it.
But immediately we are met with the question: Why do no great
original investigators appear during all these later centuries?
We have already offered a part explanation in the fact that the
borders of civilization, where racial mingling naturally took
place, were peopled with semi-barbarians. But we must not forget
that in the centres of civilization all along there were many men
of powerful intellect. Indeed, it would violate the principle of
historical continuity to suppose that there was any sudden change
in the level of mentality of the Roman world at the close of the
classical period. We must assume, then, that the direction in
which the great minds turned was for some reason changed. Newton
is said to have alleged that he made his discoveries by
"intending" his mind in a certain direction continuously. It is
probable that the same explanation may be given of almost every
great scientific discovery. Anaxagoras could not have thought out
the theory of the moon's phases; Aristarchus could not have found
out the true mechanism of the solar system; Eratosthenes could
not have developed his plan for measuring the earth, had not each
of these investigators "intended" his mind persistently towards
the problems in question.
Nor can we doubt that men lived in every generation of the dark
age who were capable of creative thought in the field of science,
bad they chosen similarly to "intend" their minds in the right
direction. The difficulty was that they did not so choose. Their
minds had a quite different bent. They were under the spell of
different ideals; all their mental efforts were directed into
different channels. What these different channels were cannot be
in doubt--they were the channels of oriental ecclesiasticism. One
all-significant fact speaks volumes here. It is the fact that, as
Professor Robinson[1] points out, from the time of Boethius (died
524 or 525 A.D.) to that of Dante (1265-1321 A.D.) there was not
a single writer of renown in western Europe who was not a
professional churchman. All the learning of the time, then,
centred in the priesthood. We know that the same condition of
things pertained in Egypt, when science became static there. But,
contrariwise, we have seen that in Greece and early Rome the
scientific workers were largely physicians or professional
teachers; there was scarcely a professional theologian among
them.
Similarly, as we shall see in the Arabic world, where alone there
was progress in the mediaeval epoch, the learned men were, for
the most part, physicians. Now the meaning of this must be
self-evident. The physician naturally "intends" his mind towards
the practicalities. His professional studies tend to make him an
investigator of the operations of nature. He is usually a
sceptic, with a spontaneous interest in practical science. But
the theologian "intends" his mind away from practicalities and
towards mysticism. He is a professional believer in the
supernatural; he discounts the value of merely "natural"
phenomena. His whole attitude of mind is unscientific; the
fundamental tenets of his faith are based on alleged occurrences
which inductive science cannot admit--namely, miracles. And so
the minds "intended" towards the supernatural achieved only the
hazy mysticism of mediaeval thought. Instead of investigating
natural laws, they paid heed (as, for example, Thomas Aquinas
does in his Summa Theologia) to the "acts of angels," the
"speaking of angels," the "subordination of angels," the "deeds
of guardian angels," and the like. They disputed such important
questions as, How many angels can stand upon the point of a
needle? They argued pro and con as to whether Christ were coeval
with God, or whether he had been merely created "in the
beginning," perhaps ages before the creation of the world. How
could it be expected that science should flourish when the
greatest minds of the age could concern themselves with problems
such as these?
Despite our preconceptions or prejudices, there can be but one
answer to that question. Oriental superstition cast its blight
upon the fair field of science, whatever compensation it may or
may not have brought in other fields. But we must be on our guard
lest we overestimate or incorrectly estimate this influence.
Posterity, in glancing backward, is always prone to stamp any
given age of the past with one idea, and to desire to
characterize it with a single phrase; whereas in reality all ages
are diversified, and any generalization regarding an epoch is
sure to do that epoch something less or something more than
justice. We may be sure, then, that the ideal of ecclesiasticism
is not solely responsible for the scientific stasis of the dark
age. Indeed, there was another influence of a totally different
character that is too patent to be overlooked--the influence,
namely, of the economic condition of western Europe during this
period. As I have elsewhere pointed out,[2] Italy, the centre of
western civilization, was at this time impoverished, and hence
could not provide the monetary stimulus so essential to artistic
and scientific no less than to material progress. There were no
patrons of science and literature such as the Ptolemies of that
elder Alexandrian day. There were no great libraries; no colleges
to supply opportunities and afford stimuli to the rising
generation. Worst of all, it became increasingly difficult to
secure books.
This phase of the subject is often overlooked. Yet a moment's
consideration will show its importance. How should we fare to-day
if no new scientific books were being produced, and if the
records of former generations were destroyed? That is what
actually happened in Europe during the Middle Ages. At an earlier
day books were made and distributed much more abundantly than is
sometimes supposed. Bookmaking had, indeed, been an important
profession in Rome, the actual makers of books being slaves who
worked under the direction of a publisher. It was through the
efforts of these workers that the classical works in Greek and
Latin were multiplied and disseminated. Unfortunately the climate
of Europe does not conduce to the indefinite preservation of a
book; hence very few remnants of classical works have come down
to us in the original from a remote period. The rare exceptions
are certain papyrus fragments, found in Egypt, some of which are
Greek manuscripts dating from the third century B.C. Even from
these sources the output is meagre; and the only other repository
of classical books is a single room in the buried city of
Herculaneum, which contained several hundred manuscripts, mostly
in a charred condition, a considerable number of which, however,
have been unrolled and found more or less legible. This library
in the buried city was chiefly made up of philosophical works,
some of which were quite unknown to the modern world until
discovered there.
But this find, interesting as it was from an archaeological
stand-point, had no very important bearing on our knowledge of
the literature of antiquity. Our chief dependence for our
knowledge of that literature must still be placed in such copies
of books as were made in the successive generations.
Comparatively few of the extant manuscripts are older than the
tenth century of our era. It requires but a momentary
consideration of the conditions under which ancient books were
produced to realize how slow and difficult the process was before
the invention of printing. The taste of the book-buying public
demanded a clearly written text, and in the Middle Ages it became
customary to produce a richly ornamented text as well. The script
employed being the prototype of the modern printed text, it will
be obvious that a scribe could produce but a few pages at best in
a day. A large work would therefore require the labor of a scribe
for many months or even for several years. We may assume, then,
that it would be a very flourishing publisher who could produce a
hundred volumes all told per annum; and probably there were not
many publishers at any given time, even in the period of Rome's
greatest glory, who had anything like this output.
As there was a large number of authors in every generation of the
classical period, it follows that most of these authors must have
been obliged to content themselves with editions numbering very
few copies; and it goes without saying that the greater number of
books were never reproduced in what might be called a second
edition. Even books that retained their popularity for several
generations would presently fail to arouse sufficient interest to
be copied; and in due course such works would pass out of
existence altogether. Doubtless many hundreds of books were thus
lost before the close of the classical period, the names of their
authors being quite forgotten, or preserved only through a chance
reference; and of course the work of elimination went on much
more rapidly during the Middle Ages, when the interest in
classical literature sank to so low an ebb in the West. Such
collections of references and quotations as the Greek Anthology
and the famous anthologies of Stobaeus and Athanasius and
Eusebius give us glimpses of a host of writers--more than seven
hundred are quoted by Stobaeus--a very large proportion of whom
are quite unknown except through these brief excerpts from their
lost works.
Quite naturally the scientific works suffered at least as largely
as any others in an age given over to ecclesiastical dreamings.
Yet in some regards there is matter for surprise as to the works
preserved. Thus, as we have seen, the very extensive works of
Aristotle on natural history, and the equally extensive natural
history of Pliny, which were preserved throughout this period,
and are still extant, make up relatively bulky volumes. These
works seem to have interested the monks of the Middle Ages, while
many much more important scientific books were allowed to perish.
A considerable bulk of scientific literature was also preserved
through the curious channels of Arabic and Armenian translations.
Reference has already been made to the Almagest of Ptolemy,
which, as we have seen, was translated into Arabic, and which was
at a later day brought by the Arabs into western Europe and (at
the instance of Frederick II of Sicily) translated out of their
language into mediaeval Latin.
It remains to inquire, however, through what channels the Greek
works reached the Arabs themselves. To gain an answer to this
question we must follow the stream of history from its Roman
course eastward to the new seat of the Roman empire in Byzantium.
Here civilization centred from about the fifth century A.D., and
here the European came in contact with the civilization of the
Syrians, the Persians, the Armenians, and finally of the Arabs.
The Byzantines themselves, unlike the inhabitants of western
Europe, did not ignore the literature of old Greece; the Greek
language became the regular speech of the Byzantine people, and
their writers made a strenuous effort to perpetuate the idiom and
style of the classical period. Naturally they also made
transcriptions of the classical authors, and thus a great mass of
literature was preserved, while the corresponding works were
quite forgotten in western Europe.
Meantime many of these works were translated into Syriac,
Armenian, and Persian, and when later on the Byzantine
civilization degenerated, many works that were no longer to be
had in the Greek originals continued to be widely circulated in
Syriac, Persian, Armenian, and, ultimately, in Arabic
translations. When the Arabs started out in their conquests,
which carried them through Egypt and along the southern coast of
the Mediterranean, until they finally invaded Europe from the
west by way of Gibraltar, they carried with them their
translations of many a Greek classical author, who was introduced
anew to the western world through this strange channel.
We are told, for example, that Averrhoes, the famous commentator
of Aristotle, who lived in Spain in the twelfth century, did not
know a word of Greek and was obliged to gain his knowledge of the
master through a Syriac translation; or, as others alleged
(denying that he knew even Syriac), through an Arabic version
translated from the Syriac. We know, too, that the famous
chronology of Eusebius was preserved through an Armenian
translation; and reference has more than once been made to the
Arabic translation of Ptolemy's great work, to which we still
apply its Arabic title of Almagest.
The familiar story that when the Arabs invaded Egypt they burned
the Alexandrian library is now regarded as an invention of later
times. It seems much more probable that the library bad been
largely scattered before the coming of the Moslems. Indeed, it
has even been suggested that the Christians of an earlier day
removed the records of pagan thought. Be that as it may, the
famous Alexandrian library had disappeared long before the
revival of interest in classical learning. Meanwhile, as we have
said, the Arabs, far from destroying the western literature, were
its chief preservers. Partly at least because of their regard for
the records of the creative work of earlier generations of alien
peoples, the Arabs were enabled to outstrip their contemporaries.
For it cannot be in doubt that, during that long stretch of time
when the western world was ignoring science altogether or at most
contenting itself with the casual reading of Aristotle and Pliny,
the Arabs had the unique distinction of attempting original
investigations in science. To them were due all important
progressive steps which were made in any scientific field
whatever for about a thousand years after the time of Ptolemy and
Galen. The progress made even by the Arabs during this long
period seems meagre enough, yet it has some significant features.
These will now demand our attention.
II. MEDIAEVAL SCIENCE AMONG THE ARABIANS
The successors of Mohammed showed themselves curiously receptive
of the ideas of the western people whom they conquered. They came
in contact with the Greeks in western Asia and in Egypt, and, as
has been said, became their virtual successors in carrying
forward the torch of learning. It must not be inferred, however,
that the Arabian scholars, as a class, were comparable to their
predecessors in creative genius. On the contrary, they retained
much of the conservative oriental spirit. They were under the
spell of tradition, and, in the main, what they accepted from the
Greeks they regarded as almost final in its teaching. There were,
however, a few notable exceptions among their men of science, and
to these must be ascribed several discoveries of some importance.
The chief subjects that excited the interest and exercised the
ingenuity of the Arabian scholars were astronomy, mathematics,
and medicine. The practical phases of all these subjects were
given particular attention. Thus it is well known that our
so-called Arabian numerals date from this period. The
revolutionary effect of these characters, as applied to practical
mathematics, can hardly be overestimated; but it is generally
considered, and in fact was admitted by the Arabs themselves,
that these numerals were really borrowed from the Hindoos, with
whom the Arabs came in contact on the east. Certain of the Hindoo
alphabets, notably that of the Battaks of Sumatra, give us clews
to the originals of the numerals. It does not seem certain,
however, that the Hindoos employed these characters according to
the decimal system, which is the prime element of their
importance. Knowledge is not forthcoming as to just when or by
whom such application was made. If this was an Arabic innovation,
it was perhaps the most important one with which that nation is
to be credited. Another mathematical improvement was the
introduction into trigonometry of the sine--the half-chord of the
double arc--instead of the chord of the arc itself which the
Greek astronomers had employed. This improvement was due to the
famous Albategnius, whose work in other fields we shall examine
in a moment.
Another evidence of practicality was shown in the Arabian method
of attempting to advance upon Eratosthenes' measurement of the
earth. Instead of trusting to the measurement of angles, the
Arabs decided to measure directly a degree of the earth's
surface--or rather two degrees. Selecting a level plain in
Mesopotamia for the experiment, one party of the surveyors
progressed northward, another party southward, from a given point
to the distance of one degree of arc, as determined by
astronomical observations. The result found was fifty-six miles
for the northern degree, and fifty-six and two-third miles for
the southern. Unfortunately, we do not know the precise length of
the mile in question, and therefore cannot be assured as to the
accuracy of the measurement. It is interesting to note, however,
that the two degrees were found of unequal lengths, suggesting
that the earth is not a perfect sphere--a suggestion the validity
of which was not to be put to the test of conclusive measurements
until about the close of the eighteenth century. The Arab
measurement was made in the time of Caliph Abdallah al-Mamun, the
son of the famous Harun-al-Rashid. Both father and son were
famous for their interest in science. Harun-al-Rashid was, it
will be recalled, the friend of Charlemagne. It is said that he
sent that ruler, as a token of friendship, a marvellous clock
which let fall a metal ball to mark the hours. This mechanism,
which is alleged to have excited great wonder in the West,
furnishes yet another instance of Arabian practicality.
Perhaps the greatest of the Arabian astronomers was Mohammed ben
Jabir Albategnius, or El-batani, who was born at Batan, in
Mesopotamia, about the year 850 A.D., and died in 929.
Albategnius was a student of the Ptolemaic astronomy, but he was
also a practical observer. He made the important discovery of the
motion of the solar apogee. That is to say, he found that the
position of the sun among the stars, at the time of its greatest
distance from the earth, was not what it had been in the time of
Ptolemy. The Greek astronomer placed the sun in longitude 65
degrees, but Albategnius found it in longitude 82 degrees, a
distance too great to be accounted for by inaccuracy of
measurement. The modern inference from this observation is that
the solar system is moving through space; but of course this
inference could not well be drawn while the earth was regarded as
the fixed centre of the universe.
In the eleventh century another Arabian discoverer, Arzachel,
observing the sun to be less advanced than Albategnius had found
it, inferred incorrectly that the sun had receded in the mean
time. The modern explanation of this observation is that the
measurement of Albategnius was somewhat in error, since we know
that the sun's motion is steadily progressive. Arzachel, however,
accepting the measurement of his predecessor, drew the false
inference of an oscillatory motion of the stars, the idea of the
motion of the solar system not being permissible. This assumed
phenomenon, which really has no existence in point of fact, was
named the "trepidation of the fixed stars," and was for centuries
accepted as an actual phenomenon. Arzachel explained this
supposed phenomenon by assuming that the equinoctial points, or
the points of intersection of the equator and the ecliptic,
revolve in circles of eight degrees' radius. The first points of
Aries and Libra were supposed to describe the circumference of
these circles in about eight hundred years. All of which
illustrates how a difficult and false explanation may take the
place of a simple and correct one. The observations of later
generations have shown conclusively that the sun's shift of
position is regularly progressive, hence that there is no
"trepidation" of the stars and no revolution of the equinoctial
points.
If the Arabs were wrong as regards this supposed motion of the
fixed stars, they made at least one correct observation as to the
inequality of motion of the moon. Two inequalities of the motion
of this body were already known. A third, called the moon's
variation, was discovered by an Arabian astronomer who lived at
Cairo and observed at Bagdad in 975, and who bore the formidable
name of Mohammed Aboul Wefaal-Bouzdjani. The inequality of motion
in question, in virtue of which the moon moves quickest when she
is at new or full, and slowest at the first and third quarter,
was rediscovered by Tycho Brahe six centuries later; a fact which
in itself evidences the neglect of the Arabian astronomer's
discovery by his immediate successors.
In the ninth and tenth centuries the Arabian city of Cordova, in
Spain, was another important centre of scientific influence.
There was a library of several hundred thousand volumes here, and
a college where mathematics and astronomy were taught. Granada,
Toledo, and Salamanca were also important centres, to which
students flocked from western Europe. It was the proximity of
these Arabian centres that stimulated the scientific interests of
Alfonso X. of Castile, at whose instance the celebrated Alfonsine
tables were constructed. A familiar story records that Alfonso,
pondering the complications of the Ptolemaic cycles and
epicycles, was led to remark that, had he been consulted at the
time of creation, he could have suggested a much better and
simpler plan for the universe. Some centuries were to elapse
before Copernicus was to show that it was not the plan of the
universe, but man's interpretation of it, that was at fault.
Another royal personage who came under Arabian influence was
Frederick II. of Sicily--the "Wonder of the World," as he was
called by his contemporaries. The Almagest of Ptolemy was
translated into Latin at his instance, being introduced to the
Western world through this curious channel. At this time it
became quite usual for the Italian and Spanish scholars to
understand Arabic although they were totally ignorant of Greek.
In the field of physical science one of the most important of the
Arabian scientists was Alhazen. His work, published about the
year 1100 A.D., had great celebrity throughout the mediaeval
period. The original investigations of Alhazen had to do largely
with optics. He made particular studies of the eye itself, and
the names given by him to various parts of the eye, as the
vitreous humor, the cornea, and the retina, are still retained by
anatomists. It is known that Ptolemy had studied the refraction
of light, and that he, in common with his immediate predecessors,
was aware that atmospheric refraction affects the apparent
position of stars near the horizon. Alhazen carried forward these
studies, and was led through them to make the first recorded
scientific estimate of the phenomena of twilight and of the
height of the atmosphere. The persistence of a glow in the
atmosphere after the sun has disappeared beneath the horizon is
so familiar a phenomenon that the ancient philosophers seem not
to have thought of it as requiring an explanation. Yet a moment's
consideration makes it clear that, if light travels in straight
lines and the rays of the sun were in no wise deflected, the
complete darkness of night should instantly succeed to day when
the sun passes below the horizon. That this sudden change does
not occur, Alhazen explained as due to the reflection of light by
the earth's atmosphere.
Alhazen appears to have conceived the atmosphere as a sharply
defined layer, and, assuming that twilight continues only so long
as rays of the sun reflected from the outer surface of this layer
can reach the spectator at any given point, he hit upon a means
of measurement that seemed to solve the hitherto inscrutable
problem as to the atmospheric depth. Like the measurements of
Aristarchus and Eratosthenes, this calculation of Alhazen is
simple enough in theory. Its defect consists largely in the
difficulty of fixing its terms with precision, combined with the
further fact that the rays of the sun, in taking the slanting
course through the earth's atmosphere, are really deflected from
a straight line in virtue of the constantly increasing density of
the air near the earth's surface. Alhazen must have been aware of
this latter fact, since it was known to the later Alexandrian
astronomers, but he takes no account of it in the present
measurement. The diagram will make the method of Alhazen clear.
His important premises are two: first, the well-recognized fact
that, when light is reflected from any surface, the angle of
incidence is equal to the angle of reflection; and, second, the
much more doubtful observation that twilight continues until such
time as the sun, according to a simple calculation, is nineteen
degrees below the horizon. Referring to the diagram, let the
inner circle represent the earth's surface, the outer circle the
limits of the atmosphere, C being the earth's centre, and RR
radii of the earth. Then the observer at the point A will
continue to receive the reflected rays of the sun until that body
reaches the point S, which is, according to the hypothesis,
nineteen degrees below the horizon line of the observer at A.
This horizon line, being represented by AH, and the sun's ray by
SM, the angle HMS is an angle of nineteen degrees. The
complementary angle SMA is, obviously, an angle of (180-19) one
hundred and sixty-one degrees. But since M is the reflecting
surface and the angle of incidence equals the angle of
reflection, the angle AMC is an angle of one-half of one hundred
and sixty-one degrees, or eighty degrees and thirty minutes. Now
this angle AMC, being known, the right-angled triangle MAC is
easily resolved, since the side AC of that triangle, being the
radius of the earth, is a known dimension. Resolution of this
triangle gives us the length of the hypotenuse MC, and the
difference between this and the radius (AC), or CD, is obviously
the height of the atmosphere (h), which was the measurement
desired. According to the calculation of Alhazen, this h, or the
height of the atmosphere, represents from twenty to thirty miles.
The modern computation extends this to about fifty miles. But,
considering the various ambiguities that necessarily attended the
experiment, the result was a remarkably close approximation to
the truth.
Turning from physics to chemistry, we find as perhaps the
greatest Arabian name that of Geber, who taught in the College of
Seville in the first half of the eighth century. The most
important researches of this really remarkable experimenter had
to do with the acids. The ancient world had had no knowledge of
any acid more powerful than acetic. Geber, however, vastly
increased the possibilities of chemical experiment by the
discovery of sulphuric, nitric, and nitromuriatic acids. He made
use also of the processes of sublimation and filtration, and his
works describe the water bath and the chemical oven. Among the
important chemicals which he first differentiated is oxide of
mercury, and his studies of sulphur in its various compounds have
peculiar interest. In particular is this true of his observation
that, tinder certain conditions of oxidation, the weight of a
metal was lessened.
From the record of these studies in the fields of astronomy,
physics, and chemistry, we turn to a somewhat extended survey of
the Arabian advances in the field of medicine.
ARABIAN MEDICINE
The influence of Arabian physicians rested chiefly upon their use
of drugs rather than upon anatomical knowledge. Like the
mediaeval Christians, they looked with horror on dissection of
the human body; yet there were always among them investigators
who turned constantly to nature herself for hidden truths, and
were ready to uphold the superiority of actual observation to
mere reading. Thus the physician Abd el-Letif, while in Egypt,
made careful studies of a mound of bones containing more than
twenty thousand skeletons. While examining these bones he
discovered that the lower jaw consists of a single bone, not of
two, as had been taught by Galen. He also discovered several
other important mistakes in Galenic anatomy, and was so impressed
with his discoveries that he contemplated writing a work on
anatomy which should correct the great classical authority's
mistakes.
It was the Arabs who invented the apothecary, and their
pharmacopoeia, issued from the hospital at Gondisapor, and
elaborated from time to time, formed the basis for Western
pharmacopoeias. Just how many drugs originated with them, and how
many were borrowed from the Hindoos, Jews, Syrians, and Persians,
cannot be determined. It is certain, however, that through them
various new and useful drugs, such as senna, aconite, rhubarb,
camphor, and mercury, were handed down through the Middle Ages,
and that they are responsible for the introduction of alcohol in
the field of therapeutics.
In mediaeval Europe, Arabian science came to be regarded with
superstitious awe, and the works of certain Arabian physicians
were exalted to a position above all the ancient writers. In
modern times, however, there has been a reaction and a tendency
to depreciation of their work. By some they are held to be mere
copyists or translators of Greek books, and in no sense original
investigators in medicine. Yet there can be little doubt that
while the Arabians did copy and translate freely, they also
originated and added considerably to medical knowledge. It is
certain that in the time when Christian monarchs in western
Europe were paying little attention to science or education, the
caliphs and vizirs were encouraging physicians and philosophers,
building schools, and erecting libraries and hospitals. They made
at least a creditable effort to uphold and advance upon the
scientific standards of an earlier age.
The first distinguished Arabian physician was Harets ben Kaladah,
who received his education in the Nestonian school at Gondisapor,
about the beginning of the seventh century. Notwithstanding the
fact that Harets was a Christian, he was chosen by Mohammed as
his chief medical adviser, and recommended as such to his
successor, the Caliph Abu Bekr. Thus, at the very outset, the
science of medicine was divorced from religion among the
Arabians; for if the prophet himself could employ the services of
an unbeliever, surely others might follow his example. And that
this example was followed is shown in the fact that many
Christian physicians were raised to honorable positions by
succeeding generations of Arabian monarchs. This broad-minded
view of medicine taken by the Arabs undoubtedly assisted as much
as any one single factor in upbuilding the science, just as the
narrow and superstitious view taken by Western nations helped to
destroy it.
The education of the Arabians made it natural for them to
associate medicine with the natural sciences, rather than with
religion. An Arabian savant was supposed to be equally well
educated in philosophy, jurisprudence, theology, mathematics, and
medicine, and to practise law, theology, and medicine with equal
skill upon occasion. It is easy to understand, therefore, why
these religious fanatics were willing to employ unbelieving
physicians, and their physicians themselves to turn to the
scientific works of Hippocrates and Galen for medical
instruction, rather than to religious works. Even Mohammed
himself professed some knowledge of medicine, and often relied
upon this knowledge in treating ailments rather than upon prayers
or incantations. He is said, for example, to have recommended and
applied the cautery in the case of a friend who, when suffering
from angina, had sought his aid.
The list of eminent Arabian physicians is too long to be given
here, but some of them are of such importance in their influence
upon later medicine that they cannot be entirely ignored. One of
the first of these was Honain ben Isaac (809-873 A.D.), a
Christian Arab of Bagdad. He made translations of the works of
Hippocrates, and practised the art along the lines indicated by
his teachings and those of Galen. He is considered the greatest
translator of the ninth century and one of the greatest
philosophers of that period.
Another great Arabian physician, whose work was just beginning as
Honain's was drawing to a close, was Rhazes (850-923 A.D.), who
during his life was no less noted as a philosopher and musician
than as a physician. He continued the work of Honain, and
advanced therapeutics by introducing more extensive use of
chemical remedies, such as mercurial ointments, sulphuric acid,
and aqua vitae. He is also credited with being the first
physician to describe small-pox and measles accurately.
While Rhazes was still alive another Arabian, Haly Abbas (died
about 994), was writing his famous encyclopaedia of medicine,
called The Royal Book. But the names of all these great
physicians have been considerably obscured by the reputation of
Avicenna (980-1037), the Arabian "Prince of Physicians," the
greatest name in Arabic medicine, and one of the most remarkable
men in history. Leclerc says that "he was perhaps never surpassed
by any man in brilliancy of intellect and indefatigable
activity." His career was a most varied one. He was at all times
a boisterous reveller, but whether flaunting gayly among the
guests of an emir or biding in some obscure apothecary cellar,
his work of philosophical writing was carried on steadily. When a
friendly emir was in power, he taught and wrote and caroused at
court; but between times, when some unfriendly ruler was supreme,
he was hiding away obscurely, still pouring out his great mass of
manuscripts. In this way his entire life was spent.
By his extensive writings he revived and kept alive the best of
the teachings of the Greek physicians, adding to them such
observations as he had made in anatomy, physiology, and materia
medica. Among his discoveries is that of the contagiousness of
pulmonary tuberculosis. His works for several centuries continued
to be looked upon as the highest standard by physicians, and he
should undoubtedly be credited with having at least retarded the
decline of mediaeval medicine.
But it was not the Eastern Arabs alone who were active in the
field of medicine. Cordova, the capital of the western caliphate,
became also a great centre of learning and produced several great
physicians. One of these, Albucasis (died in 1013 A.D.), is
credited with having published the first illustrated work on
surgery, this book being remarkable in still another way, in that
it was also the first book, since classical times, written from
the practical experience of the physician, and not a mere
compilation of ancient authors. A century after Albucasis came
the great physician Avenzoar (1113-1196), with whom he divides
about equally the medical honors of the western caliphate. Among
Avenzoar's discoveries was that of the cause of "itch"--a little
parasite, "so small that he is hardly visible." The discovery of
the cause of this common disease seems of minor importance now,
but it is of interest in medical history because, had Avenzoar's
discovery been remembered a hundred years ago, "itch struck in"
could hardly have been considered the cause of three-fourths of
all diseases, as it was by the famous Hahnemann.
The illustrious pupil of Avenzoar, Averrhoes, who died in 1198
A.D., was the last of the great Arabian physicians who, by
rational conception of medicine, attempted to stem the flood of
superstition that was overwhelming medicine. For a time he
succeeded; but at last the Moslem theologians prevailed, and he
was degraded and banished to a town inhabited only by the
despised Jews.
ARABIAN HOSPITALS
To early Christians belong the credit of having established the
first charitable institutions for caring for the sick; but their
efforts were soon eclipsed by both Eastern and Western
Mohammedans. As early as the eighth century the Arabs had begun
building hospitals, but the flourishing time of hospital building
seems to have begun early in the tenth century. Lady Seidel, in
918 A.D., opened a hospital at Bagdad, endowed with an amount
corresponding to about three hundred pounds sterling a month.
Other similar hospitals were erected in the years immediately
following, and in 977 the Emir Adad-adaula established an
enormous institution with a staff of twenty-four medical
officers. The great physician Rhazes is said to have selected the
site for one of these hospitals by hanging pieces of meat in
various places about the city, selecting the site near the place
at which putrefaction was slowest in making its appearance. By
the middle of the twelfth century there were something like sixty
medical institutions in Bagdad alone, and these institutions were
free to all patients and supported by official charity.
The Emir Nureddin, about the year 1160, founded a great hospital
at Damascus, as a thank-offering for his victories over the
Crusaders. This great institution completely overshadowed all the
earlier Moslem hospitals in size and in the completeness of its
equipment. It was furnished with facilities for teaching, and was
conducted for several centuries in a lavish manner, regardless of
expense. But little over a century after its foundation the fame
of its methods of treatment led to the establishment of a larger
and still more luxurious institution--the Mansuri hospital at
Cairo. It seems that a certain sultan, having been cured by
medicines from the Damascene hospital, determined to build one of
his own at Cairo which should eclipse even the great Damascene
institution.
In a single year (1283-1284) this hospital was begun and
completed. No efforts were spared in hurrying on the good work,
and no one was exempt from performing labor on the building if he
chanced to pass one of the adjoining streets. It was the order of
the sultan that any person passing near could be impressed into
the work, and this order was carried out to the letter, noblemen
and beggars alike being forced to lend a hand. Very naturally,
the adjacent thoroughfares became unpopular and practically
deserted, but still the holy work progressed rapidly and was
shortly completed.
This immense structure is said to have contained four courts,
each having a fountain in the centre; lecture-halls, wards for
isolating certain diseases, and a department that corresponded to
the modern hospital's "out-patient" department. The yearly
endowment amounted to something like the equivalent of one
hundred and twenty-five thousand dollars. A novel feature was a
hall where musicians played day and night, and another where
story-tellers were employed, so that persons troubled with
insomnia were amused and melancholiacs cheered. Those of a
religious turn of mind could listen to readings of the Koran,
conducted continuously by a staff of some fifty chaplains. Each
patient on leaving the hospital received some gold pieces, that
he need not be obliged to attempt hard labor at once.
In considering the astonishing tales of these sumptuous Arabian
institutions, it should be borne in mind that our accounts of
them are, for the most part, from Mohammedan sources.
Nevertheless, there can be little question that they were
enormous institutions, far surpassing any similar institutions in
western Europe. The so-called hospitals in the West were, at this
time, branches of monasteries under supervision of the monks, and
did not compare favorably with the Arabian hospitals.
But while the medical science of the Mohammedans greatly
overshadowed that of the Christians during this period, it did
not completely obliterate it. About the year 1000 A.D. came into
prominence the Christian medical school at Salerno, situated on
the Italian coast, some thirty miles southeast of Naples. Just
how long this school had been in existence, or by whom it was
founded, cannot be determined, but its period of greatest
influence was the eleventh, twelfth, and thirteenth centuries.
The members of this school gradually adopted Arabic medicine,
making use of many drugs from the Arabic pharmacopoeia, and this
formed one of the stepping-stones to the introduction of Arabian
medicine all through western Europe.
It was not the adoption of Arabian medicines, however, that has
made the school at Salerno famous both in rhyme and prose, but
rather the fact that women there practised the healing art.
Greatest among them was Trotula, who lived in the eleventh
century, and whose learning is reputed to have equalled that of
the greatest physicians of the day. She is accredited with a work
on Diseases of Women, still extant, and many of her writings on
general medical subjects were quoted through two succeeding
centuries. If we may judge from these writings, she seemed to
have had many excellent ideas as to the proper methods of
treating diseases, but it is difficult to determine just which of
the writings credited to her are in reality hers. Indeed, the
uncertainty is even greater than this implies, for, according to
some writers, "Trotula" is merely the title of a book. Such an
authority as Malgaigne, however, believed that such a woman
existed, and that the works accredited to her are authentic. The
truth of the matter may perhaps never be fully established, but
this at least is certain--the tradition in regard to Trotula
could never have arisen had not women held a far different
position among the Arabians of this period from that accorded
them in contemporary Christendom.
III. MEDIAEVAL SCIENCE IN THE WEST
We have previously referred to the influence of the Byzantine
civilization in transmitting the learning of antiquity across the
abysm of the dark age. It must be admitted, however, that the
importance of that civilization did not extend much beyond the
task of the common carrier. There were no great creative
scientists in the later Roman empire of the East any more than in
the corresponding empire of the West. There was, however, one
field in which the Byzantine made respectable progress and
regarding which their efforts require a few words of special
comment. This was the field of medicine.
The Byzantines of this time could boast of two great medical men,
Aetius of Amida (about 502-575 A.D.) and Paul of Aegina (about
620-690). The works of Aetius were of value largely because they
recorded the teachings of many of his eminent predecessors, but
he was not entirely lacking in originality, and was perhaps the
first physician to mention diphtheria, with an allusion to some
observations of the paralysis of the palate which sometimes
follows this disease.
Paul of Aegina, who came from the Alexandrian school about a
century later, was one of those remarkable men whose ideas are
centuries ahead of their time. This was particularly true of Paul
in regard to surgery, and his attitude towards the supernatural
in the causation and treatment of diseases. He was essentially a
surgeon, being particularly familiar with military surgery, and
some of his descriptions of complicated and difficult operations
have been little improved upon even in modern times. In his books
he describes such operations as the removal of foreign bodies
from the nose, ear, and esophagus; and he recognizes foreign
growths such as polypi in the air-passages, and gives the method
of their removal. Such operations as tracheotomy, tonsellotomy,
bronchotomy, staphylotomy, etc., were performed by him, and he
even advocated and described puncture of the abdominal cavity,
giving careful directions as to the location in which such
punctures should be made. He advocated amputation of the breast
for the cure of cancer, and described extirpation of the uterus.
Just how successful this last operation may have been as
performed by him does not appear; but he would hardly have
recommended it if it had not been sometimes, at least,
successful. That he mentions it at all, however, is significant,
as this difficult operation is considered one of the great
triumphs of modern surgery.
But Paul of Aegina is a striking exception to the rule among
Byzantine surgeons, and as he was their greatest, so he was also
their last important surgeon. The energies of all Byzantium were
so expended in religious controversies that medicine, like the
other sciences, was soon relegated to a place among the other
superstitions, and the influence of the Byzantine school was
presently replaced by that of the conquering Arabians.
THIRTEENTH-CENTURY MEDICINE
The thirteenth century marks the beginning of a gradual change in
medicine, and a tendency to leave the time-worn rut of
superstitious dogmas that so long retarded the progress of
science. It is thought that the great epidemics which raged
during the Middle Ages acted powerfully in diverting the medical
thought of the times into new and entirely different channels. It
will be remembered that the teachings of Galen were handed
through mediaeval times as the highest and best authority on the
subject of all diseases. When, however, the great epidemics made
their appearance, the medical men appealed to the works of Galen
in vain for enlightenment, as these works, having been written
several centuries before the time of the plagues, naturally
contained no information concerning them. It was evident,
therefore, that on this subject, at least, Galen was not
infallible; and it would naturally follow that, one fallible
point having been revealed, others would be sought for. In other
words, scepticism in regard to accepted methods would be aroused,
and would lead naturally, as such scepticism usually does, to
progress. The devastating effects of these plagues, despite
prayers and incantations, would arouse doubt in the minds of many
as to the efficacy of superstitious rites and ceremonies in
curing diseases. They had seen thousands and tens of thousands of
their fellow-beings swept away by these awful scourges. They had
seen the ravages of these epidemics continue for months or even
years, notwithstanding the fact that multitudes of God-fearing
people prayed hourly that such ravages might be checked. And they
must have observed also that when even very simple rules of
cleanliness and hygiene were followed there was a diminution in
the ravages of the plague, even without the aid of incantations.
Such observations as these would have a tendency to awaken a
suspicion in the minds of many of the physicians that disease was
not a manifestation of the supernatural, but a natural
phenomenon, to be treated by natural methods.
But, be the causes what they may, it is a fact that the
thirteenth century marks a turning-point, or the beginning of an
attitude of mind which resulted in bringing medicine to a much
more rational position. Among the thirteenth-century physicians,
two men are deserving of special mention. These are Arnald of
Villanova (1235-1312) and Peter of Abano (1250-1315). Both these
men suffered persecution for expressing their belief in natural,
as against the supernatural, causes of disease, and at one time
Arnald was obliged to flee from Barcelona for declaring that the
"bulls" of popes were human works, and that "acts of charity were
dearer to God than hecatombs." He was also accused of alchemy.
Fleeing from persecution, he finally perished by shipwreck.
Arnald was the first great representative of the school of
Montpellier. He devoted much time to the study of chemicals, and
was active in attempting to re-establish the teachings of
Hippocrates and Galen. He was one of the first of a long line of
alchemists who, for several succeeding centuries, expended so
much time and energy in attempting to find the "elixir of life."
The Arab discovery of alcohol first deluded him into the belief
that the "elixir" had at last been found; but later he discarded
it and made extensive experiments with brandy, employing it in
the treatment of certain diseases--the first record of the
administration of this liquor as a medicine. Arnald also revived
the search for some anaesthetic that would produce insensibility
to pain in surgical operations. This idea was not original with
him, for since very early times physicians had attempted to
discover such an anaesthetic, and even so early a writer as
Herodotus tells how the Scythians, by inhalation of the vapors of
some kind of hemp, produced complete insensibility. It may have
been these writings that stimulated Arnald to search for such an
anaesthetic. In a book usually credited to him, medicines are
named and methods of administration described which will make the
patient insensible to pain, so that "he may be cut and feel
nothing, as though he were dead." For this purpose a mixture of
opium, mandragora, and henbane is to be used. This mixture was
held at the patient's nostrils much as ether and chloroform are
administered by the modern surgeon. The method was modified by
Hugo of Lucca (died in 1252 or 1268), who added certain other
narcotics, such as hemlock, to the mixture, and boiled a new
sponge in this decoction. After boiling for a certain time, this
sponge was dried, and when wanted for use was dipped in hot water
and applied to the nostrils.
Just how frequently patients recovered from the administration of
such a combination of powerful poisons does not appear, but the
percentage of deaths must have been very high, as the practice
was generally condemned. Insensibility could have been produced
only by swallowing large quantities of the liquid, which dripped
into the nose and mouth when the sponge was applied, and a lethal
quantity might thus be swallowed. The method was revived, with
various modifications, from time to time, but as often fell into
disuse. As late as 1782 it was sometimes attempted, and in that
year the King of Poland is said to have been completely
anaesthetized and to have recovered, after a painless amputation
had been performed by the surgeons.
Peter of Abano was one of the first great men produced by the
University of Padua. His fate would have been even more tragic
than that of the shipwrecked Arnald had he not cheated the
purifying fagots of the church by dying opportunely on the eve of
his execution for heresy. But if his spirit had cheated the
fanatics, his body could not, and his bones were burned for his
heresy. He had dared to deny the existence of a devil, and had
suggested that the case of a patient who lay in a trance for
three days might help to explain some miracles, like the raising
of Lazarus.
His great work was Conciliator Differentiarum, an attempt to
reconcile physicians and philosophers. But his researches were
not confined to medicine, for he seems to have had an inkling of
the hitherto unknown fact that air possesses weight, and his
calculation of the length of the year at three hundred and
sixty-five days, six hours, and four minutes, is exceptionally
accurate for the age in which he lived. He was probably the first
of the Western writers to teach that the brain is the source of
the nerves, and the heart the source of the vessels. From this it
is seen that he was groping in the direction of an explanation of
the circulation of the blood, as demonstrated by Harvey three
centuries later.
The work of Arnald and Peter of Abano in "reviving" medicine was
continued actively by Mondino (1276-1326) of Bologna, the
"restorer of anatomy," and by Guy of Chauliac: (born about 1300),
the "restorer of surgery." All through the early Middle Ages
dissections of human bodies had been forbidden, and even
dissection of the lower animals gradually fell into disrepute
because physicians detected in such practices were sometimes
accused of sorcery. Before the close of the thirteenth century,
however, a reaction had begun, physicians were protected, and
dissections were occasionally sanctioned by the ruling monarch.
Thus Emperor Frederick H. (1194-1250 A.D.)--whose services to
science we have already had occasion to mention--ordered that at
least one human body should be dissected by physicians in his
kingdom every five years. By the time of Mondino dissections were
becoming more frequent, and he himself is known to have dissected
and demonstrated several bodies. His writings on anatomy have
been called merely plagiarisms of Galen, but in all probability
be made many discoveries independently, and on the whole, his
work may be taken as more advanced than Galen's. His description
of the heart is particularly accurate, and he seems to have come
nearer to determining the course of the blood in its circulation
than any of his predecessors. In this quest he was greatly
handicapped by the prevailing belief in the idea that
blood-vessels must contain air as well as blood, and this led him
to assume that one of the cavities of the heart contained
"spirits," or air. It is probable, however, that his accurate
observations, so far as they went, were helpful stepping-stones
to Harvey in his discovery of the circulation.
Guy of Chauliac, whose innovations in surgery reestablished that
science on a firm basis, was not only one of the most cultured,
but also the most practical surgeon of his time. He had great
reverence for the works of Galen, Albucasis, and others of his
noted predecessors; but this reverence did not blind him to their
mistakes nor prevent him from using rational methods of treatment
far in advance of theirs. His practicality is shown in some of
his simple but useful inventions for the sick-room, such as the
device of a rope, suspended from the ceiling over the bed, by
which a patient may move himself about more easily; and in some
of his improvements in surgical dressings, such as stiffening
bandages by dipping them in the white of an egg so that they are
held firmly. He treated broken limbs in the suspended cradle
still in use, and introduced the method of making "traction" on a
broken limb by means of a weight and pulley, to prevent deformity
through shortening of the member. He was one of the first
physicians to recognize the utility of spectacles, and
recommended them in cases not amenable to treatment with lotions
and eye-waters. In some of his surgical operations, such as
trephining for fracture of the skull, his technique has been
little improved upon even in modern times. In one of these
operations he successfully removed a portion of a man's brain.
Surgery was undoubtedly stimulated greatly at this period by the
constant wars. Lay physicians, as a class, had been looked down
upon during the Dark Ages; but with the beginning of the return
to rationalism, the services of surgeons on the battle-field, to
remove missiles from wounds, and to care for wounds and apply
dressings, came to be more fully appreciated. In return for his
labors the surgeon was thus afforded better opportunities for
observing wounds and diseases, which led naturally to a gradual
improvement in surgical methods.
FIFTEENTH-CENTURY MEDICINE
The thirteenth and fourteenth centuries had seen some slight
advancement in the science of medicine; at least, certain
surgeons and physicians, if not the generality, had made
advances; but it was not until the fifteenth century that the
general revival of medical learning became assured. In this
movement, naturally, the printing-press played an all-important
part. Medical books, hitherto practically inaccessible to the
great mass of physicians, now became common, and this output of
reprints of Greek and Arabic treatises revealed the fact that
many of the supposed true copies were spurious. These discoveries
very naturally aroused all manner of doubt and criticism, which
in turn helped in the development of independent thought.
A certain manuscript of the great Cornelius Celsus, the De
Medicine, which had been lost for many centuries, was found in
the church of St. Ambrose, at Milan, in 1443, and was at once put
into print. The effect of the publication of this book, which had
lain in hiding for so many centuries, was a revelation, showing
the medical profession how far most of their supposed true copies
of Celsus had drifted away from the original. The indisputable
authenticity of this manuscript, discovered and vouched for by
the man who shortly after became Pope Nicholas V., made its
publication the more impressive. The output in book form of other
authorities followed rapidly, and the manifest discrepancies
between such teachers as Celsus, Hippocrates, Galen, and Pliny
heightened still more the growing spirit of criticism.
These doubts resulted in great controversies as to the proper
treatment of certain diseases, some physicians following
Hippocrates, others Galen or Celsus, still others the Arabian
masters. One of the most bitter of these contests was over the
question of "revulsion," and "derivation"--that is, whether in
cases of pleurisy treated by bleeding, the venesection should be
made at a point distant from the seat of the disease, as held by
the "revulsionists," or at a point nearer and on the same side of
the body, as practised by the "derivationists." That any great
point for discussion could be raised in the fifteenth or
sixteenth centuries on so simple a matter as it seems to-day
shows how necessary to the progress of medicine was the discovery
of the circulation of the blood made by Harvey two centuries
later. After Harvey's discovery no such discussion could have
been possible, because this discovery made it evident that as far
as the general effect upon the circulation is concerned, it made
little difference whether the bleeding was done near a diseased
part or remote from it. But in the sixteenth century this
question was the all-absorbing one among the doctors. At one time
the faculty of Paris condemned "derivation"; but the supporters
of this method carried the war still higher, and Emperor Charles
V. himself was appealed to. He reversed the decision of the Paris
faculty, and decided in favor of "derivation." His decision was
further supported by Pope Clement VII., although the discussion
dragged on until cut short by Harvey's discovery.
But a new form of injury now claimed the attention of the
surgeons, something that could be decided by neither Greek nor
Arabian authors, as the treatment of gun-shot wounds was, for
obvious reasons, not given in their writings. About this time,
also, came the great epidemics, "the sweating sickness" and
scurvy; and upon these subjects, also, the Greeks and Arabians
were silent. John of Vigo, in his book, the Practica Copiosa,
published in 1514, and repeated in many editions, became the
standard authority on all these subjects, and thus supplanted the
works of the ancient writers.
According to Vigo, gun-shot wounds differed from the wounds made
by ordinary weapons--that is, spear, arrow, sword, or axe--in
that the bullet, being round, bruised rather than cut its way
through the tissues; it burned the flesh; and, worst of all, it
poisoned it. Vigo laid especial stress upon treating this last
condition, recommending the use of the cautery or the oil of
elder, boiling hot. It is little wonder that gun-shot wounds were
so likely to prove fatal. Yet, after all, here was the germ of
the idea of antisepsis.
NEW BEGINNINGS IN GENERAL SCIENCE
We have dwelt thus at length on the subject of medical science,
because it was chiefly in this field that progress was made in
the Western world during the mediaeval period, and because these
studies furnished the point of departure for the revival all
along the line. It will be understood, however, from what was
stated in the preceding chapter, that the Arabian influences in
particular were to some extent making themselves felt along other
lines. The opportunity afforded a portion of the Western
world--notably Spain and Sicily --to gain access to the
scientific ideas of antiquity through Arabic translations could
not fail of influence. Of like character, and perhaps even more
pronounced in degree, was the influence wrought by the Byzantine
refugees, who, when Constantinople began to be threatened by the
Turks, migrated to the West in considerable numbers, bringing
with them a knowledge of Greek literature and a large number of
precious works which for centuries had been quite forgotten or
absolutely ignored in Italy. Now Western scholars began to take
an interest in the Greek language, which had been utterly
neglected since the beginning of the Middle Ages. Interesting
stories are told of the efforts made by such men as Cosmo de'
Medici to gain possession of classical manuscripts. The revival
of learning thus brought about had its first permanent influence
in the fields of literature and art, but its effect on science
could not be long delayed. Quite independently of the Byzantine
influence, however, the striving for better intellectual things
had manifested itself in many ways before the close of the
thirteenth century. An illustration of this is found in the
almost simultaneous development of centres of teaching, which
developed into the universities of Italy, France, England, and, a
little later, of Germany.
The regular list of studies that came to be adopted everywhere
comprised seven nominal branches, divided into two groups--the
so-called quadrivium, comprising music, arithmetic, geometry, and
astronomy; and the trivium comprising grammar, rhetoric, and
logic. The vagueness of implication of some of these branches
gave opportunity to the teacher for the promulgation of almost
any knowledge of which he might be possessed, but there can be no
doubt that, in general, science had but meagre share in the
curriculum. In so far as it was given representation, its chief
field must have been Ptolemaic astronomy. The utter lack of
scientific thought and scientific method is illustrated most
vividly in the works of the greatest men of that period--such men
as Albertus Magnus, Thomas Aquinas, Bonaventura, and the hosts of
other scholastics of lesser rank. Yet the mental awakening
implied in their efforts was sure to extend to other fields, and
in point of fact there was at least one contemporary of these
great scholastics whose mind was intended towards scientific
subjects, and who produced writings strangely at variance in tone
and in content with the others. This anachronistic thinker was
the English monk, Roger Bacon.
ROGER BACON
Bacon was born in 1214 and died in 1292. By some it is held that
he was not appreciated in his own time because he was really a
modern scientist living in an age two centuries before modern
science or methods of modern scientific thinking were known. Such
an estimate, however, is a manifest exaggeration of the facts,
although there is probably a grain of truth in it withal. His
learning certainly brought him into contact with the great
thinkers of the time, and his writings caused him to be
imprisoned by his fellow-churchmen at different times, from which
circumstances we may gather that he was advanced thinker, even if
not a modern scientist.
Although Bacon was at various times in durance, or under
surveillance, and forbidden to write, he was nevertheless a
marvellously prolific writer, as is shown by the numerous books
and unpublished manuscripts of his still extant. His
master-production was the Opus Majus. In Part IV. of this work he
attempts to show that all sciences rest ultimately on
mathematics; but Part V., which treats of perspective, is of
particular interest to modern scientists, because in this he
discusses reflection and refraction, and the properties of
mirrors and lenses. In this part, also, it is evident that he is
making use of such Arabian writers as Alkindi and Alhazen, and
this is of especial interest, since it has been used by his
detractors, who accuse him of lack of originality, to prove that
his seeming inventions and discoveries were in reality
adaptations of the Arab scientists. It is difficult to determine
just how fully such criticisms are justified. It is certain,
however, that in this part he describes the anatomy of the eye
with great accuracy, and discusses mirrors and lenses.
The magnifying power of the segment of a glass sphere had been
noted by Alhazen, who had observed also that the magnification
was increased by increasing the size of the segment used. Bacon
took up the discussion of the comparative advantages of segments,
and in this discussion seems to show that he understood how to
trace the progress of the rays of light through a spherical
transparent body, and how to determine the place of the image. He
also described a method of constructing a telescope, but it is by
no means clear that he had ever actually constructed such an
instrument. It is also a mooted question as to whether his
instructions as to the construction of such an instrument would
have enabled any one to construct one. The vagaries of the names
of terms as he uses them allow such latitude in interpretation
that modern scientists are not agreed as to the practicability of
Bacon's suggestions. For example, he constantly refers to force
under such names as virtus, species, imago, agentis, and a score
of other names, and this naturally gives rise to the great
differences in the interpretations of his writings, with
corresponding differences in estimates of them.
The claim that Bacon originated the use of lenses, in the form of
spectacles, cannot be proven. Smith has determined that as early
as the opening years of the fourteenth century such lenses were
in use, but this proves nothing as regards Bacon's connection
with their invention. The knowledge of lenses seems to be very
ancient, if we may judge from the convex lens of rock crystal
found by Layard in his excavations at Nimrud. There is nothing to
show, however, that the ancients ever thought of using them to
correct defects of vision. Neither, apparently, is it feasible to
determine whether the idea of such an application originated with
Bacon.
Another mechanical discovery about which there has been a great
deal of discussion is Bacon's supposed invention of gunpowder. It
appears that in a certain passage of his work he describes the
process of making a substance that is, in effect, ordinary
gunpowder; but it is more than doubtful whether he understood the
properties of the substance he describes. It is fairly well
established, however, that in Bacon's time gunpowder was known to
the Arabs, so that it should not be surprising to find references
made to it in Bacon's work, since there is reason to believe that
he constantly consulted Arabian writings.
The great merit of Bacon's work, however, depends on the
principles taught as regards experiment and the observation of
nature, rather than on any single invention. He had the
all-important idea of breaking with tradition. He championed
unfettered inquiry in every field of thought. He had the instinct
of a scientific worker--a rare instinct indeed in that age. Nor
need we doubt that to the best of his opportunities he was
himself an original investigator.
LEONARDO DA VINCI
The relative infertility of Bacon's thought is shown by the fact
that he founded no school and left no trace of discipleship. The
entire century after his death shows no single European name that
need claim the attention of the historian of science. In the
latter part of the fifteenth century, however, there is evidence
of a renaissance of science no less than of art. The German
Muller became famous under the latinized named of Regio Montanus
(1437-1472), although his actual scientific attainments would
appear to have been important only in comparison with the utter
ignorance of his contemporaries. The most distinguished worker of
the new era was the famous Italian Leonardo da Vinci--a man who
has been called by Hamerton the most universal genius that ever
lived. Leonardo's position in the history of art is known to
every one. With that, of course, we have no present concern; but
it is worth our while to inquire at some length as to the famous
painter's accomplishments as a scientist.
From a passage in the works of Leonardo, first brought to light
by Venturi,[1] it would seem that the great painter anticipated
Copernicus in determining the movement of the earth. He made
mathematical calculations to prove this, and appears to have
reached the definite conclusion that the earth does move--or what
amounts to the same thing, that the sun does not move. Muntz is
authority for the statement that in one of his writings he
declares, "Il sole non si mouve"--the sun does not move.[2]
Among his inventions is a dynamometer for determining the
traction power of machines and animals, and his experiments with
steam have led some of his enthusiastic partisans to claim for
him priority to Watt in the invention of the steam-engine. In
these experiments, however, Leonardo seems to have advanced
little beyond Hero of Alexandria and his steam toy. Hero's
steam-engine did nothing but rotate itself by virtue of escaping
jets of steam forced from the bent tubes, while Leonardo's
"steam-engine" "drove a ball weighing one talent over a distance
of six stadia." In a manuscript now in the library of the
Institut de France, Da Vinci describes this engine minutely. The
action of this machine was due to the sudden conversion of small
quantities of water into steam ("smoke," as he called it) by
coming suddenly in contact with a heated surface in a proper
receptacle, the rapidly formed steam acting as a propulsive force
after the manner of an explosive. It is really a steam-gun,
rather than a steam-engine, and it is not unlikely that the study
of the action of gunpowder may have suggested it to Leonardo.
It is believed that Leonardo is the true discoverer of the
camera-obscura, although the Neapolitan philosopher, Giambattista
Porta, who was not born until some twenty years after the death
of Leonardo, is usually credited with first describing this
device. There is little doubt, however, that Da Vinci understood
the principle of this mechanism, for he describes how such a
camera can be made by cutting a small, round hole through the
shutter of a darkened room, the reversed image of objects outside
being shown on the opposite wall.
Like other philosophers in all ages, he had observed a great
number of facts which he was unable to explain correctly. But
such accumulations of scientific observations are always
interesting, as showing how many centuries of observation
frequently precede correct explanation. He observed many facts
about sounds, among others that blows struck upon a bell produced
sympathetic sounds in a bell of the same kind; and that striking
the string of a lute produced vibration in corresponding strings
of lutes strung to the same pitch. He knew, also, that sounds
could be heard at a distance at sea by listening at one end of a
tube, the other end of which was placed in the water; and that
the same expedient worked successfully on land, the end of the
tube being placed against the ground.
The knowledge of this great number of unexplained facts is often
interpreted by the admirers of Da Vinci, as showing an almost
occult insight into science many centuries in advance of his
time. Such interpretations, however, are illusive. The
observation, for example, that a tube placed against the ground
enables one to hear movements on the earth at a distance, is not
in itself evidence of anything more than acute scientific
observation, as a similar method is in use among almost every
race of savages, notably the American Indians. On the other hand,
one is inclined to give credence to almost any story of the
breadth of knowledge of the man who came so near anticipating
Hutton, Lyell, and Darwin in his interpretation of the geological
records as he found them written on the rocks.
It is in this field of geology that Leonardo is entitled to the
greatest admiration by modern scientists. He had observed the
deposit of fossil shells in various strata of rocks, even on the
tops of mountains, and he rejected once for all the theory that
they had been deposited there by the Deluge. He rightly
interpreted their presence as evidence that they had once been
deposited at the bottom of the sea. This process he assumed bad
taken hundreds and thousands of centuries, thus tacitly rejecting
the biblical tradition as to the date of the creation.
Notwithstanding the obvious interest that attaches to the
investigations of Leonardo, it must be admitted that his work in
science remained almost as infertile as that of his great
precursor, Bacon. The really stimulative work of this generation
was done by a man of affairs, who knew little of theoretical
science except in one line, but who pursued that one practical
line until he achieved a wonderful result. This man was
Christopher Columbus. It is not necessary here to tell the trite
story of his accomplishment. Suffice it that his practical
demonstration of the rotundity of the earth is regarded by most
modern writers as marking an epoch in history. With the year of
his voyage the epoch of the Middle Ages is usually regarded as
coming to an end. It must not be supposed that any very sudden
change came over the aspect of scholarship of the time, but the
preliminaries of great things had been achieved, and when
Columbus made his famous voyage in 1492, the man was already
alive who was to bring forward the first great vitalizing thought
in the field of pure science that the Western world had
originated for more than a thousand years. This man bore the name
of Kopernik, or in its familiar Anglicized form, Copernicus. His
life work and that of his disciples will claim our attention in
the succeeding chapter.
IV. THE NEW COSMOLOGY--COPERNICUS TO KEPLER AND GALILEO
We have seen that the Ptolemaic astronomy, which was the accepted
doctrine throughout the Middle Ages, taught that the earth is
round. Doubtless there was a popular opinion current which
regarded the earth as flat, but it must be understood that this
opinion had no champions among men of science during the Middle
Ages. When, in the year 1492, Columbus sailed out to the west on
his memorable voyage, his expectation of reaching India had full
scientific warrant, however much it may have been scouted by
certain ecclesiastics and by the average man of the period.
Nevertheless, we may well suppose that the successful voyage of
Columbus, and the still more demonstrative one made about thirty
years later by Magellan, gave the theory of the earth's rotundity
a certainty it could never previously have had. Alexandrian
geographers had measured the size of the earth, and had not
hesitated to assert that by sailing westward one might reach
India. But there is a wide gap between theory and practice, and
it required the voyages of Columbus and his successors to bridge
that gap.
After the companions of Magellan completed the circumnavigation
of the globe, the general shape of our earth would, obviously,
never again be called in question. But demonstration of the
sphericity of the earth had, of course, no direct bearing upon
the question of the earth's position in the universe. Therefore
the voyage of Magellan served to fortify, rather than to dispute,
the Ptolemaic theory. According to that theory, as we have seen,
the earth was supposed to lie immovable at the centre of the
universe; the various heavenly bodies, including the sun,
revolving about it in eccentric circles. We have seen that
several of the ancient Greeks, notably Aristarchus, disputed this
conception, declaring for the central position of the sun in the
universe, and the motion of the earth and other planets about
that body. But this revolutionary theory seemed so opposed to the
ordinary observation that, having been discountenanced by
Hipparchus and Ptolemy, it did not find a single important
champion for more than a thousand years after the time of the
last great Alexandrian astronomer.
The first man, seemingly, to hark back to the Aristarchian
conception in the new scientific era that was now dawning was the
noted cardinal, Nikolaus of Cusa, who lived in the first half of
the fifteenth century, and was distinguished as a philosophical
writer and mathematician. His De Docta Ignorantia expressly
propounds the doctrine of the earth's motion. No one, however,
paid the slightest attention to his suggestion, which, therefore,
merely serves to furnish us with another interesting illustration
of the futility of propounding even a correct hypothesis before
the time is ripe to receive it--particularly if the hypothesis is
not fully fortified by reasoning based on experiment or
observation.
The man who was destined to put forward the theory of the earth's
motion in a way to command attention was born in 1473, at the
village of Thorn, in eastern Prussia. His name was Nicholas
Copernicus. There is no more famous name in the entire annals of
science than this, yet posterity has never been able fully to
establish the lineage of the famous expositor of the true
doctrine of the solar system. The city of Thorn lies in a
province of that border territory which was then under control of
Poland, but which subsequently became a part of Prussia. It is
claimed that the aspects of the city were essentially German, and
it is admitted that the mother of Copernicus belonged to that
race. The nationality of the father is more in doubt, but it is
urged that Copernicus used German as his mother-tongue. His great
work was, of course, written in Latin, according to the custom of
the time; but it is said that, when not employing that language,
he always wrote in German. The disputed nationality of Copernicus
strongly suggests that he came of a mixed racial lineage, and we
are reminded again of the influences of those ethnical minglings
to which we have previously more than once referred. The
acknowledged centres of civilization towards the close of the
fifteenth century were Italy and Spain. Therefore, the birthplace
of Copernicus lay almost at the confines of civilization,
reminding us of that earlier period when Greece was the centre of
culture, but when the great Greek thinkers were born in Asia
Minor and in Italy.
As a young man, Copernicus made his way to Vienna to study
medicine, and subsequently he journeyed into Italy and remained
there many years, About the year 1500 he held the chair of
mathematics in a college at Rome. Subsequently he returned to his
native land and passed his remaining years there, dying at
Domkerr, in Frauenburg, East Prussia, in the year 1543.
It would appear that Copernicus conceived the idea of the
heliocentric system of the universe while he was a comparatively
young man, since in the introduction to his great work, which he
addressed to Pope Paul III., he states that he has pondered his
system not merely nine years, in accordance with the maxim of
Horace, but well into the fourth period of nine years. Throughout
a considerable portion of this period the great work of
Copernicus was in manuscript, but it was not published until the
year of his death. The reasons for the delay are not very fully
established. Copernicus undoubtedly taught his system throughout
the later decades of his life. He himself tells us that he had
even questioned whether it were not better for him to confine
himself to such verbal teaching, following thus the example of
Pythagoras. Just as his life was drawing to a close, he decided
to pursue the opposite course, and the first copy of his work is
said to have been placed in his hands as he lay on his deathbed.
The violent opposition which the new system met from
ecclesiastical sources led subsequent commentators to suppose
that Copernicus had delayed publication of his work through fear
of the church authorities. There seems, however, to be no direct
evidence for this opinion. It has been thought significant that
Copernicus addressed his work to the pope. It is, of course,
quite conceivable that the aged astronomer might wish by this
means to demonstrate that he wrote in no spirit of hostility to
the church. His address to the pope might have been considered as
a desirable shield precisely because the author recognized that
his work must needs meet with ecclesiastical criticism. Be that
as it may, Copernicus was removed by death from the danger of
attack, and it remained for his disciples of a later generation
to run the gauntlet of criticism and suffer the charges of
heresy.
The work of Copernicus, published thus in the year 1543 at
Nuremberg, bears the title De Orbium Coelestium Revolutionibus.
It is not necessary to go into details as to the cosmological
system which Copernicus advocated, since it is familiar to every
one. In a word, he supposed the sun to be the centre of all the
planetary motions, the earth taking its place among the other
planets, the list of which, as known at that time, comprised
Mercury, Venus, the Earth, Mars, Jupiter, and Saturn. The fixed
stars were alleged to be stationary, and it was necessary to
suppose that they are almost infinitely distant, inasmuch as they
showed to the observers of that time no parallax; that is to say,
they preserved the same apparent position when viewed from the
opposite points of the earth's orbit.
But let us allow Copernicus to speak for himself regarding his
system, His exposition is full of interest. We quote first the
introduction just referred to, in which appeal is made directly
to the pope.
"I can well believe, most holy father, that certain people, when
they hear of my attributing motion to the earth in these books of
mine, will at once declare that such an opinion ought to be
rejected. Now, my own theories do not please me so much as not to
consider what others may judge of them. Accordingly, when I began
to reflect upon what those persons who accept the stability of
the earth, as confirmed by the opinion of many centuries, would
say when I claimed that the earth moves, I hesitated for a long
time as to whether I should publish that which I have written to
demonstrate its motion, or whether it would not be better to
follow the example of the Pythagoreans, who used to hand down the
secrets of philosophy to their relatives and friends only in oral
form. As I well considered all this, I was almost impelled to put
the finished work wholly aside, through the scorn I had reason to
anticipate on account of the newness and apparent contrariness to
reason of my theory.
"My friends, however, dissuaded me from such a course and
admonished me that I ought to publish my book, which had lain
concealed in my possession not only nine years, but already into
four times the ninth year. Not a few other distinguished and very
learned men asked me to do the same thing, and told me that I
ought not, on account of my anxiety, to delay any longer in
consecrating my work to the general service of mathematicians.
"But your holiness will perhaps not so much wonder that I have
dared to bring the results of my night labors to the light of
day, after having taken so much care in elaborating them, but is
waiting instead to hear how it entered my mind to imagine that
the earth moved, contrary to the accepted opinion of
mathematicians--nay, almost contrary to ordinary human
understanding. Therefore I will not conceal from your holiness
that what moved me to consider another way of reckoning the
motions of the heavenly bodies was nothing else than the fact
that the mathematicians do not agree with one another in their
investigations. In the first place, they are so uncertain about
the motions of the sun and moon that they cannot find out the
length of a full year. In the second place, they apply neither
the same laws of cause and effect, in determining the motions of
the sun and moon and of the five planets, nor the same proofs.
Some employ only concentric circles, others use eccentric and
epicyclic ones, with which, however, they do not fully attain the
desired end. They could not even discover nor compute the main
thing--namely, the form of the universe and the symmetry of its
parts. It was with them as if some should, from different places,
take hands, feet, head, and other parts of the body, which,
although very beautiful, were not drawn in their proper
relations, and, without making them in any way correspond, should
construct a monster instead of a human being.
"Accordingly, when I had long reflected on this uncertainty of
mathematical tradition, I took the trouble to read again the
books of all the philosophers I could get hold of, to see if some
one of them had not once believed that there were other motions
of the heavenly bodies. First I found in Cicero that Niceties had
believed in the motion of the earth. Afterwards I found in
Plutarch, likewise, that some others had held the same opinion.
This induced me also to begin to consider the movability of the
earth, and, although the theory appeared contrary to reason, I
did so because I knew that others before me had been allowed to
assume rotary movements at will, in order to explain the
phenomena of these celestial bodies. I was of the opinion that I,
too, might be permitted to see whether, by presupposing motion in
the earth, more reliable conclusions than hitherto reached could
not be discovered for the rotary motions of the spheres. And
thus, acting on the hypothesis of the motion which, in the
following book, I ascribe to the earth, and by long and continued
observations, I have finally discovered that if the motion of the
other planets be carried over to the relation of the earth and
this is made the basis for the rotation of every star, not only
will the phenomena of the planets be explained thereby, but also
the laws and the size of the stars; all their spheres and the
heavens themselves will appear so harmoniously connected that
nothing could be changed in any part of them without confusion in
the remaining parts and in the whole universe. I do not doubt
that clever and learned men will agree with me if they are
willing fully to comprehend and to consider the proofs which I
advance in the book before us. In order, however, that both the
learned and the unlearned may see that I fear no man's judgment,
I wanted to dedicate these, my night labors, to your holiness,
rather than to any one else, because you, even in this remote
corner of the earth where I live, are held to be the greatest in
dignity of station and in love for all sciences and for
mathematics, so that you, through your position and judgment, can
easily suppress the bites of slanderers, although the proverb
says that there is no remedy against the bite of calumny."
In chapter X. of book I., "On the Order of the Spheres," occurs a
more detailed presentation of the system, as follows:
"That which Martianus Capella, and a few other Latins, very well
knew, appears to me extremely noteworthy. He believed that Venus
and Mercury revolve about the sun as their centre and that they
cannot go farther away from it than the circles of their orbits
permit, since they do not revolve about the earth like the other
planets. According to this theory, then, Mercury's orbit would be
included within that of Venus, which is more than twice as great,
and would find room enough within it for its revolution.
"If, acting upon this supposition, we connect Saturn, Jupiter,
and Mars with the same centre, keeping in mind the greater extent
of their orbits, which include the earth's sphere besides those
of Mercury and Venus, we cannot fail to see the explanation of
the regular order of their motions. He is certain that Saturn,
Jupiter, and Mars are always nearest the earth when they rise in
the evening--that is, when they appear over against the sun, or
the earth stands between them and the sun--but that they are
farthest from the earth when they set in the evening--that is,
when we have the sun between them and the earth. This proves
sufficiently that their centre belongs to the sun and is the same
about which the orbits of Venus and Mercury circle. Since,
however, all have one centre, it is necessary for the space
intervening between the orbits of Venus and Mars to include the
earth with her accompanying moon and all that is beneath the
moon; for the moon, which stands unquestionably nearest the
earth, can in no way be separated from her, especially as there
is sufficient room for the moon in the aforesaid space. Hence we
do not hesitate to claim that the whole system, which includes
the moon with the earth for its centre, makes the round of that
great circle between the planets, in yearly motion about the sun,
and revolves about the centre of the universe, in which the sun
rests motionless, and that all which looks like motion in the sun
is explained by the motion of the earth. The extent of the
universe, however, is so great that, whereas the distance of the
earth from the sun is considerable in comparison with the size of
the other planetary orbits, it disappears when compared with the
sphere of the fixed stars. I hold this to be more easily
comprehensible than when the mind is confused by an almost
endless number of circles, which is necessarily the case with
those who keep the earth in the middle of the universe. Although
this may appear incomprehensible and contrary to the opinion of
many, I shall, if God wills, make it clearer than the sun, at
least to those who are not ignorant of mathematics.
"The order of the spheres is as follows: The first and lightest
of all the spheres is that of the fixed stars, which includes
itself and all others, and hence is motionless as the place in
the universe to which the motion and position of all other stars
is referred.
"Then follows the outermost planet, Saturn, which completes its
revolution around the sun in thirty years; next comes Jupiter
with a twelve years' revolution; then Mars, which completes its
course in two years. The fourth one in order is the yearly
revolution which includes the earth with the moon's orbit as an
epicycle. In the fifth place is Venus with a revolution of nine
months. The sixth place is taken by Mercury, which completes its
course in eighty days. In the middle of all stands the sun, and
who could wish to place the lamp of this most beautiful temple in
another or better place. Thus, in fact, the sun, seated upon the
royal throne, controls the family of the stars which circle
around him. We find in their order a harmonious connection which
cannot be found elsewhere. Here the attentive observer can see
why the waxing and waning of Jupiter seems greater than with
Saturn and smaller than with Mars, and again greater with Venus
than with Mercury. Also, why Saturn, Jupiter, and Mars are nearer
to the earth when they rise in the evening than when they
disappear in the rays of the sun. More prominently, however, is
it seen in the case of Mars, which when it appears in the heavens
at night, seems to equal Jupiter in size, but soon afterwards is
found among the stars of second magnitude. All of this results
from the same cause--namely, from the earth's motion. The fact
that nothing of this is to be seen in the case of the fixed stars
is a proof of their immeasurable distance, which makes even the
orbit of yearly motion or its counterpart invisible to us."[1]
The fact that the stars show no parallax had been regarded as an
important argument against the motion of the earth, and it was
still so considered by the opponents of the system of Copernicus.
It had, indeed, been necessary for Aristarchus to explain the
fact as due to the extreme distance of the stars; a perfectly
correct explanation, but one that implies distances that are
altogether inconceivable. It remained for nineteenth-century
astronomers to show, with the aid of instruments of greater
precision, that certain of the stars have a parallax. But long
before this demonstration had been brought forward, the system of
Copernicus had been accepted as a part of common knowledge.
While Copernicus postulated a cosmical scheme that was correct as
to its main features, he did not altogether break away from
certain defects of the Ptolemaic hypothesis. Indeed, he seems to
have retained as much of this as practicable, in deference to the
prejudice of his time. Thus he records the planetary orbits as
circular, and explains their eccentricities by resorting to the
theory of epicycles, quite after the Ptolemaic method. But now,
of course, a much more simple mechanism sufficed to explain the
planetary motions, since the orbits were correctly referred to
the central sun and not to the earth.
Needless to say, the revolutionary conception of Copernicus did
not meet with immediate acceptance. A number of prominent
astronomers, however, took it up almost at once, among these
being Rhaeticus, who wrote a commentary on the evolutions;
Erasmus Reinhold, the author of the Prutenic tables; Rothmann,
astronomer to the Landgrave of Hesse, and Maestlin, the
instructor of Kepler. The Prutenic tables, just referred to, so
called because of their Prussian origin, were considered an
improvement on the tables of Copernicus, and were highly esteemed
by the astronomers of the time. The commentary of Rhaeticus gives
us the interesting information that it was the observation of the
orbit of Mars and of the very great difference between his
apparent diameters at different times which first led Copernicus
to conceive the heliocentric idea. Of Reinhold it is recorded
that he considered the orbit of Mercury elliptical, and that he
advocated a theory of the moon, according to which her epicycle
revolved on an elliptical orbit, thus in a measure anticipating
one of the great discoveries of Kepler to which we shall refer
presently. The Landgrave of Hesse was a practical astronomer, who
produced a catalogue of fixed stars which has been compared with
that of Tycho Brahe. He was assisted by Rothmann and by Justus
Byrgius. Maestlin, the preceptor of Kepler, is reputed to have
been the first modern observer to give a correct explanation of
the light seen on portions of the moon not directly illumined by
the sun. He explained this as not due to any proper light of the
moon itself, but as light reflected from the earth. Certain of
the Greek philosophers, however, are said to have given the same
explanation, and it is alleged also that Leonardo da Vinci
anticipated Maestlin in this regard.[2]
While, various astronomers of some eminence thus gave support to
the Copernican system, almost from the beginning, it
unfortunately chanced that by far the most famous of the
immediate successors of Copernicus declined to accept the theory
of the earth's motion. This was Tycho Brahe, one of the greatest
observing astronomers of any age. Tycho Brahe was a Dane, born at
Knudstrup in the year 1546. He died in 1601 at Prague, in
Bohemia. During a considerable portion of his life he found a
patron in Frederick, King of Denmark, who assisted him to build a
splendid observatory on the Island of Huene. On the death of his
patron Tycho moved to Germany, where, as good luck would have it,
he came in contact with the youthful Kepler, and thus, no doubt,
was instrumental in stimulating the ambitions of one who in later
years was to be known as a far greater theorist than himself. As
has been said, Tycho rejected the Copernican theory of the
earth's motion. It should be added, however, that he accepted
that part of the Copernican theory which makes the sun the centre
of all the planetary motions, the earth being excepted. He thus
developed a system of his own, which was in some sort a
compromise between the Ptolemaic and the Copernican systems. As
Tycho conceived it, the sun revolves about the earth, carrying
with it the planets-Mercury, Venus, Mars, Jupiter, and Saturn,
which planets have the sun and not the earth as the centre of
their orbits. This cosmical scheme, it should be added, may be
made to explain the observed motions of the heavenly bodies, but
it involves a much more complex mechanism than is postulated by
the Copernican theory.
Various explanations have been offered of the conservatism which
held the great Danish astronomer back from full acceptance of the
relatively simple and, as we now know, correct Copernican
doctrine. From our latter-day point of view, it seems so much
more natural to accept than to reject the Copernican system, that
we find it difficult to put ourselves in the place of a
sixteenth-century observer. Yet if we recall that the traditional
view, having warrant of acceptance by nearly all thinkers of
every age, recorded the earth as a fixed, immovable body, we
shall see that our surprise should be excited rather by the
thinker who can break away from this view than by the one who
still tends to cling to it.
Moreover, it is useless to attempt to disguise the fact that
something more than a mere vague tradition was supposed to
support the idea of the earth's overshadowing importance in the
cosmical scheme. The sixteenth-century mind was overmastered by
the tenets of ecclesiasticism, and it was a dangerous heresy to
doubt that the Hebrew writings, upon which ecclesiasticism based
its claim, contained the last word regarding matters of science.
But the writers of the Hebrew text had been under the influence
of that Babylonian conception of the universe which accepted the
earth as unqualifiedly central--which, indeed, had never so much
as conceived a contradictory hypothesis; and so the Western
world, which had come to accept these writings as actually
supernatural in origin, lay under the spell of Oriental ideas of
a pre-scientific era. In our own day, no one speaking with
authority thinks of these Hebrew writings as having any
scientific weight whatever. Their interest in this regard is
purely antiquarian; hence from our changed point of view it seems
scarcely credible that Tycho Brahe can have been in earnest when
he quotes the Hebrew traditions as proof that the sun revolves
about the earth. Yet we shall see that for almost three centuries
after the time of Tycho, these same dreamings continued to be
cited in opposition to those scientific advances which new
observations made necessary; and this notwithstanding the fact
that the Oriental phrasing is, for the most part, poetically
ambiguous and susceptible of shifting interpretations, as the
criticism of successive generations has amply testified.
As we have said, Tycho Brahe, great observer as he was, could not
shake himself free from the Oriental incubus. He began his
objections, then, to the Copernican system by quoting the adverse
testimony of a Hebrew prophet who lived more than a thousand
years B.C. All of this shows sufficiently that Tycho Brahe was
not a great theorist. He was essentially an observer, but in this
regard he won a secure place in the very first rank. Indeed, he
was easily the greatest observing astronomer since Hipparchus,
between whom and himself there were many points of resemblance.
Hipparchus, it will be recalled, rejected the Aristarchian
conception of the universe just as Tycho rejected the conception
of Copernicus.
But if Tycho propounded no great generalizations, the list of
specific advances due to him is a long one, and some of these
were to prove important aids in the hands of later workers to the
secure demonstration of the Copernican idea. One of his most
important series of studies had to do with comets. Regarding
these bodies there had been the greatest uncertainty in the minds
of astronomers. The greatest variety of opinions regarding them
prevailed; they were thought on the one hand to be divine
messengers, and on the other to be merely igneous phenomena of
the earth's atmosphere. Tycho Brahe declared that a comet which
he observed in the year 1577 had no parallax, proving its extreme
distance. The observed course of the comet intersected the
planetary orbits, which fact gave a quietus to the long-mooted
question as to whether the Ptolemaic spheres were transparent
solids or merely imaginary; since the comet was seen to intersect
these alleged spheres, it was obvious that they could not be the
solid substance that they were commonly imagined to be, and this
fact in itself went far towards discrediting the Ptolemaic
system. It should be recalled, however, that this supposition of
tangible spheres for the various planetary and stellar orbits was
a mediaeval interpretation of Ptolemy's theory rather than an
interpretation of Ptolemy himself, there being nothing to show
that the Alexandrian astronomer regarded his cycles and epicycles
as other than theoretical.
An interesting practical discovery made by Tycho was his method
of determining the latitude of a place by means of two
observations made at an interval of twelve hours. Hitherto it had
been necessary to observe the sun's angle on the equinoctial
days, a period of six months being therefore required. Tycho
measured the angle of elevation of some star situated near the
pole, when on the meridian, and then, twelve hours later,
measured the angle of elevation of the same star when it again
came to the meridian at the opposite point of its apparent circle
about the polestar. Half the sum of these angles gives the
latitude of the place of observation.
As illustrating the accuracy of Tycho's observations, it may be
noted that he rediscovered a third inequality of the moon's
motion at its variation, he, in common with other European
astronomers, being then quite unaware that this inequality had
been observed by an Arabian astronomer. Tycho proved also that
the angle of inclination of the moon's orbit to the ecliptic is
subject to slight variation.
The very brilliant new star which shone forth suddenly in the
constellation of Cassiopeia in the year 1572, was made the object
of special studies by Tycho, who proved that the star had no
sensible parallax and consequently was far beyond the planetary
regions. The appearance of a new star was a phenomenon not
unknown to the ancients, since Pliny records that Hipparchus was
led by such an appearance to make his catalogue of the fixed
stars. But the phenomenon is sufficiently uncommon to attract
unusual attention. A similar phenomenon occurred in the year
1604, when the new star--in this case appearing in the
constellation of Serpentarius--was explained by Kepler as
probably proceeding from a vast combustion. This explanation--in
which Kepler is said to have followed. Tycho--is fully in accord
with the most recent theories on the subject, as we shall see in
due course. It is surprising to hear Tycho credited with so
startling a theory, but, on the other hand, such an explanation
is precisely what should be expected from the other astronomer
named. For Johann Kepler, or, as he was originally named, Johann
von Kappel, was one of the most speculative astronomers of any
age. He was forever theorizing, but such was the peculiar quality
of his mind that his theories never satisfied him for long unless
he could put them to the test of observation. Thanks to this
happy combination of qualities, Kepler became the discoverer of
three famous laws of planetary motion which lie at the very
foundation of modern astronomy, and which were to be largely
instrumental in guiding Newton to his still greater
generalization. These laws of planetary motion were vastly
important as corroborating the Copernican theory of the universe,
though their position in this regard was not immediately
recognized by contemporary thinkers. Let us examine with some
detail into their discovery, meantime catching a glimpse of the
life history of the remarkable man whose name they bear.
JOHANN KEPLER AND THE LAWS OF PLANETARY MOTION
Johann Kepler was born the 27th of December, 1571, in the little
town of Weil, in Wurtemburg. He was a weak, sickly child, further
enfeebled by a severe attack of small-pox. It would seem
paradoxical to assert that the parents of such a genius were
mismated, but their home was not a happy one, the mother being of
a nervous temperament, which perhaps in some measure accounted
for the genius of the child. The father led the life of a
soldier, and finally perished in the campaign against the Turks.
Young Kepler's studies were directed with an eye to the ministry.
After a preliminary training he attended the university at
Tubingen, where he came under the influence of the celebrated
Maestlin and became his life-long friend.
Curiously enough, it is recorded that at first Kepler had no
taste for astronomy or for mathematics. But the doors of the
ministry being presently barred to him, he turned with enthusiasm
to the study of astronomy, being from the first an ardent
advocate of the Copernican system. His teacher, Maestlin,
accepted the same doctrine, though he was obliged, for
theological reasons, to teach the Ptolemaic system, as also to
oppose the Gregorian reform of the calendar.
The Gregorian calendar, it should be explained, is so called
because it was instituted by Pope Gregory XIII., who put it into
effect in the year 1582, up to which time the so-called Julian
calendar, as introduced by Julius Caesar, had been everywhere
accepted in Christendom. This Julian calendar, as we have seen,
was a great improvement on preceding ones, but still lacked
something of perfection inasmuch as its theoretical day differed
appreciably from the actual day. In the course of fifteen hundred
years, since the time of Caesar, this defect amounted to a
discrepancy of about eleven days. Pope Gregory proposed to
correct this by omitting ten days from the calendar, which was
done in September, 1582. To prevent similar inaccuracies in the
future, the Gregorian calendar provided that once in four
centuries the additional day to make a leap-year should be
omitted, the date selected for such omission being the last year
of every fourth century. Thus the years 1500, 1900, and 2300,
A.D., would not be leap-years. By this arrangement an approximate
Book of the day:
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-1,953,591,794,174,975,000 | C3G kidney disease: How is it diagnosed and how is it treated?
Complement 3 Glomerulopathy, most commonly shortened to C3G or C3G kidney disease, is a rare type of kidney disease that has only been diagnosed since 2013. “C3” refers to a blood protein that has a vital role in the immune system, and “G” is for the damage to glomeruli in the kidneys.
While all types of kidney disease are serious, C3G is unique because there is currently no treatment available for the condition. Researchers are working to learn more about this rare disease through ongoing research studies in the hopes that they will be able to one day discover a breakthrough.
To increase awareness around C3G kidney disease, we have a brief guide below about what it is, how it is diagnosed, and how it is treated. Keep reading to learn more.
What is C3G?
The complement system is a collection of proteins in the blood that help the immune system fight bacteria and viruses. If the complement system becomes overactive, normal complement proteins (such as C3) can be broken down. The breakdown of these products can then become lodged in the kidneys, causing irritations that injure the glomeruli and interfere with their ability to filter the blood. Before 2013, patients with this condition would have been diagnosed with “membranoproliferative glomerulonephritis (MPGN)” or “mesangioproliferative glomerulonephritis,” but these terms have since been updated to C3G.
How C3G kidney disease is diagnosed
While a C3G diagnosis requires a kidney biopsy to be confirmed, because it is such a rare disease, doctors will typically run a series of tests to rule out other causes beforehand. Before ordering a biopsy, a medical provider will typically perform a urinalysis, do a blood work panel, perform an ultrasound, and run tests that estimate kidney function. If these still indicate that C3G is a possibility, a biopsy will be performed to look for dense deposits of the complement protein C3 in the kidney tissue.
A look at C3G treatment
Currently, there are no FDA-approved treatments designed specifically for C3G. The treatments currently available to patients are aimed at managing blood pressure, proteinuria, and cholesterol levels low, in addition to controlling the immune system. In some cases, the cause of C3G is able to be identified, which can help doctors determine the best course of treatment.
Autoantibody C3G treatment
Sometimes, C3G is caused by an autoantibody that attacks the complement system and causes the condition. In these cases, immunosuppressants can be used in an attempt to stop the immune system from hindering the complement system.
Genetic mutation C3G treatment
In the event of C3G caused by genetic mutations, plasma infusion and plasma exchange can sometimes be a treatment option — but unfortunately, these interventions tend to only help a select few patients. Plasma infusions can replace missing proteins in the blood, so if a patient is missing the protein that prevents C3G, this may be an option. Plasma exchange removes harmful proteins and replaces them with normal ones.
While there are currently limited kinds of treatment for C3G patients, clinical trials can be an option for patients today. These trials help science move forward and can provide individuals with potential new treatments before they’re on the market. Search available trials today to learn more. | {
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-5,221,030,999,289,461,000 | Hide this
Knee Surgery
Story at-a-glance -
• A recent study found arthroscopic knee surgery for degenerative meniscal tears had no more benefit than “sham surgery”
• Four studies over the last decade cast doubt on whether arthroscopic knee surgery is offering any real benefits to knee pain sufferers
• Harnessing the power of placebo, along with adopting a disease-preventing lifestyle, is a more effective approach to treating common knee pain
• Appropriate exercise is key to preventing and relieving most knee pain by strengthening your joint and its supportive structures, improving flexibility, and helping to optimize body weight
• A number of supplements are particularly helpful, such as vitamin D, MSM, astaxanthin, turmeric, and several others
Another Study Finds Arthroscopic Knee Surgery No Better Than Sham Surgery
February 07, 2014 | 325,417 views
| Available in EspañolDisponible en Español
By Dr. Mercola
Arthroscopic knee surgery is one of the most common unnecessary surgeries performed today—along with back and hip surgeries, pacemakers, cardiac angioplasties, hysterectomies, and Cesarean sections.
Several studies over the past decade have highlighted questions about arthroscopic knee surgery, and now, you can add one more to the pile. The meniscus inside your knee is a thin crescent-shaped disc of cartilage that serves as a cushion between your femur and tibia and helps stabilize your knees.
Over time, your meniscus can develop tears, especially if you have arthritis. The standard orthopedic surgeon's intervention for meniscal tears is performing an arthroscopic partial meniscectomy—trimming the torn meniscus and smoothing the jagged edges of what remains, which assumes the tear is what's causing your pain. However, that may be a faulty assumption.
Knee Surgery No Better Than Sham
This latest study, conducted in Finland, examined 146 patients with degenerative meniscal tears (caused by "wear and tear," not acute injury).1 Researchers divided patients into two groups.
One group received the standard surgery, and the other received a "sham surgery"—in other words, a fake or placebo intervention where no actual surgery takes place. The study excluded people with knee arthritis, because they tend not to benefit as much from meniscus surgery and the researchers wanted to ascertain if the surgery helps under "ideal circumstances."2
The sham surgery involved the physician's making an incision and poking around without any actual cartilage shaving or cutting. Many of the patients were given epidural anesthesia, so they were awake, making it necessary for surgical staff to use their "theatrical talents" to pull off a believable sham surgery.
The outcome? One year later, both groups reported equally favorable responses to the procedure—primarily, reduction in knee pain. In the end, the researchers concluded that the real knee surgeries offered no better outcomes than the sham surgeries.
Arthroscopic surgery on the meniscus is the most common orthopedic procedure in the US, and according to this study, is performed about 700,000 times a year to the tune of $4 billion. Any surgeon who tells you this is the best or only option for your osteoarthritic knee pain will not have a leg to stand on when you show him or her all of the evidence to the contrary.
Arthroscopic Surgeries Have an Embarrassing Track Record
Prior to the Finnish study, there were already three prior studies of note that should have orthopedic surgeons rethinking how they treat their knee patients:
1. A landmark study in Texas set the ball rolling back, over ten years ago, in 2002. The study involved 180 participants randomly assigned to either have the real operation or sham surgery, in which surgeons simply made cuts in their knees. The real surgery turned out to have no benefits over the sham procedure.3 This was a classic multi-center (including Harvard) double blind controlled trial that clearly showed the surgery was a $3 billion waste.
2. In 2008, a Canadian study compared the benefits of physical and medical therapy to arthroscopic surgery for osteoarthritis of the knee. Researchers concluded that physical and medical therapy provided equal benefit to surgery.4
3. In 2013, researchers compared the functional outcomes of physical therapy versus arthroscopy for patients with meniscal tears. They found that arthroscopy followed by postoperative physical therapy had no benefit over physical therapy alone.5
See the pattern emerging here? It's hard to miss! Eighty percent of meniscal tears develop from wear and tear over time.6 If you have pain in your knees from ordinary activities or arthritis, you may be better off skipping the surgery and going straight to physical therapy.
Or better yet, get some treatments with an infrared laser that I discussed in detail with Dr. Harrington.
Of course, there are other non-invasive therapies that can be helpful as well. But it's becoming quite clear that a torn meniscus—at least, the wear-and-tear variety—is not going to be helped by a "surgical trim." Surgeries come with all sorts of risks, and there is no point in exposing yourself to these without some clear advantage.
If you have a torn meniscus from an accident or injury, the scenario may be different, but I would still recommend you getting a second or even third opinion before going under the knife.
The Power of Placebo
With TWO studies now highlighting the benefits of placebo knee surgeries, the power of placebo just can't be ignored. Placebos typically have far fewer side effects (if any) than prescription drugs, injections, or actual surgeries—and they often work just as well as the standard of care.
Studies have shown that if you think you're receiving a treatment, and you expect that treatment to work, it often does—even if you know you're receiving a placebo.
This was beautifully demonstrated in the Finnish study—the knee surgery patients knew they might be having a sham surgery, yet they experienced the benefits anyway. But how do placebos work? How can your brain produce healing just because you believe it should be happening?
Although the exact mechanisms of the placebo effect are not well understood, it seems related to changes in your brain in response to different psychosocial stimuli. Areas of your brain associated with expectations, anxiety, and rewards seem to be involved. Scientific American reported:7
"In recent decades reports have confirmed the efficacy of various sham treatments in nearly all areas of medicine. Placebos have helped alleviate pain, depression, anxiety, Parkinson's disease, inflammatory disorders and even cancer.
Placebo effects can arise not only from a conscious belief in a drug but also from subconscious associations between recovery and the experience of being treated—from the pinch of a shot to a doctor's white coat.
Such subliminal conditioning can control bodily processes of which we are unaware, such as immune responses and the release of hormones… Researchers have decoded some of the biology of placebo responses, demonstrating that they stem from active processes in the brain."
You can tap into your own placebo effect with techniques such as EFT or Emotional Freedom Technique. This is a new way of thinking about healing for most people that can be extremely powerful, especially when combined with a positive outlook and a proactive, disease-preventive lifestyle.
Your Secret Weapon Against Knee Pain: Exercise
Exercise is the real medicine for pain in your joints. Exercise helps prevent and relieve joint pain through a number of mechanisms, including strengthening key supportive muscles, improving flexibility and range of motion, improving bone strength, and helping you optimize your weight. The notion that exercise is detrimental to your joints is a serious misconception; there is no evidence to support this belief. It's simply a myth that you can "wear down" your knees just from average levels of exercise and/or normal activity.
This is not to say that traditional pavement-pounding, like distance running, is going to be of any benefit to your knees—I'm talking about low-impact but effective exercise, such as high-intensity interval training (HIIT), high-intensity cardio, weight training, stretching, and core work. If you find you're in pain for more than an hour after your workout, you should slow down or choose another form of exercise—there really are plenty to choose from.
If you've already developed osteoarthritis in your knees, you'll want to incorporate exercises that strengthen your quadriceps muscle at the front of your thigh. And, rather than running and other high-impact activities, you may be better off with non-weight-bearing exercises like swimming and cycling. Strengthening and stretching the areas around, above, and below your knee is key to reducing most knee pain, which is the goal of the exercises I demonstrate in the video above. I recommend a qualified physiotherapist to properly assist you with your exercises to avoid injury. Make sure to wear appropriate footwear for all of your daily activities. Spiked heels and very flat soled shoes place unnatural stresses on your knees. Good posture is important as well.
Tips for Natural Pain Relief and Growing Healthy Cartilage
For joint pain, many physicians commonly recommend anti-inflammatory drugs (non-steroidal anti-inflammatories or NSAIDs) and analgesics (such as Tylenol) to their osteoarthritis patients. I don't recommend the chronic use of these drugs due to significant side effects, which may include kidney and/or liver damage. There are safer and more effective natural options for relieving joint pain. Although popular, I am also not much of a glucosamine and chondroitin fan because studies have failed to demonstrate their effectiveness. However, there are some very effective natural remedies that are truly backed up by science. The following are my favorites:
• Vitamin D: Cartilage loss in your knees, one of the hallmarks of osteoarthritis, is associated with low levels of vitamin D. So if you're struggling with joint pain due to osteoarthritis, get your vitamin D level tested, then optimize it using appropriate sun exposure or a safe tanning bed. If neither of these options is available, you may want to consider oral vitamin D3 and K2 supplements.
• Sun exposure is your best option, because your skin produces two types of sulfur in response to sun exposure: cholesterol sulfate and vitamin D3 sulfate. Sulfur plays a vital role in the structure and biological activity of both proteins and enzymes. If you don't have sufficient sulfur in your body, this deficiency can create a number of health problems, including negative impacts on your joints and connective tissue. Which brings us to the next item...
• Sulfur/Epsom salt soaks/MSM: In addition to making sure you're getting ample amounts of sulfur-rich foods in your diet, such as organic and/or grass-fed/pastured beef and poultry, Dr. Stephanie Seneff, a senior scientist at MIT, recommends soaking your body in magnesium sulfate (Epsom salt) baths to counteract sulfur deficiency. She uses about 1/4 cup in a tub of water, twice a week. It's particularly useful if you have joint problems or arthritis.
• Methylsulfonylmethane (known as MSM) is another alternative you might find helpful. MSM is an organic form of sulfur and a potent antioxidant naturally found in many plants, and is available in supplement form. For more on the benefits of MSM, I recommend listening to this interview.
Download Interview Transcript
• Infrared laser: Infrared laser treatment (also called K-Laser) is a relatively new type of therapy that speeds healing by increasing tissue oxygenation and allowing injured cells to absorb photons of light. This special type of laser has positive affects on muscles, ligaments and even bones, so it can be used to speed the healing of traumatic injuries, as well as chronic problems like arthritis of the knee.
• Astaxanthin: An antioxidant that affects a wide range of inflammation mediators, but in a gentler, less concentrated manner and without the negative side effects of steroidal and NSAID drugs. Astaxanthin significantly reduces inflammation in many people—in one study, more than 80 percent of arthritis sufferers improved8.
• Eggshell membrane: The eggshell membrane is the unique protective barrier between the egg white and the mineralized eggshell. The membrane contains elastin, a protein that supports cartilage health, and collagen, a fibrous protein that supports cartilage and connective tissue strength and elasticity.
• Eggshell membrane also contains transforming growth factor-B, a protein that helps with tissue rejuvenation, in addition to other amino acids and structural components that provide your joints with the building blocks they need to build cartilage.
• Hyaluronic acid (HA): Hyaluronic acid is a key component of cartilage required for moving nutrients into and waste out of your cells. One of HA's most important biological functions is the retention of water. Unfortunately, as you age, your body produces less and less HA. Oral HA supplementation may improve your joint cushioning in just two to four months.
• Boswellia: Also known as boswellin or "Indian frankincense," I've found this Indian herb to be particularly useful in treating the pain and inflammation of osteoarthritis. With sustained use, boswellia may improve the blood flow to your joints, which may boost their strength and flexibility.
• Turmeric/curcumin: A study in the Journal of Alternative and Complementary Medicine9 found that taking turmeric extracts each day for six weeks was just as effective as ibuprofen for relieving knee osteoarthritis pain. This is most likely related to the anti-inflammatory effects of curcumin—the pigment that gives turmeric its vibrant yellow color.
• Animal-based omega-3 fats: Omega-3 fats are excellent for arthritis because they are well known for reducing inflammation. Look for a high-quality, animal-based source such as krill oil.
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-7,618,590,231,978,674,000 | Respiratory distress of the newborn (RDS) is a syndrome that occurs in premature infants secondary to insufficient surfactant production and structural immaturity of the infant’s lungs. Clinical assessment and interventions must be instituted quickly to reduce infant mortality and morbidity.
By Kenneth Miller MEd, MSRT, RRT-ACCS, NPS, AE-C, FAARC
Introduction
Respiratory distress of the newborn (RDS) is a syndrome that occurs in premature infants secondary to an insufficient surfactant production and structural immaturity of the infant’s lungs. Other etiologies include neonatal infection, often a gram-negative bacteremia and genetic lack of normal surfactant protein production.
RDS affects approximately one percent of newborns and is one of the leading causes of mortality in preterm infants.1 The incidence of RDS is reduced with advancing gestational age, from 50% in infants born between 26-28 weeks to 25% in those born at weeks 30-32.2 The clinical presentation is most frequent in males, Caucasians, infants of diabetic mothers, cesarean section delivery, and the second born premature twin. (See Figure 1.) Historically, this disease was called hyaline membrane disease for its wax-like layers of hyaline membrane lining the collapsed alveoli of the lung. If not recognized quickly, gas exchange can deteriorate suddenly and invasive interventions will be required. The syndrome usually develops with first 24 hours after birth and can remain for several days.
Figure 1. Risk factors for the development of RDS
? Increased Risk
? Prematurity
? Male gender
? Familial predisposition
? Cesarean section without labor
? Perinatal asphyxia
? Caucasian race
? Diabetic mother
? Non-immune hydrops fetalis (excessive fetal fluid syndrome)
Regardless of the cause of RDS, if not recognized and managed quickly, respiratory distress can escalate to respiratory failure and cardiopulmonary arrest. Therefore, it is imperative that the respiratory care practitioner caring for any newborn infants can readily recognize the signs and symptoms of respiratory distress, differentiate various causes, and initiate management strategies to prevent significant complications or death. Despite great clinical advancements RDS remains one of the single greatest causes of infant death in the developed world.3
Signs and Symptoms
Clinical signs of RDS manifest the following: tachypnea with respiratory rates often exceeding 60 breaths per minute, tachycardia with heart rates often above 180 beats per minute, chest wall retractions with intercostal collapse, expiratory grunting, nasal flaring, and central cyanosis. Retractions occur as the infant is forced to generate a high intrathoracic pressure to compensate for the poor compliance associated with stiff lungs. Grunting results from the partial closure of the glottis during forced exhalation to maintain the infant’s functional residual capacity (PEEP effect). As the syndrome progresses, the infant may develop ventilatory failure noted by an elevation PaCO2 and exhibit prolonged periods of apnea. The acute phase of the disease process commonly lasts two to three days, with the first day requiring the highest levels of clinical interventions.
Complications of RDS include metabolic acidosis, hypoglycemia, patent ductus arteriosus, hypotension, reduced urine output, the development of chronic lung disease (bronchopulmonary dysplasia) and cerebral bleeding.4 Macroscopically, the lung appears congested, atelectatic, and solid. Microscopically, diffusive atelectasis and pulmonary edema are visible. Infants that die secondary to RDS on autopsy have wax-like layers of hyaline membrane lining their lung tissue. In addition, a hemorrhagic lung and hyperinflation are common presentations.
Diagnosis
Diagnosis of RDS is primarily made based on clinical assessment of the newborn infant and chest X-ray. The chest X-ray demonstrates a reduced lung volume associated with a bell-shaped chest appearance, and ground glass diffuse airspace with interstitial opacities.5 Air-bronchograms may be present and in severe cases a “white lung” may be evident with a loss of the cardiac borders.
Often, application of positive pressure ventilation can improve the infant’s X-ray quickly but the disease process continues. Arterial blood gases generally reveal hypoxemia and an elevated carbon dioxide level. Also a metabolic acidosis may be present in the face of hypoperfusion and lactate acid production. Often electrography of the heart is performed to rule out cardiogenic etiologies.
Prevention
Most important in decreasing the incidence of RDS is prevention of prematurity, including avoidance of unnecessary and poorly timed cesarean sections.6
In pregnancies of greater than 30 weeks, fetal lung maturity may be determined by sampling the amount of surfactant in the amniotic fluid by amniocentesis. The most common diagnostic test is the lecithin-sphingomyelin ratio (L/S ratio). If the L/S ratio is then 2:1 the fetal lungs are at risk for surfactant deficiency.7
The two major management approaches to prevent the development of RDS are the use of antenatal treatment of women in preterm labor with glucocorticoid hormone to accelerate fetal lung maturation and the early use of surfactant replacement therapy.
Several randomized controlled clinical trials have been performed on the efficacy of antenatal corticosteroids in preterm birth to decrease the rates of RDS and the first structured review on corticosteroids in preterm birth was published in 1990. A recent Cochrane review showed that treatment with antenatal corticosteroids reduces the risk of neonatal death, RDS, intraventricular hemorrhage, necrotizing enterocolitis, infectious morbidity, need for respiratory support and neonatal intensive care unit admission.8
Antenatal administration of corticosteroids accelerates lung growth by several mechanisms, including maturation of type II pneumocytes and production of surfactant. However, repeated doses to the mother in threatened preterm labor may affect the final numbers of alveoli and somatic growth; this has been shown at least in animal models. Thyrotropin-releasing hormone Thyroxine increases surfactant production and lung maturation.9 However, unlike T3 and T4, thyrotropin-releasing hormone (TRH) readily crosses the placenta and increases the amount of surfactant phospholipid. TRH in combination with corticosteroids has been used in the past.
Prophylactic or preventive surfactant administration is defined as endotracheal intubation and surfactant administration to infants at high risk of developing RDS. For infants at high risk for RDS, prophylactic surfactant replacement therapy is preferable to later rescue therapy for established RDS as survival, chronic lung disease or death, and air leak are significantly decreased.10
Together with antenatal corticosteroid treatment, the use of prophylactic surfactant has made the greatest contribution to decreasing the incidence of RDS and its associated mortality and morbidity.
Treatment
The clinical management of the infant with RDS includes the following: avoid hypoxemia and acidosis, optimize fluid management specifically attempting to avoid fluid overload while preventing hypovolemia and hypotension, minimizing metabolic demands while maximizing nutrition, and finally, preventing lung injury secondary to volutrauma or causing oxygen toxicity.11
Treatment of infants with RDS include exogenous surfactant administration to improve oxygenation, decrease air leaks, and reduce mortality. Prophylactic administration involves administering surfactant soon after birth to help avoid or ameliorate lung injury caused by mechanical ventilation.12 Rescue administration of surfactant involves giving surfactant to infants that have established RDS that are requiring mechanical ventilation and a high level of oxygen delivery. The advantage to this approach is only symptomatic infants are intubated and administered the surfactant which avoids unnecessary interventions. Early evidence demonstrated improved outcomes with prophylactic administration, however, with the advent of nasal CPAP and higher rates of maternal steroid administration there currently exists the optimal timing of surfactant administration in RDS.13 Typically two doses of surfactant is administered every 12 hours and may be more effective than giving just a single dose.
Oxygen administration should be delivered to maintain a PaO2 between 55-70 torr or SpO2 between 85-92%.14 High concetrations of oxygen should be avoided to prevent the risk of retinopathy of prematurity. Oxygen can be delivered via high-flow nasal cannula (HFNC), CPAP, or mechanical ventilation.
The main ventilatory management of the infant with RDS is the stabilization of gas exchange while minimizing the ventilator-induced lung injury. To achieve these goals the utilization of permissive hypercarbia to maintain a PaCO2 between 45-55 torr may reduce the chance of ventilator induced trauma and prevent the negative effects of hyperventilation.15 Exhaled tidal volume should be targeted between 4-5 mL/kg to prevent volutrauma. Meticulous attention to exhaled tidal volume, blood gases, transcutaneous CO2 and pulse oximetry to prevent hyperventilation, hyperoxia, and lung overdistention. Adequate PEEP >5 cmH2O should be maintained to facilitate lung stabilization and prevention of atelectasis.
Nasal CPAP 4-6 cmH2O can be delivered via nasal prongs in lieu of mechanical ventilation in larger sized infants and those responding to early surfactant replacement. Limitations of CPAP utilization include hypercarbia, skin pressure injury, gastric distention and frequent periods of apnea. Infants can be extubated to CPAP from mechanical ventilation when they have an adequate respiratory drive, require a mean airway pressure <8 cmH2O and FiO2 <35%.16
Another clinical intervention that has been gaining increased utilization in RDS is high-flow oxygen via HFNC. Able to deliver a precise FiO2, molecular humidification, and an obligatory CPAP at 1-2 LPM, HFNC is an attractive alternative to CPAP or invasive ventilation. More clinical trials and outcomes assessment are still needed to determine the best time for clinical utilization of this intervention in RDS.17
In severe or refractory RDS, rescue ventilator or clinical strategies may be needed. High-frequency oscillatory ventilation or high-frequency jet ventilation may be beneficial to improve gas exchange and minimize ventilator-induced lung injury. Both strategies employee small tidal volume delivery with an increased mean airway pressure. Other rescue therapies include extracorporeal oxygenation membrane (ECMO) and the administration of inhaled nitric oxide. However, infants under four pounds may not be ECMO candidates secondary to the small size of their blood vessels. Inhaled nitric oxide can be very helpful in not only improving oxygenation by selective vasodilation but also reducing pulmonary artery pressures and unloading right ventricular work.18
Conclusion
In the past four decades, the introduction of antenatal steroids and exogenous surfactant administration has improved RDS outcomes. However, RDS continues to be a clinical challenge to the neonatal clinical team. Quick assessment and intervention are essential in reducing infant morbidity and mortality. If interventions are needed, a systematic approach to clinical interventions is critical in achieving optimal outcomes. There exists an arsenal of interventions available to the neonatal respiratory therapy practitioner to treat RDS and it is vital that they are knowledgeable on how to utilize and implement them. Prevention with appropriate prenatal care appears to be the best method to prevent RDS. Clinical management strategies for the treatment of RDS will continue to evolve to optimize clinical outcomes.
RT
Kenneth Miller MEd, MSRT, RRT-ACCS, NPS, AE-C, FAARC is the educational coordinator and dean of wellness, Respiratory Care Services, for Lehigh Valley Health Network in Allentown, Pa. For more information, contact editor@RTmagazine.com.
References
1. Sakonidou S, Dhaliwal J. The management of neonatal respiratory distress syndrome in preterm infants (European Consensus Guidelines–2013 update). Arch Dis Child Educ Pract Ed 2015; 100:257.
2. Mahoney AD, Jain L. Respiratory disorders in moderately preterm, late preterm, and early term infants. Clin Perinatol. 2013;40(4):665–678.
3. Sweet DG, Carnielli V, Greisen G, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants – 2010 update. Neonatology 2010; 97:402.
4. Schmölzer GM, Kumar M, Pichler G, et al. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013; 347:f5980
5. Polin RA, Carlo WA, Committee on Fetus and Newborn, American Academy of Pediatrics. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 2014; 133:156.
6. Hintz SR, Poole WK, Wright LL, et al. Changes in mortality and morbidities among infants born at less than 25 weeks during the post-surfactant era. Arch Dis Child Fetal Neonatal Ed 2005; 90:F128.
7. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010; 362:1970.
8. Carlo WA, McDonald SA, Fanaroff AA, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25
9. Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132:S543
10. Tarawneh A, Kaczmarek J, Bottino MN, Sant’anna GM. Severe airway obstruction during surfactant administration using a standardized protocol: a prospective, observational study. J Perinatol 2012; 32:270.
11. Ho JJ, Subramaniam P, Davis PG. Continuous distending pressure for respiratory distress in preterm infants. Cochrane Database Syst Rev 2015; :CD002271.
12. Göpel W, Kribs A, Ziegler A, et al. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomized, controlled trial. Lancet 2011; 378:1627.
13. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2012; 11:CD001456.
14. Doyle LW, Carse E, Adams AM, et al. Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years. N Engl J Med 2017; 377:329.
15. Thome UH, Genzel-Boroviczeny O, Bohnhorst B, et al. Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomized controlled multicenter trial. Lancet Respir Med 2015; 3:534.
16. Subramaniam P, Ho JJ, Davis PG. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst Rev 2016; :CD001243.
17. Roberts CT, Owen LS, Manley BJ, et al. Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants. N Engl J Med 2016; 375:1142.
18. Carey WA, Weaver AL, Mara KC, Clark RH. Inhaled Nitric Oxide in Extremely Premature Neonates With Respiratory Distress Syndrome. Perinatol 2016; 55:310. | {
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-6,760,534,236,787,873,000 | How Can I Flush Alcohol Out of My System?
The legal alcohol limit to drive can theoretically change at any time if new legislation is created. For quite some time, however, the limit in the U.S. has been a BAC of 0.08. This will normally take three to five drinks for most people to reach, but different people may have different responses affecting how quickly they reach the 0.08 limit. There are many remedies marketed as “hangover cures,” but none have much evidence to support how can you flush alcohol out of your system their use. Like many other drugs, alcohol can be detected with a hair follicle drug test for up to 90 days. This medication is an opiate antagonist and blocks opioid receptors in the brain. It can reduce cravings for alcohol and reduces the feeling of euphoria you experience when you drink. Women typically have higher body fat percentage and lower percentage of body water compared to men, so women will process alcohol slower.
Ninety percent of the time, the alcohol goes through the liver, and only around 10% of it gets out through sweat and urine. Alcohol flushing is eliminating or flushing out all the alcohol in your body. Since your body is already chemically adjusted to the regular presence of alcohol in your system, flushing can be quite challenging. Having some guidance on how to flush alcohol from your body might help make this an easier task.
How Long Does It Take for Alcohol to Leave Your System?
Additionally, adults of legal drinking age can choose not to drink or drink in moderation. This refers to limiting intake to 2 drinks or fewer in a day for males or no more than 1 drink in a day for females. A cold shower may make a person alert for a short period, but they are still impaired. However, there is no effective way to sober up quickly other than to stop drinking and allow time to pass. If you get positive results, you will have to send the sample to the lab for further analysis. The lab-based tests might identify the drug metabolites from 1 to 3 weeks before consumption. Licensed medical professionals review material we publish on our site. The material is not a substitute for qualified medical diagnoses, treatment, or advice.
how can you flush alcohol out of your system
The testing is not as widely available as a standard urine screening for ethanol and it costs more. EtG/EtS testing can’t tell you how much alcohol a person consumed, and it can’t differentiate between ethanol from alcoholic beverages and exposure to alcohol from other products. Urine alcohol content is sometimes used to estimate a person’sblood alcohol content. The amount of alcohol in a person’s urine is approximately 1.33 times greater than the amount of alcohol in their bloodstream. For accuracy, at least two urine samples are usually collected 30 minutes to an hour apart. When someone drinks large amounts of alcohol in a short period of time they may experience alcohol poisoning. This occurs when the liver is overwhelmed and the alcohol levels in your bloodstream rise to dangerous levels.
Factors that Affect BAC
Regardless of how fast your body absorbs alcohol, it eliminates it at the average rate of 0.016 BAC per hour. Nothing you do will speed up the elimination process, including drinking coffee, drinking water, taking a shower, or even vomiting. Determining exactly how long alcohol is detectable in the body depends on many variables, including which kind of drug test is being used. Alcohol can be detected for a shorter time with some tests but can be visible for up to three months in others. According to the NHS, the liver is very resilient and is capable of regenerating itself. However, a portion of your liver cells die each time your liver has to process alcohol. The liver can regenerate cells, but chronic heavy drinking can result in damage to the liver. Minor detox symptoms may show up in just 2 to 6 hours after your last drink, she says. They will typically peak in 1 to 3 days for a lighter drinker, but may last for a week with heavy drinkers. Persistent withdrawal symptoms are fairly rare, she says, but they may last for a month or more.
What is the best drink to flush your liver?
• Coffee. Coffee is good for the liver, especially because it protects against issues such as fatty liver disease.
• Ginger and lemon drink.
• Oatmeal drink.
• Tumeric drink.
• Green tea.
• Grapefruit drink.
In simpler terms, it usually takes a grown male one hour to process one drink. How long alcohol will remain in your body depends solely on your BAC level. This level can vary based on your gender, weight, age, how many drinks you had one night, or even what type of alcohol you’re drinking. Working out can help your body to feel more alert, reducing the feeling of intoxication.
Type of Alcoholic Beverage Consumed
The second is a chronic phase in which you drink large amounts of alcohol, but you are conscious and moving naturally due to the high tolerance developed over time. Your experience of the condition’s toxic effect differs depending on whether you are in the acute or chronic phase. However, the organ can only metabolize a little at a time, leaving the excess to circulate throughout your body. So, how much alcohol you consume in a specific amount of time gives you an idea of its intensity. When you drink alcohol, it is quickly absorbed in the stomach and small intestines. From there, it enters your bloodstream to travel to the liver. The idea of someone being able to sober up fast so they can drive is not realistic. BAC levels will remain high until the liver has had time to metabolize alcohol. It is advisable to eat before drinking, especially foods that are high in protein.
What removes alcohol from your system?
The liver does the heavy lifting when it comes to processing alcohol. After the alcohol passes through your stomach, small intestine and bloodstream, your liver starts its cleanup. It removes about 90% of the alcohol from your blood. The rest comes out through your kidneys, lungs and skin.
Now I’m going to tell you how to get alcohol out of your system and ways you can support your body’s detoxification process. I’m going to tell you how alcohol affects your body, how to get alcohol out of your system, and natural ways you can support your body’s detoxification process. Once a BAC reaches about 0.07, the drinker’s mood may worsen. Our community offers unique perspectives on lifelong recovery and substance use prevention, empowering others through stories of strength and courage. What are the health effects of not drinking alcohol for one month? A promising study that looks at what one month free of booze can do to your body. The performance of alcohol markers including ethyl glucuronide and ethyl sulphate to detect alcohol use in clients in a community alcohol treatment programme. Alcohol is often okay to consume in moderation, but it’s essential to know how long alcohol stays in your body to ensure you remain safe and healthy. The liver contains an enzyme known as alcohol dehydrogenase , which metabolizes the alcohol and helps to remove it from the body.
A urine screening can typically detect ethanol — the type of alcohol found in alcoholic beverages — forup to 12 hours. When someone drinks alcohol, the vast majority isbroken down by the liverand a tiny amount is expelled through breath and sweat. Alcohol will usually show up in a person’s urine within an hour of drinking, and it usually remains detectable for up to 12 hours. The actual timeframe may vary, depending on a number of factors, including weight, health, gender and the amount of alcohol consumed. Detox should be handled by professionals as the first step of residential treatment. For some people, severe alcohol withdrawal symptoms can be life-threatening without proper medical attention. When you drink in moderation, the equivalent to one drink per hour, the liver can process that one drink without the build-up of acetaldehyde in the blood at toxic levels.
how can you flush alcohol out of your system
This makes Alcohol the third most preventable cause of death in the United States. The remaining alcohol will get to the digestive and urinary tract and get out of the system via urine and feces. Week Two – At this point, some symptoms start to taper off while others may persist for Sober House a few weeks, such as fatigue, headaches, and insomnia. By submitting this form you agree to the terms of use and privacy policy of the website. Since it is not possible to get rid of acetaldehyde, your body will turn it into carbon dioxide, which is easy to remove from your system.
In accordance with the American Society of Addiction Medicine, we offer information on outcome-oriented treatment that adheres to an established continuum of care. In this section, you will find information and resources related to evidence-based treatment models, counseling and therapy and payment and insurance options. Drinking can be a healthy social experience, but consuming large amounts of alcohol, even one time, can lead to serious health complications. The risk factors of the alcohol use disorders – through review of its comorbidities. Alcohol use disorder affects many, but some are at a higher risk than others of receiving the diagnosis. In addition, mental health disorders are often a part of the health history of those affected.
Eco Sober House
But you need about five half-lives to get rid of alcohol completely. So, it takes about 25 hours for your body to clear all the alcohol. The liver gets most of the attention when it comes to alcohol metabolism. Eating high protein foods, such as tofu or cheese, before or while drinking can slow the absorption of alcohol. Treatment for addiction takes many forms and depends on the needs of the individual.
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475,346,693,325,266,300 | Toxoplasmosis
Toxoplasmosis
[tok-soh-plaz-moh-sis]
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid (cat) family. Animals are infected by eating infected meat, by ingestion of faeces of a cat that has itself recently been infected, or by transmission from mother to fetus. Cats have been shown as a major reservoir of this infection.
Up to one third of the world's population is estimated to carry a Toxoplasma infection. The Centers for Disease Control and Prevention notes that overall seroprevalence in the United States as determined with specimens collected by the National Health and Nutritional Assessment Survey (NHANES) between 1999 and 2004 was found to be 10.8%, with seroprevalence among women of childbearing age (15 to 44 years) of 11%.
During the first few weeks, the infection typically causes a mild flu-like illness or no illness. After the first few weeks of infection have passed, the parasite rarely causes any symptoms in otherwise healthy adults. However, people with a weakened immune system, such as those infected with HIV or pregnant, may become seriously ill, and it can occasionally be fatal. The parasite can cause encephalitis (inflammation of the brain) and neurologic diseases and can affect the heart, liver, and eyes (chorioretinitis).
Symptoms
Infection has two stages:
Acute toxoplasmosis
During acute toxoplasmosis, symptoms are often influenza-like: swollen lymph nodes, or muscle aches and pains that last for a month or more. Rarely, a patient with a fully functioning immune system may develop eye damage from toxoplasmosis. Young children and immunocompromised patients, such as those with HIV/AIDS, those taking certain types of chemotherapy, or those who have recently received an organ transplant, may develop severe toxoplasmosis. This can cause damage to the brain or the eyes. Only a small percentage of infected newborn babies have serious eye or brain damage at birth.
Latent toxoplasmosis
Most patients who become infected with Toxoplasma gondii and develop toxoplasmosis do not know it. In most immunocompetent patients, the infection enters a latent phase, during which only bradyzoites are present, forming cysts in nervous and muscle tissue. Most infants who are infected while in the womb have no symptoms at birth but may develop symptoms later in life.
Diagnosis
Detection of Toxoplasma gondii in human blood samples may be achieved by using the polymerase chain reaction (PCR). Inactive cysts may exist in a host which would evade detection.
Transmission
Transmission may occur through:
• Ingestion of raw or partly cooked meat, especially pork, lamb, or venison containing Toxoplasma cysts. Infection prevalence in countries where undercooked meat is traditionally eaten has been related to this transmission method. Oocysts may also be ingested during hand-to-mouth contact after handling undercooked meat, or from using knives, utensils, or cutting boards contaminated by raw meat.
• Ingestion of contaminated cat faeces. This can occur through hand-to-mouth contact following gardening, cleaning a cat's litter box, contact with children's sandpits, or touching anything that has come into contact with cat faeces.
• Drinking water contaminated with Toxoplasma.
• Transplacental infection in utero.
• Receiving an infected organ transplant or blood transfusion, although this is extremely rare.
The cyst form of the parasite is extremely hardy, capable of surviving exposure to freezing down to −12 degrees Celsius (10 degrees Fahrenheit), moderate temperatures and chemical disinfectants such as bleach, and can survive in the environment for over a year. It is, however, susceptible to high temperatures—above 66 degrees Celsius (150 degrees Fahrenheit), and is thus killed by thorough cooking, and would be killed by 24 hours in a typical domestic freezer.
Cats excrete the pathogen in their faeces for a number of weeks after contracting the disease, generally by eating an infected rodent. Even then, cat faeces are not generally contagious for the first day or two after excretion, after which the cyst 'ripens' and becomes potentially pathogenic. Studies have shown that only about 2% of cats are shedding oocysts at any one time, and that oocyst shedding does not recur even after repeated exposure to the parasite. Although the pathogen has been detected on the fur of cats, it has not been found in an infectious form, and direct infection from handling cats is generally believed to be very rare.
Pregnancy precautions
Congenital toxoplasmosis is a special form in which an unborn child is infected via the placenta. A positive antibody titer indicates previous exposure and immunity and largely ensures the unborn baby's safety. A simple blood draw at the first pre-natal doctor visit can determine whether or not the woman has had previous exposure and therefore whether or not she is at risk. If a woman receives her first exposure to toxoplasmosis while pregnant, the baby is at particular risk. A woman with no previous exposure should avoid handling raw meat, exposure to cat feces, and gardening (cat feces are common in garden soil). Most cats are not actively shedding oocysts and so are not a danger, but the risk may be reduced further by having the litterbox emptied daily (oocysts require longer than a single day to become infective), and by having someone else empty the litterbox. However, while risks can be minimized, they cannot be eliminated. For pregnant women with negative antibody titer, indicating no previous exposure to T. gondii, as frequent as monthly serology testing is advisable as treatment during pregnancy for those women exposed to T. gondii for the first time decreases dramatically the risk of passing the parasite to the fetus.
Despite these risks, pregnant women are not routinely screened for toxoplasmosis in most countries (France, Austria and Italy being the exceptions) for reasons of cost-effectiveness and the high number of false positives generated as the disease is so rare (an example of Bayesian statistics). As invasive prenatal testing incurs some risk to the fetus (18.5 pregnancy losses per toxoplasmosis case prevented), postnatal or neonatal screening is preferred. The exceptions are cases where foetal abnormalities are noted, and thus screening can be targeted.
Some regional screening programmes operate in Germany, Switzerland and Belgium.
Treatment is very important for recently infected pregnant women, to prevent infection of the fetus. Since a baby's immune system does not develop fully for the first year of life, and the resilient cysts that form throughout the body are very difficult to eradicate with anti-protozoans, an infection can be very serious in the young.
Transplacental transmission:(a) infection in 1st trimester - incidence of transplacental infection is low (15%) but disease in neonate is most severe. (b) infection in 3rd trimester - incidence of transplacental infection is high (65%) but infant is usually asymptomatic at birth.
Treatment
Treatment is often only recommended for people with serious health problems, because the disease is most serious when one's immune system is weak.
Medications that are prescribed for acute Toxoplasmosis are:
(Other antibiotics such as minocycline have seen some use as a salvage therapy).
In people with latent toxoplasmosis, the cysts are immune to these treatments, as the antibiotics do not reach the bradyzoites in sufficient concentration.
Medications that are prescribed for latent Toxoplasmosis are:
• atovaquone — an antibiotic that has been used to kill Toxoplasma cysts inside AIDS patients.
• clindamycin — an antibiotic which, in combination with atovaquone, seemed to optimally kill cysts in mice.
However, in latent infections successful treatment is not guaranteed, and some subspecies exhibit resistance.
Biological modifications of the host
The parasite itself can cause various effects on the host body, some of which are not fully understood.
Reproductive changes
A recent study has indicated Toxoplasmosis correlates strongly with an increase in boy births in humans. According to the researchers, depending on the antibody concentration, the probability of the birth of a boy can increase up to a value of 0.72 ... which means that for every 260 boys born, 100 girls are born. The study also notes a mean rate of 0.60 to 0.65 (as opposed to the normal 0.51) for Toxoplasma positive mothers.
Behavioral changes
It has been found that the parasite has the ability to change the behavior of its host: infected rats and mice are less fearful of cats — in fact, some of the infected rats seek out cat-urine-marked areas. This effect is advantageous to the parasite, which will be able to sexually reproduce if its host is eaten by a cat. The mechanism for this change is not completely understood, but there is evidence that toxoplasmosis infection raises dopamine levels and concentrates in the amygdala in infected mice.
The findings of behavioral alteration in rats and mice have led some scientists to speculate that toxoplasma may have similar effects in humans, even in the latent phase that had previously been considered asymptomatic. Toxoplasma is one of a number of parasites that may alter their host's behaviour as a part of their life cycle. The behaviors observed, if caused by the parasite, are likely due to infection and low-grade encephalitis, which is marked by the presence of cysts in the brain, which may produce or induce production of a neurotransmitter, possibly dopamine, therefore acting similarly to dopamine reuptake inhibitor type antidepressants and stimulants.
Correlations have been found between latent Toxoplasma infections and various characteristics:
• Decreased novelty-seeking behaviour
• Slower reactions
• Lower rule-consciousness and jealousy (in men)
• More warmth and conscientiousness (in women)
The evidence for behavioral effects on humans is relatively weak. No prospective research has been done on the topic, e.g., testing people before and after infection to ensure that the proposed behavior arises only afterwards. Although some researchers have found potentially important associations with toxoplasma, the causal relationship, if any, is unknown, i.e., it is possible that these associations merely reflect factors that predispose certain types of people to infection.
Studies have found that toxoplasmosis is associated with an increased car accident rate, roughly doubling or tripling the chance of an accident relative to uninfected people. This may be due to the slowed reaction times that are associated with infection. "If our data are true then about a million people a year die just because they are infected with toxoplasma," the researcher Jaroslav Flegr told The Guardian. The data shows that the risk decreases with time after infection, but is not due to age. Ruth Gilbert, medical coordinator of the European Multicentre Study on Congenital Toxoplasmosis, told BBC News Online these findings could be due to chance, or due to social and cultural factors associated with toxoplasma infection.However there is also evidence of a delayed effect which increases reaction times.
Other studies suggest that the parasite may influence personality. There are claims of toxoplasma causing antisocial attitudes in men and promiscuity (or even "signs of higher intelligence" ) in women, and greater susceptibility to schizophrenia and bipolar disorder in all infected persons. A 2004 study found that toxoplasma "probably induce[s] a decrease of novelty seeking."
According to Sydney University of Technology infectious disease researcher Nicky Boulter in an article that appeared in the January/February 2007 edition of Australasian Science magazine, Toxoplasma infections lead to changes depending on the sex of the infected person.
The study suggests that male carriers have lower IQs, a tendency to achieve a lower level of education and have shorter attention spans, a greater likelihood of breaking rules and taking risks, and are more independent, anti-social, suspicious, jealous and morose. It also suggests that these men are deemed less attractive to women. Women carriers are suggested to be more outgoing, friendly, more promiscuous, and are considered more attractive to men compared with non-infected controls. The results are shown to be true when tested on mice, though it is still inconclusive. A few scientists have suggested that, if these effects are genuine, prevalence of toxoplasmosis could be a major determinant of cultural differences.
Toxoplasma's role in schizophrenia
The possibility that toxoplasmosis is one cause of schizophrenia has been studied by scientists since at least 1953. These studies had attracted little attention from U.S. researchers until they were publicized through the work of prominent psychiatrist and advocate E. Fuller Torrey. In 2003, Torrey published a review of this literature, reporting that almost all the studies had found that schizophrenics have elevated rates of toxoplasma infection. A 2006 paper has even suggested that prevalence of toxoplasmosis has large-scale effects on national culture.
These types of studies are suggestive but cannot confirm a causal relationship (because of the possibility, for example, that schizophrenia increases the likelihood of toxoplasma infection rather than the other way around).
• Acute Toxoplasma infection sometimes leads to psychotic symptoms not unlike schizophrenia.
• Some anti-psychotic medications that are used to treat schizophrenia, such as Haloperidol, also stop the growth of Toxoplasma in cell cultures.
• Several studies have found significantly higher levels of Toxoplasma antibodies in schizophrenia patients compared to the general population.
• Toxoplasma infection causes damage to astrocytes in the brain, and such damage is also seen in schizophrenia .
Epidemiology
In humans
The U.S. NHANES (1999-2004) national probability sample found that 10.8% of U.S. persons 6-49 years of age, and 11.0% of women 15-44 years of age, had Toxoplasma-specific IgG antibodies, indicating that they had been infected with the organism. This prevalence has significantly decreased from the NHANES III (1988-1994).
It is estimated that between 30% and 65% of all people worldwide are infected with Toxoplasmosis. However, there is large variation countries: in France, for example, around 88% of the population are carriers, probably due to a high consumption of raw and lightly cooked meat. Germany, the Netherlands and Brazil also have high prevalences of around 80%, over 80% and 67% respectively. In Britain, about 22% are carriers, and South Korea's rate is only 4.3%.
Two risk factors for contracting toxoplasmosis are:
• Infants born to mothers who became infected with Toxoplasma for the first time during or just before pregnancy.
• Persons with severely weakened immune systems, such as those with AIDS. Illness may result from an acute Toxoplasma infection or reactivation of an infection that occurred earlier in life.
In other animals
A University of California, Davis study of dead sea otters collected from 1998 to 2004 found that toxoplasmosis was the cause of death for 13% of the animals. Proximity to freshwater outflows into the ocean were a major risk factor. Ingestion of oocysts from cat faeces is considered to be the most likely ultimate source. According to an article in the New Scientist, the parasites have also been found in dolphins and whales. Researchers Black and Massie believe that anchovies, which travel from estuaries into the open ocean, may be helping to spread the disease. Michael Grigg of the US National Institute of Health mentioned that a new type of T. gondii, type X, has been found which is responsible for the large deaths of sea otters, and may be "poised to sweep the world".
History
The protozoan was first discovered by Nicolle & Manceaux, who in 1908 isolated it from the African rodent Ctenodactylus gundi, then in 1909 differentiated the disease from Leishmania and named it Toxoplasmosis gondii The first recorded congenital case was not until 1923, and the first adult case not until 1940. In 1948, a serological dye test was created by Sabin & Feldman, which is now the standard basis for diagnostic tests.
Notable people with toxoplasmosis
• Arthur Ashe developed neurological problems from toxoplasmosis (and was later found to be HIV-positive)
• Leslie Ash contracted toxoplasmosis in the second month of pregnancy
• François, comte de Clermont, Dauphin of France and Orléans pretender to the French throne. Both he and his younger sister, Princess Blanche, are mentally disabled due to congenital toxoplasmosis.
• Sebastian Coe (British middle distance runner)
• Martina Navrátilová (tennis player) retired from a competition in 1982 with symptoms of a mystery 'virus' that were later found to be due to toxoplasmosis
• Louis Wain was a prominent cat artist who later developed schizophrenia, which some believe was due to toxoplasmosis resulting from his prolonged exposure to cats.
References
External links
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-5,025,322,197,826,523,000 | Not all cholesterol is bad
Cholesterol is necessary to produce certain hormones and to aid cell formation. 75% of the cholesterol in our blood comes from our liver, and the other 25% comes from the food we ingest. Saturated and trans fat foods can increase blood cholesterol levels.
Total Blood Cholesterol
The three components of total blood cholesterol include low-density lipoproteins (LDL), high density lipoproteins (HDL), and triglycerides. According to the National Cholesterol Education Program (NCEP), the desirable level for Total Blood Cholesterol is less than 200 mg/dL.
Low-density lipoproteins (LDL) are known as the “bad” cholesterol because they contribute to the formation of fatty build-up, or plaque, that can clog our arteries. Too much fatty build-up poses a risk for cardiovascular disease. According to the NCEP, the optimal LDL level is less than 100 mg/dL.
High density lipoproteins (HDL) are the “good” cholesterol because they help remove cholesterol from the blood, which in turn helps prevent plaque build-up. So having higher levels of HDL is a good thing. According to the NCEP, HDL levels greater than 40 mg/dL is recommended.
Triglycerides
Most fat exists in food and in the body in the chemical form known as triglycerides. Together with the HDL and LDL lipoproteins, they make up the total blood cholesterol.
See your doctor
The American Heart Association recommends everyone over age 20 should have their cholesterol levels tested regularly. Consult your doctor before getting your cholesterol tested, as an overnight fast may be recommended for the most accurate results.
Family connection
Sometimes your liver and other cells will make too much cholesterol for genetic reasons, no matter what food you eat. If your family has a history of high blood cholesterol, there are dietary and lifestyle changes that can help lower your cholesterol. | {
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2,944,622,158,320,748,500 | Creating Magic Moments in Dementia Care
73773425
by Mary Ann Drummond, RN
From the moment we take our first breath a time line begins marking the moments of our lives. There are many events to celebrate such as first steps, first words, first bike ride, first car, first kiss and even first love. We continue adding to our time line as we age, starting families, careers and doing those things that we know to be important and expected of us.
Education? Check.
Providing for our family? Check.
Taking care of our self? Well, at least we try.
Time passes and the story of life unfolds with each defining moment a permanent thread in our tapestry. Some are fragrant roses while others are the thorns we wish we could remove.
For dementia caregivers the thorns can begin as soon as the diagnosis is received. Many of us will experience what it means to have a loved one diagnosed with dementia. With one in eight individuals over 65, and one in two over 80 currently having Alzheimer’s disease it is hard to find someone not impacted in some way by Alzheimer’s alone, not to mention the many other forms of dementia that exist such as Lewy body, vascular and frontal-temporal.
The key to creating “magic moments” in dementia care is to seek “opportunities for success.” Too often we approach individuals who have dementia with a mindset of “disability” thinking of all they can not do for themselves. While this is necessary in daily care, it is also necessary to be highly mindful of the “ability” still present, and do our best to capitalize on what the individual can still do for themselves, even if it is not 100% as perfect as you would do.
As loving and willful caregivers we take over all tasks, leaving them with nothing to do all day but sit around and become bored. To be left without cognitive, physical, sensory and spiritual stimulation is bad for anyone, and especially bad for the person with dementia. Studies have proven the result of inappropriate stimulation will be restlessness, lack of sleep, disruptive behavior, inability to focus and there will even be increased potential for combative behaviors. These are not the magic moments we are striving for!
So what would be appropriate activities to promote opportunities for success and bring the magic moments? Below is a list of five ideas to try. You will find it may take a few attempts before you are comfortable, but one thing is certain: The closer you come to the individuals personal long term hobbies, likes, interests and routine the closer you will be to a magic moment in your care giving journey!
Sing like no one is listening!
It has been said that music is the universal language and this remains true in dementia care. No matter what the stage of disease process, singing a familiar tune out loud such as Jingle Bells, You Are My Sunshine, or their favorite song usually elicits a positive response. You may even find individuals who no longer communicate verbally can still hum or follow along some with you in familiar lyrics.
Take a stroll down memory lane together.
Reminiscing therapy is a powerful art form that can be done any time two or more are gathered together. All you need are a few props such as an old photograph, magazine, or trinket that has a story, and then begin to tell the story. “This is a picture of you and Dad on your wedding day…you are wearing your Mother’s wedding dress…” Place the picture in their hand and let them hold it. “You had a bouquet of roses…” If you can give them a rose to smell at this point, you have likely just hit a home run as you now have used auditory, verbal and tactile cuing, all of which is necessary to increase the chances that your message will be successful. Sit back and watch the magic moments begin…
Household chores can be fun together.
While there needs to be discretion in regards to the complexity of the task, allowing them to help you with certain chores such as dusting with a feather duster, wiping off the table, putting the napkins out before dinner, etc., is not only an opportunity for success but it also gives one a feeling of self worth. Practice this as frequently as one allows you to do so. Sorting, stacking, folding, snacking: Colored socks need to be matched. Assorted wash cloths and hand towels need to be folded. The books need to be stacked. Whew! We have worked really hard today. Would you like to join me for a snack? I have your FAVORITE? And that is when you pull out the PIÈCE DE RÉSISTANCE that is truly their favorite snack as we know it can be difficult to keep the calories high enough when they are in the pacing/wandering stages of the disease process.
Normalization Time:
What was their routine for getting up each day? For going to bed at night? Did they do devotion in the evening with their family? Did they have a glass of orange juice and bowl of cereal every morning? If there was a particular habit that was routine and normal for the individual try as much as possible to ensure this is “normalized” into their daily routine.
For additional information, the Alzheimer’s Association is an excellent resource and has an abundance of information readily available.
More Senior Articles | {
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-3,183,070,160,847,166,000 | Acid Reflux Causes Arm Pain
Posted on: April 10, 2019, by : admin
Indigestion; Stop drinking soda (pop) (cola) (coke) I've had acid reflux the more gross soda starts to taste. Can Acid Reflux Cause Right Arm Pain Cause Race.
Heartburn occurs when stomach acid backs up into the tube that carries food from your mouth to your stomach (esophagus). Normally when you swallow, a band of muscle around the bottom of your esophagus (lower esophageal sphincter) relaxes to allow food and liquid to flow down into your stomach.
If you have experienced acid reflux, as most people have, you have probably felt a burning sensation in the area of the breastbone, or maybe it even extended up into your throat.
The terms heartburn, acid reflux, and GERD are often used interchangeably. They actually have very different meanings.
Heartburn vs. Acid Reflux vs. GERD – Healthline – The terms heartburn, acid reflux, and GERD are often used interchangeably. They actually have very different meanings.
Doctors help you with trusted information about Acid Reflux in Reflux: Dr. Legha on can acid reflux cause left arm pain: -it is frequently referred to the back, but not armpit. If it does it again take a liquid antacid, if it goes away or helps a lot you have your answer.
Causes. GERD is caused by frequent acid reflux. When you swallow, a circular band of muscle around the bottom of your esophagus (lower esophageal sphincter).
Some people experience pain along their right arm or leg as well. Other symptoms of a clogged duct include acid reflux, bloating, and belching after meals.
The Scoop on Acid Reflux Remedies through the eyes of a friendly Nurse. Fast, instant and quick acid reflux remedies, natural home remedies for acid reflux, indigestion and heartburn can be as close as your kitchen cabinet.
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.
Sep 19, 2016. Was told that my esophagus was "raw" because of all the acid reflux and. by any means, do not prevent the GERD symptoms from occurring.
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.
Acid Reflux Lasting For Days Aug 28, 2018. Heartburn can affect your ability to get a good night's sleep. If you experience acid reflux at night, here are tips that can help mitigate the. Acid reflux is a big problem. 44% of Americans have heartburn at least once a month. 25 to 35% have reflux. Acid-blocking drugs or what we
If you have experienced acid reflux, as most people have, you have probably felt a burning sensation in the area of the breastbone, or maybe it even extended up into your throat.
Mar 31, 2019. Epigastric pain is located in a region of the upper abdomen. It is experienced in the area of the abdomen that is approximately in the middle,
For occasional reflux, an antacid is often a good choice for providing quick symptom relief. Antacids work by neutralizing stomach acid and usually provide relief within 30 minutes.
Acid reflux occurs when stomach acid backs up into your esophagus, resulting in symptoms like chest pain, a burning sensation in your throat and a sour taste in.
Q. Is yogurt good for acid reflux ? A. Yogurt could be great for strengthening the stomach walls and digestive enzymes. It could help with acid reflux because of the pain-relieving properties that so many acid reflux sufferers go through.
Heartburn occurs when stomach acid backs up into the tube that carries food from your mouth to your stomach (esophagus). Normally when you swallow, a band of muscle around the bottom of your esophagus (lower esophageal sphincter) relaxes to allow food and liquid to flow down into your stomach.
Acid reflux is a fairly common condition that occurs when stomach acids and other stomach contents back up into the esophagus through the lower esophageal sphincter (LES).
Causes. GERD is caused by frequent acid reflux. When you swallow, a circular band of muscle around the bottom of your esophagus (lower esophageal sphincter).
Can Antibiotics Cause Stomach Acid Feb 1, 2014. Often, dyspepsia is caused by a stomach ulcer or acid reflux disease. If you have acid. Sometimes no cause of dyspepsia can be found. If you have an infection in your stomach, you may also need to take an antibiotic. 9 Ways Digestive Problems Could Be Totally Screwing With Your Weight. It
Q. Is yogurt good for acid reflux ? A. Yogurt could be great for strengthening the stomach walls and digestive enzymes. It could help with acid reflux because of the pain-relieving properties that so many acid reflux sufferers go through.
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-4,454,516,207,317,932,500 | So You’ve Gained Weight During the Pandemic: Now What?
Person weighing themself on scale.
JGI/ Jamie Grill / Getty Images
We’ve all been through an extremely challenging time. The COVID-19 pandemic has affected each of us in different and inequitable ways.
Some of us have lost friends and loved ones to the virus. Others have lost jobs or been furloughed or struggled financially. Most of us have sheltered at home. Vast parts of our lives ground to a halt or were moved online. Those who had the privilege to work from home did so while schooling children and caring for other family members. Those who lived alone became cut off.
If you survived the pandemic, that is an accomplishment in and of itself. Many more people than ever before are experiencing anxiety, depression, and suicidal ideation.
Sadly, many people have been fretting about weight gain in themselves or others, or have been pathologizing emotional eating. Many are berating themselves for not “using the time more productively.”
If you are one of these people, we hope this article provides some context. Whether you decided to use any newfound time to undertake a new exercise regimen, bake bread, or just watch Netflix, the first thing is to remember that none of those activities is morally superior to any other.
Weight Gain During Quarantine
Eating disorder specialist and dietitian Anna Sweeney, MS, RD, LDN, CEDRD-S says, “Gaining weight in the context of surviving the last year is not the worst-case scenario. Diet and wellness culture suggesting that it is? A marketing tactic with the intention of keeping us all at the behest of a $71 billion industry. The fact that the industry started pandering about body change 10 days into quarantine is a very clear demonstration that the industry is not actually invested in your well-being.”
Most importantly, bodies change! And age! And grow! And we all must accept that reality. Despite the many messages in our society and from industries that try to sell us products to prevent these outcomes, we are better off accepting than resisting. This is normal.
What to Do Instead of Dieting
So rather than jumping on the diet bandwagon, consider these strategies for developing a healthy relationship with food.
Focus on Eating Regularly Without Restriction
Do not diet! In addition to not working, diets are often the gateway to an eating disorder. It will make you feel deprived and can lead to poor concentration and preoccupation with food. It can also lead to binge eating and weight cycling which brings negative health consequences.
There’s no need to be rigid—just try to have a general plan for each day so you know when each meal will occur and some idea of what you will eat. Continue to eat foods that you enjoy while trying to include some foods from each of the various food groups.
When we become restrictive and try to eliminate fun foods, we increase our likelihood of bingeing on them.
Beware of the Exercise Trap
As alluring as the pull to restrict one’s eating is the urge to return to or add intense exercise. Many will be returning to gyms and there will be many people announcing resolutions to “get back in shape.”
Movement should be done for the sake of overall health including cardiovascular and muscle strength, flexibility, and mood improvement. But exercise for the sake of weight loss or to offset eating or undo weight gain quickly becomes punishing, unpleasant, burdensome, and harder to sustain.
Furthermore, excessive exercise can be dangerous. Try to pick activities that are joyful and be sure to moderate and not overdo it.
Practice Body Respect and Compassion
Don’t shame yourself or others for weight gain—let’s treat all bodies with respect. Bodies come in all sizes and shapes and we should acknowledge and celebrate the diversity of nature.
If you have the financial security to do so, focus on having regular meals evenly distributed throughout the day—for most people this will comprise three meals and one to three snacks. Plan your meals ahead of time to reduce the likelihood of binge episodes, minimize waste, and create a feeling of emotional security.
For those who have used food to cope with an extremely difficult situation: we see you and we commend your resilience. There’s no shame in having done what you needed to survive a tough year. If you baked bread or muffins or brought in fast food, congratulate yourself for your creativity, problem-solving, and self-care.
Beating yourself up for gaining weight serves no purpose. It will not help you lose weight, and it will not make you feel better. When we engage in self-criticism, it increases emotional distress.
Dieting will likely just lead to more distress. We know that diets only work in the short term, if they work at all. At five years, weight loss maintenance is around 3%. One-third to two-thirds of dieters regain more weight than they lost.
Instead, practice self-compassion. Acts of kindness and self-compassion can improve our mental well-being. Practice speaking kindly to yourself and appreciating your body for getting you through this tough year.
Refresh Your Wardrobe
Ensure you have clothes that fit you now. If you have clothes that you have outgrown, fold them up. If you are not ready to donate them, put them in the back of the closet out of view.
Refusing to buy clothes in a bigger size while struggling with clothes that do not fit you now only exacerbates the distress of getting dressed in the morning.
You do not need to spend a fortune—just gather a few pieces that fit your body now and make you feel good. Going up a size should not be the subject of judgement—it is what it is. It is not a personal failure, although the culture will try to get you to believe that.
Curate Your Social Media Feed
Check your social media feed. Diet culture is rampant and ubiquitous on social media. If your social media feed is inundated by posts focusing on weight loss or before and after photos or “shedding the quarantine weight,” it will make you feel worse.
Unfollow anyone glorifying dieting and follow instead people promoting body positivity and Health At Every Size.
Accept That Anxiety Is Normal
As you venture out post-pandemic, you may have anxiety. Quarantine has allowed us all to avoid in-person social situations. It has enabled those with body image concerns to conveniently avoid and feel temporary relief from in person contact. Many of us were not even seen from the neck down by anyone other than immediate family for over a year.
Opening back up means the return to in-person activities, which can aggravate underlying insecurity, reignite problematic behaviors, or lead to increased anxiety in the aftermath of weight gain. Accept that this anxiety is to be expected and talk about it and plan for it.
If you’re having an urge to avoid seeing people after it is safe to do so, please reach out for support. Avoidance of social circumstances—whether due to social anxiety or body image concerns—can make problems worse.
How to Re-Engage With Society After Quarantine
Make a list of different social situations in which you will re-engage. Rank them in terms of level of fear or difficulty. Make a ladder, and start to approach some of the easier situations first.
You can make the first such outings easier by perhaps enlisting a sympathetic friend to accompany you. Once you have been successful at that first outing, remind yourself that you can do it and then slowly work your way up the ladder.
Set Boundaries With People Still in Diet Culture
Sweeney suggests, “As you re-join your communities, make it a priority to establish boundaries about acceptable conversations: Ask your people to join you in making your return to normal a space for no body talk, or calorie talk, or diet talk. Stop greeting other humans with reflective body commentary."
Sweeney goes on to note that if your body has changed, you might feel the need to announce that or make fun of yourself. But doing so might make the person you're speaking to feel badly about themselves.
Although we realize our body may have changed, it is most likely not something someone else is going to be focusing on, so why bring more attention to it? Plus, if you're too focused on how you look or how other people look, you'll miss out on the chance to tell others just how much you've missed them.
Seek community among others who are resisting diet culture. The Health at Every Size movement acknowledges that body size does not determine health or worthiness. Join an online or other group focused on Health at Every Size, Intuitive Eating, or Fat Positivity to learn more.
Focus on Your Values
If you find yourself focusing on your weight, consider whether this focus is aligned with your values. Does it advance the values you hold dear? Does it add to or detract from the important relationships in your life?
Similarly, think about whether reducing your body size will really change things in the way you want. How will your life really be different if you lose however many pounds? How do you want to be remembered after you die—do you want to be remembered for your body size or your other features?
Work to Challenge Weight Stigma
Please don’t feel shame for not wanting to gain weight, or for wanting to lose weight. It is okay to want to change your behaviors that may have caused the weight gain. That is understandable. Diet culture and the glorification of thinner bodies are the soup we all swim in. Fatphobia is a normal response to growing up in this culture.
But please don’t disparage your or other people’s bodies that are bigger or may have gained weight.
Let’s focus on creating a respectful, judgment-free community. By making the world a safer place to have a bigger body we make the world a safer place for all bodies.
Emerging From the Pandemic
As we come out of this challenging time, practice moving ahead without succumbing to the pressure to focus on any weight gain.
Sweeney notes, “Bodies change. This is a fact. If they changed in the last 12 months, they may well have changed pandemic or not. Your body is not a problem. Please don’t let wellness culture suggest that a changing body is a reflection of your humanity, your goodness, and your belonging.”
5 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
1. Czeisler MÉ, Lane RI, Petrosky E, et al. Mental health, substance use, and suicidal ideation during the COVID-19 pandemic — United States, June 24–30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1049–1057. doi:10.15585/mmwr.mm6932a1
2. Stice E. Interactive and mediational etiologic models of eating disorder onset: Evidence from prospective studies. Annu Rev Clin Psychol. 2016;12:359-81. doi:10.1146/annurev-clinpsy-021815-093317.
3. Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr. 2001;74(5):579-584. doi:10.1093/ajcn/74.5.579
4. Mann T, Tomiyama AJ, Westling E, Lew A-M, Samuels B, Chatman J. Medicare’s search for effective obesity treatments: Diets are not the answer. Am Psychol. 2007;62(3):220-233. doi:10.1037/0003-066x.62.3.220
5. Neff KD, Long P, Knox MC, et al. The forest and the trees: Examining the association of self-compassion and its positive and negative components with psychological functioning. Self Identity. 2018;17(6):627-645. doi:10.1080/15298868.2018.1436587
By Lauren Muhlheim, PsyD, CEDS
Lauren Muhlheim, PsyD, is a certified eating disorders expert and clinical psychologist who provides cognitive behavioral psychotherapy. | {
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-816,649,645,022,878,100 | Detergent-resistant membrane association of NS2 and E2 during Hepatitis C virus replication
Saravanabalaji Shanmugam, Dhanaranjani Saravanabalaji, Min Kyung Yi
Research output: Contribution to journalArticle
14 Scopus citations
Abstract
Previously, we demonstrated that the efficiency of hepatitis C virus (HCV) E2-p7 processing regulates p7-dependent NS2 localization to putative virus assembly sites near lipid droplets (LD). In this study, we have employed subcellular fractionations and membrane flotation assays to demonstrate that NS2 associates with detergent-resistant membranes (DRM) in a p7-dependent manner. However, p7 likely plays an indirect role in this process, since only the background level of p7 was detectable in the DRM fractions. Our data also suggest that the p7-NS2 precursor is not involved in NS2 recruitment to the DRM, despite its apparent targeting to this location. Deletion of NS2 specifically inhibited E2 localization to the DRM, indicating that NS2 regulates this process. Treatment of cells with methyl-β-cyclodextrin (MβCD) significantly reduced the DRM association of Core, NS2, and E2 and reduced infectious HCV production. Since disruption of the DRM localization of NS2 and E2, either due to p7 and NS2 defects, respectively, or byMβCD treatment, inhibited infectious HCV production, these proteins' associations with the DRM likely play an important role during HCV assembly. Interestingly, we detected the HCV replication-dependent accumulation of ApoE in the DRM fractions. Taking into consideration the facts that ApoE was shown to be a major determinant for infectious HCV particle production at the postenvelopment step and that the HCV Core protein strongly associates with the DRM, recruitment of E2 and ApoE to the DRM may allow the efficient coordination of Core particle envelopment and postenvelopment events at the DRM to generate infectious HCV production.
Original languageEnglish (US)
Pages (from-to)4562-4574
Number of pages13
JournalJournal of virology
Volume89
Issue number8
DOIs
StatePublished - Jan 1 2015
ASJC Scopus subject areas
• Microbiology
• Immunology
• Insect Science
• Virology
Fingerprint Dive into the research topics of 'Detergent-resistant membrane association of NS2 and E2 during Hepatitis C virus replication'. Together they form a unique fingerprint.
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-6,727,596,067,139,945,000 | Skip to main content
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4-Aminopyridine Decreases Progesterone Production by Porcine Granulosa Cells
Abstract
Background
Ion channels occur as large families of related genes with cell-specific expression patterns. Granulosa cells have been shown to express voltage-gated potassium channels from more than one family. The purpose of this study was to determine the effects of 4-aminopyridine (4-AP), an antagonist of KCNA but not KCNQ channels.
Methods
Granulosa cells were isolated from pig follicles and cultured with 4-AP, alone or in combination with FSH, 8-CPT-cAMP, estradiol 17β, and DIDS. Complimentary experiments determined the effects of 4-AP on the spontaneously established pig granulosa cell line PGC-2. Granulosa cell or PGC-2 function was assessed by radio-immunoassay of media progesterone accumulation. Cell viability was assessed by trypan blue exclusion. Drug-induced changes in cell membrane potential and intracellular potassium concentration were documented by spectrophotometric determination of DiBAC4(3) and PBFI fluorescence, respectively. Expression of proliferating cell nuclear antigen (PCNA) and steroidogenic acute regulatory protein (StAR) was assessed by immunoblotting. Flow cytometry was also used to examine granulosa cell viability and size.
Results
4-AP (2 mM) decreased progesterone accumulation in the media of serum-supplemented and serum-free granulosa cultures, but inhibited cell proliferation only under serum-free conditions. 4-AP decreased the expression of StAR, the production of cAMP and the synthesis of estradiol by PGC-2. Addition of either 8-CPT-cAMP or estradiol 17β to serum-supplemented primary cultures reduced the inhibitory effects of 4-AP. 4-AP treatment was also associated with increased cell size, increased intracellular potassium concentration, and hyperpolarization of resting membrane potential. The drug-induced hyperpolarization of resting membrane potential was prevented either by decreasing extracellular chloride or by adding DIDS to the media. DIDS also prevented 4-AP inhibition of progesterone production.
Conclusion
4-AP inhibits basal and FSH-stimulated progesterone production by pig granulosa cells via drug action at multiple interacting steps in the steroidogenic pathway. These inhibitory effects of 4-AP on steroidogenesis may reflect drug-induced changes in intracellular concentrations of K+and Cl- as well as granulosa cell resting membrane potential.
Background
Ion channels located in the plasma membrane provide one means to mediate cellular adaptation to local environmental changes. Voltage-gated K+ channels in non-nerve, non-muscle cells play crucial roles in cell development, proliferation, migration, volume regulation, as well as maintenance of membrane potential and cell viability. This is in part because these channels regulate the cytoplasmic concentrations of K+, Ca2+, and Na+ ions [110]. The diversity of voltage-gated K+ channels and currents present in these "non-excitable" (non-muscle, non-nerve) cells is impressive. Thus, the assignment of specific functions to particular subclasses of K+ channel proteins represents a significant challenge [4, 1016].
Voltage-gated K+ currents with distinct electrophysiological and pharmacological properties are present in granulosa cells (GC), and modulate resting membrane potential [4, 12, 13, 16, 17]. Furthermore, selective antagonism of GC K+ channels with distinct molecular correlates, electrophysiological properties and expression patterns can influence differentially GC proliferation, steroidogenic capability, and apoptosis [17, 18]. Our laboratory has previously identified two distinct delayed rectifier K+ currents in pig GC: a slow current (IKs) associated with channels formed by co-assembly of KCNQ1 pore-forming and KCNE1 accessory proteins, and an ultra-rapid current (IKur) formed by co-assembly of KCNA pore-forming and KCNAB accessory proteins [4]. Moreover, we have shown that selective block of IKs enhances basal progesterone synthesis, while complete block of both IKs and IKur accelerates apoptosis [18].
Here, our goal was to determine the functional effects of antagonizing GC K+ channels formed by KCNA vs. KCNQ family proteins. To this end, we treated primary cultures of GC and monolayers of the immortalized granulosa cell line PGC-2 [19] with the K+ channel antagonist 4-aminopyridine (4-AP). 4-aminopyridine, at millimolar concentrations, completely inhibits K+ currents conducted by heterologously expressed KCNA channels and native GC IKur, but lacks significant effects on native GC IKs [4, 12, 13, 20]. Kusaka showed that antagonism of 4-AP sensitive slowly inactivating delayed rectifier K+ currents suppressed both basal and luteinizing hormone (LH)-stimulated progesterone production [21]. In this report, we extend those findings by demonstrating 4-AP inhibition of follicle stimulating hormone (FSH)-stimulated progesterone production, and by elucidating the underlying mechanisms.
Methods
Reagents
Cell culture media, supplements, phosphate-buffered saline (PBS, 10 X) and sera were obtained from Life Technologies (Gaithersburg, MD) unless stated otherwise. Chemicals were obtained from Sigma (St. Louis, MO) unless stated otherwise. Regular pork insulin (100 units/mL) was obtained from Eli Lilly (Indianapolis, IN). PBFI-AM (1,3-Benzenedicarboxylic acid, 4,4'-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis [(acetyloxy)methyl] ester) and DiBAC4(3) (bis-(1,3-dibutylbarbituric acid) trimethine oxonol) were obtained from Molecular Probes (Eugene, OR). Primary antibodies were obtained from commercial sources for detection of proliferating cell nuclear antigen (PCNA, Oncogene Science, Cambridge, MA) and actin (Sigma). Nitrocellulose membranes (Hybond ECL), secondary antibodies, enhanced chemiluminescence (ECL) reagent, and film (Hyperfilm ECL) were obtained from Amersham Pharmacia Biotech (Piscataway, NJ). Porcine FSH (2039 IU/mg) was obtained from the National Hormone and Pituitary Program (NHPP). PGC-2 cells were provided by B.R. Downey (McGill University, Montreal, Canada). Antibody directed against steroidogenic acute regulatory protein (StAR) was a gift from D.B. Hales (University of Illinois, Chicago).
GC Isolation and Culture
Porcine ovaries were collected at a local slaughterhouse, and GC were isolated using techniques described previously in detail [4, 18]. Briefly, small (1–3 mm diameter) to medium (4–6 mm diameter) follicles were aspirated by hand using a 19-gauge needle attached to a 10 cc syringe. GC were separated from follicular fluid by centrifugation at 500 × g for 5 minutes. Cells were washed twice with a 1:1 mixture of Ham F10 nutrient medium and Dulbecco modified Eagle medium (DMEM) containing 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES, 25 mM), penicillin (50 U/ml) and streptomycin (50 μg/ml). Culture conditions for GC were similar to those described previously by our laboratory and others [4, 18, 22, 23]. The basic culture medium consisted of HEPES-buffered DMEM: F10 (1:1) supplemented with fetal bovine serum (FBS, 10%), penicillin (50 U/ml), streptomycin (50 μg/ml), gentamicin (57 ng/ml) and amphotericin (2.5 μg/ml).
Freshly isolated GC were plated in the basic serum-supplemented culture media on collagen-coated 24-well (500 μl/well) or 6-well (2 ml/well) culture dishes, and incubated at 37° C in a humidified atmosphere of 5% CO2 and air. In every experiment, cells were plated at equal density for each treatment group. Plating density between experiments varied from 2 × 104 cells/well/24-multiwell to 1 × 106 cells/well/6-multiwell. Culture wells in the 6-multiwell clusters had a well diameter of 34.8 mm and a growth area of 9.4 cm2, while culture wells in the 24-multiwell clusters had a well diameter of 15.6 mm and a growth area of 1.9 cm2. The culture media were changed 16 h after plating to fresh serum-supplemented media that contained either vehicle or treatment(s). Media were collected and replaced at 24 h intervals thereafter. 4-AP was dissolved directly into the culture media on the day of use, and the pH was readjusted to 7.4 with saturated HCl after addition of drug. DIDS (4',4' diisothicyanato-stilbene-2-2'-disulfonic acid) was diluted into culture media from a 200X aqueous stock. Stock solutions of forskolin (10 mM) and 3-isobutyl-1-methylxanthine (IBMX, 80 mM) were in DMSO.
In a subset of experiments, GC were cultured in a defined serum-free medium of HEPES-buffered DMEM:F10 (1:1) containing insulin (300 mU/ml), hydrocortisone (40 ng/ml), transferrin (5 μg/ml), bovine serum albumin (4 mg/ml, Bovine Albumin Fraction V, albumin = 95%), gentamicin (57 μg/ml), penicillin (50 U/ml), streptomycin (50 μg/ml), and amphotericin (2.5 μg/ml). This medium significantly increases the magnitude and duration of basal and FSH-stimulated progesterone output by GC [22].
PGC-2 Cell Culture and Patch Clamp
The pig granulosa cell line PGC-2 was obtained from Bruce Downey (McGill University) and maintained in culture in McCoy's modified 5A medium supplemented with 10% FBS, as described previously in detail [19]. PGC-2 cells have been well-characterized with respect to steroidogenic capability, cAMP response, and gonadotropin insensitivity [19]. Here, PGC-2 were seeded at a density of approximately 5 × 105 cells/ml of serum-containing medium in 24-well tissue culture plates. After 24 h the medium was replaced with serum-free medium containing either pregnenolone (1 μg/ml), androstenedione (100 μM), 5α-dihydrotestosterone (5α-DHT, 10 or 100 μM), or forskolin (5 μM) and IBMX (10 μM). To ensure the validity of this model for assessing the functional effects on the K+ channel antagonists, we used whole-cell patch clamp techniques [4] to document the presence of 4-AP sensitive K+ currents in PGC-2 (see additional file 1).
Measurement of Membrane Potential
The resting membrane potentials of cultured GC were assessed by spectrophotometric determination of DiBAC4(3) fluorescence (excitation= 485 nM; emission= 527 nM; Fluoroskan Ascent FL, LabSystems Inc., Helsinki, Finland). Cells were equilibrated with 2 μM DiBAC4(3) for 30 minutes at 37°C prior to fluorescence measurement. In most experiments, GC were bathed in culture media. However, one set of fluorescence measurements compared GC incubated in a normal Tyrode solution containing (in mM): 132 NaCl; 4 KCl; 1 MgCl2; 1 CaCl2; 5 dextrose; 10 HEPES (pH = 7.4) to GC similarly incubated in a relatively low-chloride Tyrode solution in which the NaCl was replaced with sodium aspartate.
Measurement of Intracellular Potassium
Intracellular levels of potassium were assessed by determination of PBFI fluorescence. Cells were equilibrated with the cell permeant acetoxylmethyl ester of the ion sensitive dye PBFI (5 μM) for 1 h, then washed and resuspended in PBS. Fluorescence was measured using a plate-reader (excitation = 340 nM; emission = 505 nM; Fluoroskan Ascent FL, LabSystems Inc., Helsinki, Finland).
Preparation of GC Lysates
Whole cell lysates were made from GC monolayers by standard techniques using a lysis buffer consisting of PBS with 1% Nonidet P40, 0.5% sodium deoxycholate, 0.1% SDS and protease inhibitor cocktail (1:100, Sigma P8340). Lysis buffer was added to the culture dish after washing with cold PBS 3 times. The culture dishes were scraped and the lysate was aspirated into a syringe with a 21-gauge needle to shear DNA. The lysates were rocked in the cold for 1 h and centrifuged for 10 min at 10,000 × g. In some cases, a highly enriched mitochondrial fraction was obtained using a commercially available kit (Mitchondrial Fractionation Kit, Active Motif, Carlsbad, CA) according to the manufacturer's instructions. Protein concentrations of GC lysates were determined by the bicinchoninic acid method (Micro BCA Protein Assay, Pierce, Rockford IL).
Immunoblotting
For direct comparisons of protein expression between drug-treated and untreated cells, equal amounts of protein were loaded in adjacent lanes on a single polyacrylamide gel, separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions and transferred to nitrocellulose membranes by the semi-dry transfer method. The membranes were blocked for 1 h at room temperature with 5% nonfat milk in Tris-buffered saline (TBS: 100 mM Tris, 0.9% NaCl, pH 7.5) containing 0.1% Tween 20, then incubated overnight at 4°C with primary antibody diluted in the blocking solution. Primary antibody dilutions were: PCNA (1:200); actin (1:500); StAR (1:500). After three washes with 0.1% Tween/TBS, the membranes were incubated for 1 h at room temperature with the appropriate horseradish peroxidase conjugated secondary antibody diluted 1:1500 in 5% nonfat milk/0.1% Tween/TBS. After four additional washes with 0.1% Tween/TBS, bound primary antibodies were visualized using an ECL detection system and recorded on radiographic film (Amersham Pharmacia Biotech). Densitometric analysis was performed using Scion Image (Scion Corporation, Frederick, MD). Equal loading was confirmed by either immunoblotting for actin or Coomassie-blue staining of gel lanes loaded and subjected to SDS-PAGE in a manner identical to those used for immunoblotting.
Immunoassays
Progesterone concentrations were determined by a solid-phase radioimmunoassay (CAC Progesterone, Diagnostic Products Corp, Los Angeles, CA) validated for measuring progesterone in the culture media. The assay sensitivity was approximately 0.3 ng/ml. The cross-reactivity with androstenedione (1000 ng/mL) was 0.047%. The cross-reactivity with pregnenolone (500 ng/mL) was 0.30%. The within and between assay coefficients of variation for the progesterone assay were 4.3 and 11.7%, respectively.
Aliquots of culture media were stored at -20°C for up to 60 days prior to progesterone assay. In the initial series of experiments where serial progesterone measurements were made from a single culture well, media progesterone concentrations 24–48 hours post-treatment were normalized to pre-treatment concentrations. In subsequent experiments, progesterone concentrations at various time-points post-treatment were normalized to either cell number or protein concentration.
Estradiol-17β was measured using commercially available reagents (TKE2, Diagnostic Products Corp, Los Angeles, CA). This assay had been validated previously for porcine serum [24], and was further modified and validated for use with culture media containing FBS. In brief, estradiol-17β could be quantitatively recovered when added to culture media, and increasing dilutions of media spiked with estradiol-17β produced similar concentrations when evaluated in the assay. The sensitivity was 4.9 pg/ml. The intra- and interassay coefficients of variation for estradiol assay were 4.8 and 8.3%, respectively.
Cyclic AMP was measured in GC lysates using an enzyme immunoassay according to the instructions provided by the manufacturer (Assay Designs, Ann Arbor, MI).
Determination of Cell Number
The number of viable GC in the monolayer cultures was determined by first harvesting the attached cells with a trypsin-containing solution (mg/ml): NaCl 8; KCl 0.4; dextrose 1; NaHCO3 0.6; ethylenediaminetetraacetic acid sodium salt (Na-EDTA) 0.2; trypsin 0.5, and then counting directly the number of viable cells using trypan blue exclusion and hemacytometry.
Flow Cytometry
Flow cytometry was also used to assess GC viability and size, using methods described previously in detail to determine propidium iodide uptake and forward (small angle light) scatter, respectively [18, 25]. Briefly, ten thousand cells were examined per sample using a Becton Dickinson FACSCalibur to excite the cells with a 488 nM argon laser, and the collected data obtained were analyzed using Cell Quest™ software (Becton Dickinson, Mount View, CA). Changes in the forward light scattering properties of GC were used to infer changes in GC size. Debris, shrunken (apoptotic) GC and dead GC stained by propidium iodide were excluded from analysis.
Statistical Analysis
Data are expressed as mean ± SEM unless stated otherwise. Statistical analysis of treatment effects on forward scatter characteristics was performed using the non-parametric Friedman test. For all other data, significant differences between groups were identified by analysis of variance (ANOVA) using appropriate general linear models, and multiple comparisons were made using the least significant differences (LSD) procedure (Statistix, Analytical Software, Tallahassee, FL). Differences were considered to be significant when P ≤ 0.05. The numbers of replicates per treatment group and independent experiments associated with specific studies are provided in the figures or accompanying legends.
Results and Discussion
Effects of 4-AP on GC Viability and Progesterone Production
Treatment with 4-AP (2 mM) decreased progesterone accumulation in the media of serum-supplemented GC cultures at 24 h and 48 h post-treatment, in the presence and absence of FSH (Figure 1). The decreased progesterone concentrations in the media of drug-treated cultures did not reflect significant differences in the number of viable cells under these culture conditions, (Figure 2A). Densitometric analysis of data from 3 experiments similar to that shown in Figure 2B revealed no significant effect of 4-AP treatment on the expression of proliferating cell nuclear antigen (PCNA). These data provide additional evidence that 4-AP exerts neither an anti-proliferative nor a pro-apoptotic influence on serum-supplemented GC cultures, because PCNA expression is a sensitive marker of GC proliferation and apoptosis [18, 26, 27]. The lack of 4-AP effect on GC viability is also evident from the flow cytometric analysis; the percentages of cells staining positive for propidium iodide were 8 ± 2% and 7 ± 2% in the presence and absence of drug (n = 4 samples of 10,000 cells/each from 4 GC isolations).
Figure 1
figure1
1 4-AP decreased progesterone output by serum-supplemented granulosa cell cultures. A) Progesterone accumulation by 24 h GC cultures maintained in the basic culture media containing 10% FBS (Control) in the absence or presence of 4-AP (2 mM). B) Progesterone accumulation by 24 h GC cultures maintained in the basic culture media in the absence or presence of added FSH (200 ng/mL) and/or 4-AP (2 mM). Data are normalized to day 0 progesterone concentrations, and represent the mean ± SEM of either 33 culture wells from 6 GC harvests (panel A) or 17 culture wells from 4 GC harvests (panel B). Asterisks indicate P < 0.05 compared with GC cultured under similar conditions in the absence of 4-AP.
Figure 2
figure2
4-AP does not affect granulosa cell viability in serum-supplemented cultures. A) The numbers of viable cells (mean ± SEM) 24 h after treatment for GC cultures maintained in the absence (CON) of FSH with and without the addition of 2 mM 4-AP (10 culture wells from 5 different GC isolations), and in the presence of FSH with and without the addition of 2 mM 4-AP (8 culture wells from 4 GC isolations). B) Western blot analysis of proliferating cell nuclear antigen (PCNA, left) and actin (loading control, right) in GC lysates (40 μg protein/lane) from cultures described in panel A. Arrows indicate molecular mass (kDa). The results shown are representative of 3 independent experiments.
Treatment with 4-AP (2 mM) also diminished progesterone accumulation on days 1 and 2 post-treatment in GC cultures maintained in the defined serum-free media in the presence and absence of FSH. However, in these serum-free cultures, 4-AP treatment was associated with not only decreased progesterone accumulation but also decreased numbers of viable cells (Table 1). The percentage of viable cells was unaffected by 4-AP (Control = 90 ± 4% vs. 4-AP = 88 ± 4%, n = 5; FSH = 86 ± 2%, FSH+4-AP = 86 ± 2%, n = 9), suggesting that 4-AP inhibited growth rather than promoted cell death.
Table 1 4-AP Effects on Granulosa Cells Cultured in Defined Serum-free Media
Overall, these data are consistent with previous reports that endocrine cells express voltage-sensitive ion channels that can contribute to the regulation of not only resting membrane potential and cell volume, but also cell proliferation and steroidogenesis [12, 13, 16, 18, 21, 2837]. The K+ currents blocked by 4-AP in pig GC are conducted by ion channels formed by heteromeric complexes of pore-forming subunits from the KCNA (also called Kv1 or Shaker) family of proteins and accessory subunits from the KCNAB (also called Kvβ) family of proteins [4]. Similar 4-AP-sensitive K+ currents play a key role in transduction of mitogenic signals in a variety of cell types, and 4-AP treatment has been associated with not only growth arrest but also apoptosis [2, 3, 810, 14, 3842].
Our finding that 24 h exposure to 4-AP decreased the number of viable GC in serum-free but not serum-supplemented primary cultures is consistent with the reported effects of 4-AP and other K+ channel antagonists on other cell types [8, 43, 44]. It has been shown that the concentrations of K+ channel antagonists required to inhibit growth of human bladder tumor cells can be 70 times higher in the presence than the absence of serum [43]. 4-AP has been shown to inhibit the proliferation of human myelobastic leukemia cells by preventing growth factor activation of mitogen activated protein kinase (MAPK) pathways [42]. This mechanism may be responsible for the anti-proliferative effect of 4-AP manifest in Table 1. It is likely that MAPK pathways are less robust in GC grown in defined serum-free vs. serum-supplemented media; however, validation of this hypothesis would require additional experiments beyond the scope of the present investigation. We concluded that the anti-proliferative effect of 4-AP may contribute to the decreased progesterone accumulation observed in serum-free but not serum-supplemented GC cultures, then focused additional efforts on understanding other mechanisms responsible for 4-AP inhibition of progesterone production.
The effects of 4-AP in serum-supplemented GC cultures are consistent with previous reports that antagonism of voltage-sensitive K+ currents can modulate basal and gonadotropin-stimulated progesterone accumulation in the absence of any effect on cell growth or death. We have shown previously that antagonism of the slowly activating non-inactivating granulosa K+ current (IKs) enhances basal progesterone production by depolarizing membrane potential and thus enhancing calcium influx via pimozide-sensitive Ca2+ channels [18]. In contrast, Kusaka [21] showed that antagonism of 4-AP sensitive slowly inactivating delayed rectifier K+ currents suppressed both basal and LH-stimulated progesterone production. Data presented in Figures 1 and 2 confirm the inhibitory effects of 4-AP on basal progesterone production by cultured pig GC, and demonstrate for the first time a similar inhibitory effect of 4-AP on FSH-stimulated progesterone synthesis.
Effects of 4-AP on Pathways for Steroid Hormone Biosynthesis
The inhibitory action of 4-AP on progesterone production was investigated further using not only primary cultures, but also the spontaneously established granulosa cell line, PGC-2[19]. Although PGC-2 lack FSH receptors, these cells can serve as a useful in vitro model for GC function, because they produce cAMP in response to forskolin and synthesize progesterone and estradiol when supplied with appropriate substrates. We examined the effects of 4-AP on cAMP, progesterone and estradiol production by PCG-2 after confirming that these cells express 4-AP sensitive voltage-gated K+ currents similar to those in primary cells (see additional file 1).
4-AP decreased production of cAMP (Figure 3A), and expression of StAR by PGC-2 (Figure 3B). 4-AP had no significant effect on progesterone production by PCG-2 cultured in the presence of pregnenolone, androstenedione or 5α-DHT (Figure 4A). In contrast, 4-AP significantly reduced estradiol production by PGC-2 cultures provided with androstenedione (Figure 4B).
Figure 3
figure3
4-AP decreases cAMP and StAR in PGC-2 cultures. A) Accumulation of cAMP in PGC-2 (n = 4 culture wells). PGC-2 were cultured in serum-free media (McCoy's modified 5A) in the presence of IBMX (10 μM) without (Control) or with the addition of 4-AP (2 mM) and forskolin (5 μM) for 2 h, then pelleted and lysed in HCl (0.1 N) prior to analysis of cAMP levels. B) Western blot analysis of StAR in mitochondrial extracts from PGC-2 cells (10 ug protein/lane) cultured in serum-free media for 2 h in the absence (Con) or presence of 4-AP. The results shown are representative of 3 independent experiments. Astericks indicates P < 0.05 compared with PGC-2 cultures under similar conditions in the absence of 4-AP.
Figure 4
figure4
4-AP decreases estradiol production by PGC-2 cultures. A) Accumulation of progesterone in media of PGC-2 (n = 4 culture wells) cultured with pregnenolone (1 μg/ml), androstenedione (100 μM), or 5α-dihydrotestosterone (5α-DHT, 100 μM). B) Accumulation of estradiol in media of PGC-2 (n = 4 culture wells) cultured with androstenedione (100 μM). In all panels, asterisk indicates P < 0.05 compared with PGC-2 cultured under similar conditions in the absence of 4-AP.
To evaluate the relevance of the experimental results obtained using PGC-2, we examined the effect of 4-AP on the progesterone output of primary GC cultures supplemented with either the membrane permeable cAMP analog, 8-(4-chlorophenylthio) adenosine-3',5'-cyclic monophosphorothioate (8-CPT-cAMP, 1 mM) or estradiol 17β (500 ng/ml). The inhibitory effect of 4-AP on progesterone accumulation was partially but not completely overcome by the addition of 8-CPT-cAMP (Table 2). 4-AP had no inhibitory effects on either basal or FSH-stimulated progesterone production by GC cultures supplemented with estradiol 17β (Figure 5). Thereby, the combined results of experiments performed using PGC-2 and primary GC cultures suggest that 4-AP-inhibition of GC progesterone production may be linked to decreased expression of StAR, decreased generation of cAMP, and decreased output of estradiol.
Figure 5
figure5
Estradiol prevents 4-AP inhibition of progesterone production by granulosa cell cultures. Progesterone (P4) accumulation by 24 h GC cultures maintained in the basic culture media supplemented with 500 ng/mL estradiol 17β (E2), in the absence or presence of FSH (200 ng/mL), with or without the addition of 4-AP (2 mM). Data were obtained from 9 (E2+FSH) or 10 (E2, E2+4-AP, E2+FSH+4-AP) culture wells from two GC isolations. Different superscripts indicate significant difference (P < 0.05).
Table 2 4-AP Effects on cAMP-stimulated Progesterone Accumulation (ng/ml)
StAR plays a key role in the initial steps of steroidogenesis, because it is required for transport of cholesterol to the inner mitochondrial membrane where CYP11A1 resides and the first reaction in progesterone synthesis occurs [45]. cAMP is a well known second messenger in FSH- and LH-stimulated progesterone synthesis, and a key effect of the cAMP-dependent protein kinase in GC is transcriptional control of StAR [46, 47]. Estradiol is recognized as a biological amplifier of basal, FSH- and cAMP-stimulated progesterone production in pig GC, with significant synergistic effects distal to the generation of cAMP at one or more steps in cholesterol transport and metabolism [48]. Our experimental results are thus consistent with 4-AP inhibition of GC progesterone output via drug effects on multiple interacting sites in the steroidogenic pathway. Moreover, despite multiple sites of action, the drug's actions cannot be dismissed as non-specific, because 4-AP had no effects on either 3β-hydroxysteroid dehydrogenase (3β-HSD)-mediated conversion of pregnenolone to progesterone, or androgen (androstenedione, 5αDHT)-stimulated progesterone synthesis.
Estradiol has been reported to affect K+ channel expression and gating in smooth muscle [4953]. The data presented here do not address directly the potential for estradiol modulation of voltage-gated K+ channel expression or activity in GC. However, such a mechanism seems unlikely to account for the ability of estradiol to oppose the inhibitory effects of 4-AP on GC progesterone production. The K+ channel subunits and currents modulated by estradiol in vascular and uterine smooth muscle differ from the 4-AP sensitive KCNA family channels that contribute to the 4-AP sensitive current IKur in pig GC [4, 49, 50, 52, 53]. Moreover, in the single study where estradiol was shown to influence the gating of a uterine delayed rectifier current with electrophysiological characteristics resembling those of GC IKur, the observed effect of the hormone was inhibitory [51], and thereby similar rather than opposite to the effect of 4-AP.
Additional experiments were performed in an attempt to identify signaling pathways that transduce specific inhibitory effects of 4-AP. These focused on 4-AP modulation of membrane potential, intracellular ion concentrations, and cell size, as described below.
Effects of 4-AP on Membrane Potential, Intracellular Ions, Cell Size
Hormonal signal transduction and steroidogenesis can be affected by changes in intracellular and extracellular concentrations of inorganic ions, cellular resting membrane potential, and cell size [29, 30, 35, 5459]. Blockade of 4-AP sensitive K+ channels in non-nerve, non-muscle cells can lead to changes in transmembrane ion gradients, membrane potential and cell volume [42, 60]. On this basis, we determined the effects of 24 h exposure to 4-AP on GC size, membrane potential and intracellular potassium ([K+]in).
Samples (10,000 cells) of GC from 24 hour cultures associated with 4 GC isolations were analyzed by flow cytometry to determine if 4-AP treatment influenced GC size. Light scattering properties did not differ significantly with GC isolate. However, the average forward scatter (median, coefficient of variation) of GC cultured for 24 hours in the presence of 4-AP (768, 15%) was significantly greater than that of GC maintained similarly in the absence of drug (694, 15%). Representative dot plots are shown in Figure 6. Resting membrane potential (Figure 7A) and [K+]in (Figure 7B) were also found to be increased in GC exposed to 4-AP, based on DiBAC4(3) and PBFI fluorescence, respectively.
Figure 6
figure6
4-AP increases granulosa cell size. Dot plots of forward scatter (SIZE FSC) vs. propidium iodide fluorescence (PI FL-2) for granulosa cells cultured in either the absence (CON) or presence of 4-AP (2 mM). Each dot represents one cell. Dead cells stained with propidium iodide appear in two upper quadrants. Cellular debris and shrunken apoptotic cells are displayed in the lower left quadrant. Viable granulosa cells are represented in the lower right quadrant. Median forward scatter was 637 and 735 for viable CON and 4-AP, respectively.
Figure 7
figure7
4-AP hyperpolarizes granulosa cell resting potential and increases intracellular potassium. A) Granulosa cells (GC) were cultured in the basic media, alone (Con), or with 4AP (2 mM), FSH (200 ng/mL) or FSH+4AP. After 24 hours, resting membrane potentials were compared using DiBAC4(3) fluorescence. Decreased DiBAC4(3) fluorescence indicates hyperpolarization of resting membrane potential. Data were obtained from 16 (Con, 4-AP) or 17 (FSH, FSH+4AP) culture wells from 4 GC isolations. B) GC were cultured in the basic media, alone, or with 4AP, FSH or FSH+4AP. After 24 hours, intracellular K+ concentrations were compared by PBFI fluorescence. Increased PBFI fluorescence indicates increased intracellular potassium concentration. Data were obtained from 5 (FSH, FSH+4-AP) or 7 (Con, 4-AP) culture wells from 3 GC isolations. In both panels, asterisk indicates P < 0.05 compared with GC cultured under similar conditions in the absence of 4-AP.
The observed drug-induced increases in cell size and [K+]in suggest that 4-AP sensitive K+ channels represent a significant K+ efflux pathway involved in maintenance of cell volume in GC. Interestingly, the increased [K+]in may contribute directly to the inhibitory effects of 4-AP on production of cAMP and progesterone. Loss of K+ from the intracellular compartment of rat GC has been associated with opposite effects, namely enhanced synthesis of both cAMP and progesterone [61].
The observed increase (hyperpolarization) of GC resting membrane potential cannot be explained easily by any direct effect of the drug. In fact, 4-AP inhibition of K+ efflux would be expected to depolarize rather than hyperpolarize membrane potential. Data obtained previously in our laboratory suggest that inhibition of granulosa IKur should be associated with a +10 to +20 mV depolarization of cell resting membrane potential; block of IKs alone decreased resting potential by +10 mV while block of both IKs and IKur decreased resting potential by +20 to +30 mV [18]. Most previous investigations of 4-AP effects on the resting membrane potentials of non-nerve, non-muscle cells have similarly demonstrated drug-induced depolarization [42, 60], although there is a single report showing 4-AP-induced hyperpolarization of chondrocyte membrane potential [62].
We hypothesized that hyperpolarization of 4-AP-treated GC could reflect anion influx associated with activation of a Cl- entry pathway sensitive to changes in cell volume as well as membrane-potential. To test this hypothesis, the effects of 4-AP on membrane potential were examined using GC incubated in either media modified to contain the chloride channel antagonist DIDS, or a physiological buffer solution modified to contain a low (8 mM) concentration of chloride. In contrast to the results obtained in the standard media (Figure 7A), 4-AP did not induce significant hyperpolarization of GC under these conditions (Figure 8A,8B). Exposure to DIDS alone significantly decreased (depolarized) GC resting membrane potential (Figure 8B), suggesting that an outward chloride current (chloride influx) contributes to the normal resting potential of pig GC. Membrane potential was further depolarized in GC exposed to 4-AP in the presence of DIDS (Figure 8B), consistent with the hypothesis that 4-AP-induced hyperpolarization depends on chloride influx.
Figure 8
figure8
Chloride influx mediates the effect of 4-AP on granulosa cell membrane potential and progesterone production. A) Effect of 4-AP (2 mM) on membrane potential of granulosa cells (GC) bathed in Tyrode solution modified to contain a low concentration (8 mM) of chloride (Low [Cl-]out). Data represent DiBAC4(3) fluorescence of untreated GC (n = 8) and GC exposed to 4-AP for 0.5 h (n = 7). B) Effect of DIDS (100 μM) and 4-AP (2 mM) on membrane potential (DiBAC4(3) fluorescence) of GC (n = 6) cultured for 24 h in the presence or absence of drugs. Decreased DiBAC4(3) fluorescence indicates hyperpolarization of resting membrane potential, while increased DiBAC4(3) fluorescence indicates depolarization of resting membrane potential. C) Progesterone (P4) accumulation by 24 h GC cultures maintained in the basic culture media (CON) alone or with 4-AP (2 mM), DIDS (100 μM) or DIDS+4AP. Data were obtained from 4 (CON, 4-AP) or 6 (DIDS, DIDS+4-AP) culture wells from a single GC isolation. Different superscripts indicate significant difference (P < 0.05).
Interestingly, concomitant exposure to DIDS prevented 4-AP from diminishing the accumulation of progesterone in GC culture media (Figure 8C), suggesting that chloride influx, membrane hyperpolarization or both might mediate this effect of 4-AP. Chloride channels or chloride ions are known to influence cAMP-stimulated steroidogenesis by adrenal cells [29], human chorionic gonadotropin (hCG)-stimulated steroidogenesis by amphibian follicle-enclosed oocytes [56], as well as LH-stimulated steroidogenesis in rat Leydig cells [29], MA-10 cells [59], and chicken GC [35]. In mammalian cells, removal of extracellular chloride stimulates basal and protein kinase A (PKA)-dependent steroid hormone production by increasing the expression of StAR and potentiating the effects of submaximal concentrations of cAMP [29, 59]. The proposed mechanism of action involves chloride efflux, depolarization of the mitochondrial and plasma membranes, and alterations to protein synthesis and cholesterol transport [29, 59].
The data shown here in Figures 7 and 8 suggest strongly that chloride ions can influence progesterone production in pig GC by similar mechanisms. In our experiments, the chloride influx and membrane hyperpolarization associated with 4-AP treatment not only decreased expression of StAR, but also inhibited cAMP production and steroidogenesis. The observed effects of Cl- channel antagonists differ significantly between the present study where DIDS prevented 4-AP from decreasing progesterone synthesis and previous investigations where DIDS and other Cl- channel antagonists prevented LH from enhancing progesterone production [29, 35, 56]. However, this discrepancy is expected, because DIDS antagonizes a chloride influx pathway in pig GC, and chloride efflux pathways in Leydig cells.
In summary, the data demonstrate that 4-AP inhibits basal and FSH-stimulated progesterone production by pig GC via a complex mechanism involving drug action at multiple interacting steps in the steroidogenic pathway. Drug block of the voltage-gated potassium channels that conduct the ultra-rapid delayed rectifier current IKur is associated with increased intracellular potassium concentration, increased cell volume, activation of chloride influx and hyperpolarization of resting membrane potential. These changes in the GC internal milieu appear to modulate the inhibitory effects of 4-AP on expression of StAR and production of steroid hormones.
The physiological implications of the data are significant, as they suggest novel roles for granulosa cell ion channels. We demonstrate for the first time not only that delayed rectifier K+ channels play a significant role in GC volume regulation, but also that voltage and/or volume-sensitive Cl- channels modulate GC membrane potential and progesterone production. Additional experiments are required to link these data obtained in vitro to functionally significant changes in GC volume and chloride flux during normal follicular development.
Conclusions
In conclusion, the present studies indicate that the K+ channel antagonist 4-AP inhibits basal and FSH-stimulated progesterone production by pig GC. Exposure to 4-AP is associated with decreased production of cAMP, decreased expression of StAR, and decreased synthesis of estradiol. These inhibitory actions of 4-AP on adenylate cyclase activity, StAR expression and steroidogenesis may reflect drug-induced changes in the intracellular concentrations of K+ and Cl- and the GC resting membrane potential. Further studies are required to elucidate fully the mechanisms involved.
Additional investigation is warranted. 4-AP is reported to have therapeutic potential for the relief of symptoms associated with demyelinating diseases such as spinal cord injury and multiple sclerosis [6368]. The drug is currently being studied in large scale human trials [68]. Drug-induced inhibition of steroid hormone production could have significant effects in these patients. For example, 4-AP could exacerbate abnormal steroid hormone profiles associated with spinal cord injury and multiple sclerosis, and thereby contribute to dysmenorrhea and infertility [69, 70].
Abbreviations
(4-AP):
4-aminopyridine
(ANOVA):
analysis of variance
(8-CPT-cAMP):
8-(4-chlorophenylthio)adenosine-3';5'-cyclic monophosphorothioate
(DIDS):
4'4' diisothicyanato-stilbene-2-2'-disulfonic acid
(DiBAC4(3)):
bis-(13-dibutylbarbituric acid)trimethine oxonol
(5α-DHT):
5α-dihydrotestosterone
(DMEM):
Dulbecco's modified eagle's medium
(ECL):
enhanced chemiluminescence
(EDTA):
ethylenediaminetetraacetic acid
(FBS):
fetal bovine serum
(FSH):
follicle stimulating hormone
(GC):
granulosa cells
(hCG):
human chorionic gonadotropin
(HEPES):
4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid
(3β-HSD):
3β-hydroxysteroid dehydrogenase
(IBMX):
3-isobutyl-1-methylxanthine
(LSD):
least significant difference
(LH):
luteinizing hormone
(MAPK):
mitogen activated protein kinase
(PBFI-AM):
1,3-Benzenedicarboxylic acid, 4,4'-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis [(acetyloxy)methyl] ester
(PBS):
phosphate-buffered saline
(PCNA):
proliferating cell nuclear antigen
(PKA):
protein kinase A
(SDS-PAGE):
sodium dodecyl sulphate-polyacrylamide gel electrophoresis
(StAR):
steroidogenic acute regulatory protein
(TBS):
tris-buffered saline
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Acknowledgements
These studies were supported by National Institutes of Health Grant HD-36002 (to L. Freeman) and a Kansas State University Cancer Center Award (to B. Mitchell). Dr. Jorge Chedrese (University of Saskatchewan, Saskatoon, Canada) provided useful input regarding experimental design.
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Correspondence to Yan Li.
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YL participated in experimental design, performed all experimental techniques, and played a primary role in data analysis and interpretation. SG provided general technical support and participated in cell isolation and culture, immunoblotting, fluorescence measurements and flow cytometry. FvS performed patch clamp experiments and analyses, and assisted with preparation of the figures and manuscript. DEM contributed to data presented in Figure 1 and Table 1. BMM contributed to data presented in Figures 1 and 2. LCF conceived of the study, coordinated design and performance of experiments, and drafted the manuscript.
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Additional File 1: 4-AP-sensitive delayed rectifier K+ current in PGC-2. Whole-cell patch clamp currents recorded from a PGC-2 cell, in response to a series of six depolarizing test pulses of 1 s duration (step +20 mV) from a holding potential of -50 mV, before (left) and after (middle) application of 2 mM 4-aminopyridine (4-AP). The right panel shows the 4-AP sensitive current obtained by subtracting the current traces recorded in the presence (middle) of the drug from those recorded in the absence (left) of the drug. Recording conditions are identical to those used previous by our laboratory to record voltage-dependent K+ currents from pig granulosa cells (Mol Pharmacol 2002 61:201-13). The data demonstrate that PGC-2 cells express K+ currents similar to the granulosa cell ultra-rapid delayed rectifier current (IKur) in terms of the voltage-dependence and kinetics of activation and deactivation, as well as the sensitivity to 4-AP. Similar currents were recorded in 7 of 7 cells assayed using patch-clamp techniques. (PDF 38 KB)
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Li, Y., Ganta, S., von Stein, F.B. et al. 4-Aminopyridine Decreases Progesterone Production by Porcine Granulosa Cells. Reprod Biol Endocrinol 1, 31 (2003). https://doi.org/10.1186/1477-7827-1-31
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Keywords
• Granulosa Cell
• Proliferate Cell Nuclear Antigen
• Follicle Stimulate Hormone
• Rest Membrane Potential
• Progesterone Production | {
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-5,614,667,313,503,200,000 | What is Scabies?
Scabies is an itchy skin condition caused by a tiny burrowing mite called Sarcoptes scabiei. The presence of the mite leads to intense itching in the area of its burrows. The urge to scratch may be especially strong at night.
Scabies is contagious and can spread quickly through close physical contact in a family, child care group, school class or nursing home. Because of the contagious nature of scabies, doctors often recommend treatment for entire families or contact groups to eliminate the mite.
Take heart in that scabies is readily treated. Medications applied to your skin kill the mites that cause scabies and their eggs, although you may still experience some itching for several weeks.
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-7,568,912,936,636,776,000 | Impact of renal denervation on atrial arrhythmogenic substrate in ischemic model of heart failure
Shinya Yamada, Man Cai Fong, Ya Wen Hsiao, Shih Lin Chang, Yung Nan Tsai, Li Wei Lo, Tze Fan Chao, Yenn Jiang Lin, Yu Feng Hu, Fa Po Chung, Jo Nan Liao, Yao Ting Chang, Hsing Yuan Li, Satoshi Higa, Shih Ann Chen*
*此作品的通信作者
研究成果: Article同行評審
31 引文 斯高帕斯（Scopus）
摘要
Background--Myocardial infarction increases the risk of heart failure (HF) and atrial fibrillation. Renal denervation (RDN) might suppress the development of atrial remodeling. This study aimed to elucidate the molecular mechanism of RDN in the suppression of atrial fibrillation in a HF model after myocardial infarction. Methods and Results--HF rabbits were created 4 weeks after coronary ligation. Rabbits were classified into 3 groups: normal control (n=10), HF (n=10), and HF-RDN (n=6). Surgical and chemical RDN were approached through midabdominal incisions in HF-RDN. Left anterior descending coronary artery in HF and HF-RDN was ligated to create myocardial infarction. After electrophysiological study, the rabbits were euthanized and the left atrial appendage was harvested for real-time polymerase chain reaction analysis and Trichrome stain. Left atrial dimension and left ventricular mass were smaller in HF-RDN by echocardiography compared with HF. Attenuated atrial fibrosis and tyrosine hydroxylase levels were observed in HF-RDN compared with HF. The mRNA expressions of Cav1.2, Nav1.5, Kir2.1, KvLQT1, phosphoinositide 3-kinase, AKT, and endothelial nitric oxide synthase in HF-RDN were significantly higher compared with HF. The effective refractory period and action potential duration of HF-RDN were significantly shorter compared with HF. Decreased atrial fibrillation inducibility was noted in HF-RDN compared with HF (50% versus 100%, P < 0.05). Conclusions--RDN reversed atrial electrical and structural remodeling, and suppressed the atrial fibrillation inducibility in an ischemic HF model. The beneficial effect of RDN may be related to prevention of the downregulation of the phosphoinositide 3-kinase/AKT/endothelial nitric oxide synthase signaling pathway.
原文English
文章編號e007312
期刊Journal of the American Heart Association
7
發行號2
DOIs
出版狀態Published - 1 1月 2018
指紋
深入研究「Impact of renal denervation on atrial arrhythmogenic substrate in ischemic model of heart failure」主題。共同形成了獨特的指紋。
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2,213,625,202,397,374,000 | The Surprising Link Between Concussions, Hormones, and Mood Swings
— BY Condition Information | Reading Time: 2 min
Corey looking at a monitor explaining something
Would you believe that one small bump to the head could feel like an entire asteroid has crashed into your universe? Something as common as a concussion can not only cause endless physical symptoms but also a variety of unexpected emotional changes. From unexplained anxiety to sudden intrusive thoughts, there’s a surprising link between concussions, hormones, and mood instability.
When certain structures and pathways within the brain are damaged by a concussion, it can create complications among the body’s hormone production and natural inflammatory response that impact the areas of the brain responsible for mood regulation. To better understand why this happens — and learn how to get unpredictable mood swings under control — just keep reading.
It’s no secret that there’s a possibility you can damage the underlying structures of your brain any time you hit your head. After all, that’s why a concussion is called a traumatic brain injury (TBI)! But what most people don’t know is which parts of the brain primarily become injured… and that’s the true key as to why hormonal dysregulation and mood instability issues spike after a concussion.
When you hit your head, there’s a gland called the hypothalamus that’s particularly vulnerable to injury. The hypothalamus sits directly above the brainstem at the base of your brain and regulates all the hormones in your body. It calculates the number of hormones currently circulating in your bloodstream and makes adjustments by communicating with another brain gland, the pituitary.
Unfortunately, studies have shown that nearly 60% of traumatic brain injuries result in damage to the hypothalamus and/or pituitary gland. When these crucial brain structures become injured due to a concussion, the body becomes more vulnerable to problems with hormone production that can lead to — you guessed it! — problems with mood regulation and mood instability.
Hormone Imbalances and Mood Instability
A little-known side effect of a concussion is a hormonal imbalance, which occurs when your hormone levels get thrown out of whack (or really, whacked out of whack). Hormones are your body’s chief communicators, so when they fall out of balance, communication in your body can go awry. There are two primary types of hormones that can be disrupted after a concussion:
1. Steroid hormones like pregnenolone, progesterone, testosterone, estrogen, and cortisol.
2. Peptide hormones like insulin, vasoactive intestinal peptide (VIP), and gastrin.
Here’s how each type of hormone can impact mood regulation after a concussion.
1. Steroid Hormones and Mood
One of the most common hormonal imbalances that occurs after a concussion is a reduction in pregnenolone production. Pregnenolone is the precursor to all steroid hormones and also acts as a neurosteroid, which means it works to rebuild and regrow the brain after an injury. The body can’t build hormones or repair itself when pregnenolone levels drop, which makes it harder to recover.
Pregnenolone, along with the other steroid hormones it helps produce, all play a role in regulating neurotransmitters. Neurotransmitters, like dopamine and serotonin, are what help the body regulate mood. Once neurotransmitters fail to regulate properly after a concussion, it’s common to experience mood instability that causes you to become anxious, irritable, or completely shut down.
2. Peptide Hormones and Mood
Aside from steroid hormone production, the next most common hormonal imbalance is a reduction in peptide hormones like vasoactive intestinal polypeptide (VIP), which control numerous bodily functions. When these drop low, it actually makes it so that we can’t regulate inflammation in either division of the immune system: the innate immune system or the adaptive immune system.
The innate immune system activates an inflammatory response whenever the body is exposed to a pathogen or virus that it’s never been exposed to before, like the flu. After a few days, the adaptive immune system figures out what the innate immune system’s firing to, builds the necessary antibodies and memory cells, and then brings the previous inflammation back to baseline.
However, the body relies on peptide hormones to regulate the innate immune system. When a concussion reduces hormone production, the body gets stuck in an inflammatory response that can break pathways in the brain — pathways that make it possible to regulate mood. Such micro-structure neurological changes can cause frequent intrusive thoughts and mood swings.
How to Know if a Concussion is to Blame
If you’ve been experiencing mood swings or unexpected emotional changes after a concussion, it’s very likely that hormonal imbalances are to blame. To assess if a concussion has caused issues with hormone production or regulation, we generally start with a quantified electroencephalograph (qEEG) or a digital brain map that evaluates brain function (or in this case, dysfunction).
A qEEG will reveal any signs of hormone instability that may be causing impairment in certain areas of the brain, such as the hypothalamus and pituitary gland. It will also allow us to determine if there is a network engagement problem, which is not only common after prolonged periods of innate immune system inflammation in the brain but is also significantly linked to mood swings.
For further hormone analysis, we’ll conduct blood testing as well as a 24-hour urine assessment, which will allow us to evaluate how the body is producing hormones and how the liver is breaking down and detoxing those hormones. The analysis process will also uncover how hormone levels fluctuate throughout different times of the day for the most optimal treatment plan.
Man laying down in a consult with Corey Deacon
How to Treat Mood Instability After a TBI
The good news is, mood instability following a concussion is very rarely permanent. However, the conventional treatment options on the market today are fairly limited. So, it’s common for people to find when they go on first-line therapies, like oral medications, that only 10 to 25% of them will actually receive therapeutic benefits — primarily the regulation of mood instability.
Fortunately, several non-traditional methods can help. Treatments like functional neurology, neurofeedback, neuromodulation, and even hormone replacement therapy can repair the underlying structural damage and get mood swings under control once and for all. Where conventional treatments may fail, alternative medicine practices have been shown to succeed.
Take control over mood instability.
Has a concussion rocked your world and destroyed your mood with it? Seek guidance from the top-rated post-concussion rehabilitation clinic in Calgary. | {
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1,072,506,320,251,624,000 | Prescription Drugs Anxiety Depression
April 28th is Prescription Drug Take Back Day ; Find out where you can dispose of unused drugs; Disposal of Unused Medicines: What You Should Know
Nov 24, 2015. As the leading advocate for healthy psychotherapy, we are approached daily by people who want advice about psychotropic medication. The most common question people have is whether GoodTherapy.org recommends medication to deal with mental health concerns such as depression, anxiety, and.
“If depression or anxiety is getting in the way of living a full life, medication or therapy can help you feel better.” "Many people who are depressed don’t enjoy socializing anymore. Everything feels futile, like life is over, why bother?
Prescription drug addiction caught media attention in 2010 with the rise of Ambien abuse, though it has been wreaking havoc for decades. Rx abuse is a particularly dangerous epidemic because of.
What’s the difference between anxiety and depression? Learn the difference and why so many people confuse the two.
These thoughts are typically driven by anxiety. Having these intrusive anxious.
Many experts, including the American Psychological Association, believe that the best mental health treatment is a mix of psychotropic medication and therapy.
Nov 16, 2011. When it comes to feeling depressed or anxious, or inattentive, women are more likely to take prescription medication than men, according to a new report from Medco Health Solutions, the pharmacy-benefit manager. One of the more startling statistics in the report, which analyzed prescription claims data.
Dog Anxiety Attack Treatment Gad Symptoms Anger Symptoms of borderline personality disorder include rapid mood changes, anger, aggression. significantly impact your ability to function. Bipolar disorder is sometimes mistaken for an anxiety disorder because anxiety, agitation, and. User registration is done in this screen. User can access the module only after registering it. System will generate a unique registration
It’s worth it because we still live in a society that puts an immense amount of.
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Consumer Reports evaluates the treatment of Anxiety, ADHD, Depression, Insomnia, and PTSD Off-Label with Newer Antipsychotic Drugs.
Misuse of prescription drugs means taking a medication in a manner or dose other than prescribed; taking someone else’s prescription, even if for a legitimate medical complaint such as pain; or taking a medication to feel euphoria (i.e., to get high).
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Compare risks and benefits of common medications used for Depression. Find the most popular drugs, view ratings, user reviews, and more.
Gad Symptoms Anger Symptoms of borderline personality disorder include rapid mood changes, anger, aggression. significantly impact your ability to function. Bipolar disorder is sometimes mistaken for an anxiety disorder because anxiety, agitation, and. User registration is done in this screen. User can access the module only after registering it. System will generate a unique registration code for each
MY EXPERIENCE WITH LEXAPRO (Anxiety and Depression Medication)Non-Prescription Medications for Depression | LIVESTRONG.COM – Aug 14, 2017. Many people with depression are uncomfortable taking a continuous regimen of prescription drugs, and opt to use supplements as a treatment for their. When a person has a deficiency in B vitamins, he can experience symptoms that mimic depression and anxiety such as fatigue, sleep problems, stress.
WebMD provides an overview of drugs commonly used to treat depression and anxiety disorders.
The FDA had initially issued a Refusal to File letter on Mar 30 for the candidate stating that the NDA did not have enough evidence for the oral medication to work. The FDA suggested that additional studies might be required to demonstrate.
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Your email address will not be published. Required fields are marked * | {
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The pineal body (epiphysis) is a small reddish-gray body, about 8 mm. in length which lies in the depression between the superior colliculi. It is attached to the roof of the third ventricle near its junction with the mid-brain. It develops as an outgrowth from the third ventricle of the brain.
In early life it has a glandular structure which reaches its greatest development at about the seventh year. Later, especially after puberty, the glandular tissue gradually disappears and is replaced by connective tissue.
Structure.The pineal body is destitute of nervous substance, and consists of follicles lined by epithelium and enveloped by connective tissue. These follicles contain a variable quantity of gritty material, composed of phosphate and carbonate of calcium, phosphate of magnesium and ammonia, and a little animal matter.
It contains a substance which if injected intravenously causes fall of blood-pressure. It seems probable that the gland furnishes an internal secretion in children that inhibits the development of the reproductive glands since the invasion of the gland in children, by pathological growths which practically destroy the glandular tissue, results in accelerated development of the sexual organs, increased growth of the skeleton and precocious mentality.
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Br J Pharmacol. 1993 Nov;110(3):983-8.
Intracellular calcium in canine cultured tracheal smooth muscle cells is regulated by M3 muscarinic receptors.
Author information
1
Department of Pharmacology, Chang Gung Medical College, Tao-Yuan, Taiwan.
Abstract
1. The regulation of cytosolic Ca2+ concentrations ([Ca2+]i) during exposure to carbachol was measured directly in canine cultured tracheal smooth muscle cells (TSMCs) loaded with fura-2. Stimulation of muscarinic cholinoceptors (muscarinic AChRs) by carbachol produced a dose-dependent rise in [Ca2+]i which was followed by a stable plateau phase. The EC50 values of carbachol for the peak and sustained plateau responses were 0.34 and 0.33 microM, respectively. 2. Atropine (10 microM) prevented all the responses to carbachol, and when added during a response to carbachol, significantly, but not completely decreased [Ca2+]i within 5 s. Therefore, the changes in [Ca2+]i by carbachol were mediated through the muscarinic AChRs. 3. AF-DX 116 (a selective M2 antagonist) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a selective M3 antagonist) inhibited the carbachol-stimulated increase in [Ca2+]i with pKB values of 6.4 and 9.4, respectively, corresponding to low affinity for AF-DX 119 and high affinity for 4-DAMP in antagonizing this response. 4. The plateau elevation of [Ca2+]i was dependent on the presence of external Ca2+. Removal of Ca2+ by the addition of 2 mM EGTA caused the [Ca2+]i to decline rapidly to the resting level. In the absence of external Ca2+, only an initial transient peak of [Ca2+]i was seen which then declined to the resting level; the sustained elevation of [Ca2+]i could then be evoked by the addition of Ca2+ (1.8 mM) in the continued presence of carbachol. 5.Ca2+ influx was required for the changes of [Ca2+]i, since the Ca2+-channel blockers, diltiazem(10 microM), nifedipine (10 microM), verapamil (10 microM) and Ni2+ (5 mM), decreased both the initial and sustained elevation of [Ca2+], in response to carbachol. These Ca2+-channel blockers also decreased the sustained elevation of [Ca2+], when applied during the plateau phase.6. In conclusion, we have demonstrated that the initial detectable increase in carbachol-stimulated[Ca2+]J is due to the release of Ca2+ from internal stores, followed by the flux of external Ca2+ into the cells. This influx of extracellular Ca2+ partially involves an L-type Ca2+-channel. M3 muscarinic receptors appear to mediate the Ca2+ mobilization in canine TSMCs.
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-4,866,743,186,154,804,000 | Health and Beauty
Why take spirulina during a slimming diet?
Weight-loss diets are becoming more popular these days, but losing weight in a healthy and sustainable way can be a challenge. That's why many people turn to spirulina, one of the popular nutritional supplements due to its many health benefits, including its ability to support the diet. Discover how spirulina becomes your ally in losing weight.
What is spirulina?
Spirulina is a blue-green algae known for centuries for its health benefits. Spirulina is rich in essential nutrients such as protein, vitamins, minerals, iron and antioxidants. This nutritional richness is what makes it an interesting dietary supplement for those on a slimming diet.
Be aware that exclusive consumption of this microalgae is not enough for significant weight loss, but it can play an indirect role in promoting fat burning. In reality, Spirulina It will work in different ways on your body to support weight loss.
Spirulina and weight loss: benefits for your body
Spirulina is known to facilitate weight loss, and is particularly recommended to help support a slimming diet thanks to its many benefits.
Eat protein
Spirulina is an excellent source of protein, making it an ideal ingredient if you want to lose weight. In your overall diet, protein is essential for muscle growth and maintaining muscle mass.
When dieting, it's important to retain as much muscle as possible because muscle mass burns more calories than fat, even at rest. By consuming it as an essential supplement to your basic diet, you ensure protein storage.
Appetite suppressant effect
Thanks to its high protein content, spirulina proves to be a naturally satiating food. A high-protein diet can be a valuable ally for weight loss, because the metabolism requires a longer period of time to digest proteins. A feeling of fullness that lasts much longer than if you had eaten a meal consisting mainly of vegetables, for example.
Regulating metabolism
Due to its rich micronutrient composition, spirulina is also known for its benefits on metabolism. The vitamins and minerals in spirulina, such as iron and vitamin B6, play a key role in energy production and fat metabolism. Efficient metabolism promotes fat loss.
Spirulina, an excellent health ally during a slimming diet.
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Managing food intake
On your slimming diet journey, spirulina will help regulate sugar levels and provide you with all the nutrients you need. When the body benefits from all essential nutrients, cravings for snacks and low-nutrition products naturally decrease. An effective way to fight cravings.
Remove toxins from the body
Another property of spirulina is its ability to deeply eliminate toxins from the body. As a dietary supplement, spirulina acts as a powerful detoxifying agent, promoting weight loss.
Spirulina, the miracle algae for weight loss? Spirulina becomes a valuable ally for those looking to achieve lasting results on their weight loss journey. It is important to remember that spirulina cannot replace a healthy, balanced diet or an active lifestyle. It should be used in addition to these items for best results. It is recommended to consult a healthcare professional to determine the best approach to this dietary supplement for your slimming diet.
Why take spirulina during a slimming diet?
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2,534,268,626,495,062,500 | Main> Viagra> How often can soma be perscribed
How often can soma be perscribed
Soma Cheap Cod Soma, a well-known brand name of the drug carisoprodol, is prescribed by doctors in the U. Soma is now a Schedule III or Schedule IV controlled substance in about twenty states, and the DEA may soon make it a Schedule IV drug in all states. <strong>Soma</strong> Cheap Cod
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Fpgec and indinana boared of pharmacy - 02-Pharma-iframe-0000 Carisoprodol, marketed under the brand name Soma among others, is a prescription drug marketed since 1959. Fpgec and indinana boared of pharmacy - 02-Pharma-iframe-0000
How often can soma be perscribed. dea 222 retention new york pharmacy. viagra in the uk. cvs pharmacy broadway 02145
Carisoprodol MedlinePlus Drug Information Question: When Are Muscle Relaxers Prescribed for Arthritis Patients? Carisoprodol MedlinePlus Drug Information
Do not take more or less of it or take it more often than prescribed by your doctor. until you know how carisoprodol affects you. remember that alcohol can add.
Prescription Muscle Relaxers List Healdove Hey guys-Went to my PM on Monday and he informed me that he is no longer allowed to write Soma because it's "bad for you" (what pills aren't anymore rht? Wondering if anyone else has run into this recently? Prescription Muscle Relaxers List Healdove
They are often used for short-term relief of back or neck spasm or stiffness. Sometimes finding the appropriate prescription muscle relaxer can be. My doctor just prescribed me Soma and I experienced bad side effects.
QSlim Simplification Software PRESCRIPTION: Yes GENERIC AVAILABLE: Yes USES: Carisoprodol is used together with rest and physical therapy for the short-term relief of acute painful muscle and skeletal conditions in adults. SIDE EFFECTS: The most common side effects of carisoprodol are: Examine the varying causes of pain. QSlim Simplification Software
This page has moved. I left CMU at the end of July 1999 and am now an assistant professor in the Department of Computer Science at the University of.
SOMA. Anyone use it? Pain may be caused by simple, everyday objects, tasks and activities such as the way you sit, wear your hair, what you eat and many other surprising reasons you are in pain. <b>SOMA</b>. Anyone use it?
I have tried Soma in the past no, it wasn't prescribed to me and that. You could go in and tell your doctor that the other 2 didn't work, and what. However, drs will not usually prescribe it for any long term use anymore.
Smule - Connecting the world through music. Muscle relaxers, AKA "skeletal muscle relaxants," make up an important category of prescription medication useful for the relief of muscle pain and muscle spasms. Smule - Connecting the world through music.
Smule develops music-making apps that connect people Sing! Karaoke, AutoRap, Magic Piano, Guitar. I Am T-Pain, Ocarina, and more
So Long Soma Janaburson's Blog Recently active Soma forums and community discussion threads. I dont seem to get any relief from the pain pill, but... So Long <em>Soma</em> Janaburson's Blog
Soma, a well-known brand name of the drug carisoprodol, is prescribed by doctors in the U. S. as a muscle relaxant. However, it does have the.
Carisoprodol Soma Tablet Side Effects and Dosage - MedicineNet Carisoprodol, a muscle relaxant, is used with rest, physical therapy, and other measures to relax muscles and relieve pain and discomfort caused by strains, sprains, and other muscle injuries. Carisoprodol <strong>Soma</strong> Tablet Side Effects and Dosage - MedicineNet
Carisoprodol Soma is a drug prescribed for the treatment of the relief of. SIDE EFFECTS The most common side effects of carisoprodol are. Pain in the low back can relate to the bony lumbar spine, discs between the.
• Fpgec and indinana boared of pharmacy - 02-Pharma-iframe-0000
• Carisoprodol MedlinePlus Drug Information
• Prescription Muscle Relaxers List Healdove
• How often can soma be perscribed:
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-3,130,758,546,285,233,700 | Regular Physical Activity Is Recommended to Fight Age
If you’re looking for the fountain of youth, the answer may lie in the great outdoors. By putting on a pair of running shoes and heading out for a walk or jog, you can improve your health to fight the visible effects of age.
You may be shocked to find that only 40% of the adult population in the US exercises regularly. And only 25% of Americans have exercised regularly for five or more years.
While a large percentage of young adults engage in physical activity, numbers begin to drop considerably with age. Unfortunately, this sedentary practice is counter intuitive at best. Aging adults who want to remain youthful need exercise most of all to keep that pep in their step and reduce the risk of disease!
Exercise Provides Anti-Aging Benefits
If you need a good reason to get active, think about your health and quality of life. Exercise can provide anti-aging benefits to keep your body in optimal condition so that you look as young as you feel:
1. Improve bone health. Roughly 25 million Americans suffer from osteoporosis, a disease that results in severe bone loss. Regular physical activity with age can strengthen bone density to reduce the risk of fractures and breaks caused by day-to-day movement. Even if you have already lost bone density due to osteoporosis, you can build some of it back through strength training and high-intensity aerobic exercises like walking and jogging.
2. Strengthen cardiovascular health. The leading health-related cause of mortality for both men and women in the US is heart disease. Supporting cardiovascular health can be achieved with regular exercise, reducing the risk of cardiovascular disease by up to 50% in men. When exercise is used in combination with a heart-healthy diet, a low-stress lifestyle, and not smoking, it can significantly increase longevity.
3. Boost memory. To fight the effects of dementia associated with age, exercise can help to trigger new brain cell formation. As areas of the brain are stimulated through regular exercise, it can help to support both memory and learning. Older adults who exercise regularly have performed better in tests related to problem solving, memory, and decision-making.
4. Fight depression. Regular exercise can help to improve mental health and will reduce symptoms of depression. In fact, the antidepressant effects of consistent physical activity can be compared to prescription antidepressants like Zoloft. For the best results, exercise for a half hour 3 to 5 days per week to improve mental health and ease depression.
5. Sleep better at night. With age, many people struggle with restless nights of sleep. Fortunately, staying active each day can make a world of difference. After exercising, body temperatures will naturally dip 5 to 6 hours later, which can help to aid in a sound night of rest.
When you make exercise a priority, you can stay youthful, regardless of your age. Adults who are looking for a new, interesting way to get fit can join a local soccer team to burn calories, build muscle, improve flexibility, and boost cardiovascular health.
Darcey Deeds is a freelance writer out of Austin, Texas. She currently has teamed up with Avila Soccer which is the leader in Winter Soccer Camp Austin for both kids and adults.
Article Source: http://EzineArticles.com/expert/Darcey_Deeds/1405530
Article Source: http://EzineArticles.com/7339876
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-8,857,366,859,329,699,000 | How do you use little remedies gas relief drops?
How do you use little remedies gas relief drops?
Use the special measuring device/dropper to give the liquid by mouth. Try to give it slowly, aiming for the side of the inside cheek to prevent spitting or choking. The dosage may also be added to 1 ounce (30 milliliters) of cool water, infant formula, or juice. Mix well and give the liquid right away.
Do you give gas drops before or after feeding?
It may be necessary to give a baby gas drops right before each feed if this helps protect it from gas problems, but make sure to consult your pediatrician. Keep a close eye on the bottle and be sure there aren’t any drops containing sodium benzoate or benzoic acid. These acids can be harmful to your baby.
How long does it take for Little Remedies gas drops to work?
Little Remedies Gas Relief Drops with simethicone help break down the gas bubbles in baby’s tummy and can provide relief from gas in minutes. The drops can easily be administered orally or mixed in formula or water up to 12 doses a day.
How many times can you use Little Remedies gas drops?
Directions. All dosages may be repeated as needed, after meals and at bedtime or as directed by a physician. Do not exceed 12 doses per day.
Do infant gas drops help with spitting up?
However, if your colicky baby swallows too much air, it may cause gas, which can add to their discomfort. In that case, Mylicon gas drops can help break up gas bubbles to help your baby pass them as they normally would. If you have a colicky baby, you may want to give our Infants’ Mylicon Daily Probiotic Drops a try.
How often can I give newborn gas drops?
Simethicone gas drops (such as Mylicon, Little Tummys gas relief drops, and Phazyme) are thought to be safe to give—as often as 12 times a day, if necessary—and many parents do just that.
Is it OK to give baby gas drops daily?
Can you give a baby gas drops every day?
It is safe to use every day. If gas drops make your baby feel better, you can continue using them. When you choose gas drops, however, check the ingredient information, and avoid drops that contain sodium benzoate or benzoic acid. These substances can be harmful to babies in large quantities.
Do baby gas drops work instantly?
Infants’ Mylicon Gas Relief Drops work quickly to break down gas bubbles to help your baby naturally expel them by either burping or tooting. They’re safe to give infants—even the newest of newborns—at every feeding, up to 12 times a day.
Do gas drops make a baby sleep?
They work quickly to break gas bubbles up to help your baby naturally expel them. And the active ingredient, simethicone, won’t stay in their system, it’s not even absorbed. So, rest easy, you two—and sleep well.
Can babies have gripe water and gas drops at the same time?
We recommend trying Little Remedies® Gas Relief Drops if your baby is just gassy and see how they respond. You may add Little Remedies® Gripe Water to the mix as well if they have hiccups and/or seem to be irritable at times.
Can you put little remedies gas drops in breast milk?
Gas drops explained Examples of available gas drops for babies include Little Tummys Gas Relief Drops, Phazyme, and Mylicon. The drops can be mixed in water, formula, or breast milk and given to baby. Gas drops are generally considered safe for use in babies unless a baby is being given thyroid hormone medications.
What are Little Remedies® gas relief drops?
Little Remedies® Gas Relief Drops 1 Relieves excess gas from food or swallowing of air 2 No alcohol, parabens, artificial dyes, or artificial flavors 3 Pediatrician Recommended More
How do you use little tummys gas relief suspension?
How to use Little Tummys Gas Relief Suspension. Fill the dropper to the correct dosage and squeeze the liquid slowly into the baby’s mouth, towards the inner cheek. You can also measure the correct dosage with the dropper and mix it in 1 ounce of cool water, infant formula, or juice. Mix well and give the solution to your baby.
What to do if you overdose on gas drops?
Little Remedies Gas Relief Drops Drug Facts Simethicone Emulsion USP 66.7 mg/ Simethicone 20 mg Antigas Relieves discomfort of infant gas frequently caused by excessive swallowing of air or certain formulas or food. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away.
Does little remedies gripe water help with gas?
Little Remedies® Gripe Water. Gently relieves stomach discomfort from gas, colic, and hiccups*. *This statement has not been evaluated by the Food and Drug Administration (FDA). This product is not intended to diagnose, treat, cure or prevent any disease.
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-1,963,564,975,269,357,000 | Skip to main content
Selective proliferative response of microglia to alternative polarization signals
Abstract
Background
Microglia are resident myeloid cells of the central nervous system (CNS) that are maintained by self-renewal and actively participate in tissue homeostasis and immune defense. Under the influence of endogenous or pathological signals, microglia undertake biochemical transformations that are schematically classified as the pro-inflammatory M1 phenotype and the alternatively activated M2 state. Dysregulated proliferation of M1-activated microglia has detrimental effects, while an increased number of microglia with the alternative, pro-resolving phenotype might be beneficial in brain pathologies; however, the proliferative response of microglia to M2 signals is not yet known. We thus evaluated the ability of interleukin-4 (IL-4), a typical M2 and proliferative signal for peripheral macrophages, to induce microglia proliferation and compared it with other proliferative and M2 polarizing stimuli for macrophages, namely colony-stimulating factor-1 (CSF-1) and the estrogen hormone, 17β-estradiol (E2).
Methods
Recombinant IL-4 was delivered to the brain of adult mice by intracerebroventricular (i.c.v.) injection; whole brain areas or ex vivo-sorted microglia were analyzed by real-time PCR for assessing the mRNA levels of genes related with cell proliferation (Ki67, CDK-1, and CcnB2) and M2 polarization (Arg1, Fizz1, Ym-1) or by FACS analyses of in vivo BrdU incorporation in microglia. Primary cultures of microglia and astrocytes were also tested for proliferative effects.
Results
Our results show that IL-4 only slightly modified the expression of cell cycle-related genes in some brain areas but not in microglia, where it strongly enhanced M2 gene expression; on the contrary, brain delivery of CSF-1 triggered proliferation as well as M2 polarization of microglia both in vivo and in vitro. Similar to IL-4, the systemic E2 administration failed to induce microglia proliferation while it increased M2 gene expression.
Conclusions
Our data show that, in contrast to the wider responsiveness of peripheral macrophages, microglia proliferation is stimulated by selected M2 polarizing stimuli suggesting a role for the local microenvironment and developmental origin of tissue macrophages in regulating self-renewal following alternative activating stimuli.
Background
Microglia are the resident population of innate immune cells of the central nervous system (CNS), representing up to 10% of total brain cells, with differences in cell density depending on the brain area [1]. It has been demonstrated that microglia derive from yolk sac progenitors that colonize the neuroepithelium in early stages of embryogenesis [2] and are maintained by self-renewal from embryonal to adult life by constant and rapid cell turnover, without the contribution of circulating monocytes [3,4,5].
Under physiological conditions, microglia display a ramified shape and actively sustain neuronal activity. In analogy to peripheral tissue macrophages, micro-environmental and pathogenic stimuli activate microglia to acquire different immunometabolic properties that are schematically defined as classical, or “M1,” activation phenotype that is induced by bacterial or immune molecules, such as lipopolysaccharide (LPS) or TNFα, and promotes an inflammatory cytotoxic response; an alternative, “M2” phenotype that is activated in response to stimuli, such as interleukin (IL)-4 and IL-13, and allows tissue repair and resolution of inflammation [6]. Although M1- and M2-like activation phenotypes have been described in chronic brain diseases, still debated are their specific mediators and functions during neurotoxicity.
Recently, it has been hypothesized that dysregulated proliferation of microglia plays a detrimental role on neuronal cell viability, as shown in the case of experimental models of neurodegenerative disorders, such as Alzheimer’s disease [7,8,9], amyotrophic lateral sclerosis [10, 11], and Huntington’s disease [12], as well as acute CNS injuries [13, 14]. M1-activating stimuli were demonstrated to induce microglia proliferation [15, 16], while the ability of microglia to proliferate in response to M2 signals has not been addressed yet. On the contrary, IL-4 has been recently shown to induce peripheral macrophage proliferation [17]; moreover, brain IL-4 levels may increase during pathological events, while administration of this molecule associates with beneficial effects on neuronal survival [18,19,20,21]; thus, promoting proliferation of microglia endowed with pro-resolving properties may have beneficial effects on disease progression and offer new therapeutic strategies to selectively modulate disease outcome. Interestingly, also endocrine signals such as the sex steroid hormone 17β-estradiol (E2) were shown to modulate the phenotypic activation and to induce proliferation of peritoneal macrophages in vivo, exerting anti-inflammatory effects also in diverse macrophage populations including microglia [22, 23].
The aim of this study was thus to assess whether the M2-like polarization effects of IL-4 in microglia are associated with a proliferative response. To this purpose, we analyzed cell proliferation in the mouse brain following the intracerebroventricular (i.c.v.) injection of IL-4, an in vivo method that efficiently induces alternative activation of microglia [24]. Our data show that, differently from peripheral macrophages, microglia do not proliferate in response to IL-4; similarly, E2 polarizing effects in microglia are not associated with cell proliferation, which is instead induced by colony-stimulating factor-1 (CSF-1), a typical macrophage growth factor that also induces M2 polarization effects.
Methods
Animals and treatments
C57BL/6 female mice of 4 months of age were supplied by Charles River Laboratories (Calco, Italy). Animals were allowed to food and water access ad libitum and kept in temperature-controlled facilities on a 12-h light and dark cycle. Animals were housed in the animal care facility of the Department of Pharmacological and Biomolecular Sciences at the University of Milan.
Animal investigation has been conducted in accordance with the ethical standards and according to the Declaration of Helsinki and according to the Guide for the Care and Use of Laboratory Animals, as adopted and promulgated by the US National Institute of Health, and in accordance with the European Guidelines for Animal Care and Use of Experimental Animals.
Female mice identified in metaestrous phase were selected for our analyses; the phase of the reproductive cycle in female mice was assessed by blind analysis of vaginal smears mounted on glass microscope slides and stained with May-Grünwald-Giemsa method (MGG Quick Stain Kit; Bio-Optica, Milan, Italy) according to the manufacturer’s protocol.
Mice were injected i.p. with 100 μl of 0.9% NaCl containing 5 μg of mouse recombinant IL-4 (Peprotech, London, UK). 17β-estradiol (E2; Sigma-Aldrich Corp., Milan, Italy) was administered by a 100-μL subcutaneous (s.c.) injection of 5 μg/kg E2 dissolved in corn oil by stirring in the dark and at room temperature o/n.
For in vivo BrdU labeling experiments, mice were injected i.p. with 30 μl of a 10 mg/ml solution of BrdU (Sigma-Aldrich) dissolved in 0.9% NaCl. Animals were sacrificed 2 h after BrdU injection (n = 6).
Two-day-old newborn rats (CD rats, Charles River) were supplied by Charles River Laboratories for the preparation of microglia and astrocytes primary cultures.
Intracerebroventricular injection
Intracerebroventricular (i.c.v.) injections were performed as previously described [24]. Briefly, mice were anesthetized with a s.c. injection of a ketamine/xylazine solution (78 and 6 mg/kg, respectively) and positioned on a specific stand for surgical operation. Injections in the third cerebral ventricle were performed according to specific stereotaxic coordinates (bregma, − 0.25 mm; lateral, 1 mm; depth, 2.25 mm). IL-4 was injected at the concentration of 5 μg in 3.0 μl of 0.9% NaCl for expression studies on purified adult microglia or 250 ng in 2.5 μl 0.9% NaCl for all other experiments; CSF-1 (Peprotech) was injected at the concentration of 1 μg in 3 μl of 0.9% NaCl. Animals injected with the same volume of vehicle alone (0.9% NaCl) were used as controls. Injections were made using a 26S–gauge Hamilton syringe at a rate of 0.1 μl/3 s, and the needle was kept in place for additional 30 s and then removed slowly. The skin incision was closed with a suture and animals were allowed to recover for 24 h before sacrifice by a lethal ketamine/xylazine solution (150 and 12 mg/kg, respectively). Whole brains were removed and immediately processed for microglia isolation; brain areas (frontal cortex, hippocampus, and striatum of left hemisphere, ipsilateral to the injection site) were collected, immediately frozen on dry ice, and stored at − 80 °C until processed for RNA preparation. Whole brains were fixed in 4% formalin solution and stored until processed for immunohistochemistry.
Isolation of peritoneal macrophages
After 24 h of IL-4 or vehicle i.p. injections, peritoneal cells were isolated by peritoneal lavage and incubated with anti-CD11b antibody-loaded MicroBeads (Miltenyi Biotec, Bologna, Italy), as previously described [22]. Briefly, 5 ml of pre-chilled 0.9% NaCl were injected into the peritoneal cavity using a 21 G needle; cell suspension was recovered and centrifuged; following incubation with ammonium-chloride-potassium (ACK) solution (0.15 M NH4Cl, 1 mM KHCO3, 0.1 mM EDTA; pH 7.3) for 5 min at 4 °C, cells were either plated and treated as described in the primary cell culture section or incubated with cd11b beads for macrophage purification. For cd11b+ cell isolation, after washing with PBS + 0.5% BSA, cells were resuspended in 90 μL PBS + 0.5% BSA and incubated with 10 μL CD11b MicroBeads for 15 min at 4 °C. After washing, cells were resuspended in 500 uL PBS + 0.5% BSA and applied to MS Miltenyi columns (Miltenyi Biotec) for the magnetic separation procedure. After three washing steps, CD11b-positive cells were eluted from the columns and counted. CD11b-positive cells obtained from each animal were divided into three aliquots; two aliquots of 2.5 × 105 cells each were used to detect BrdU and Ki67 by flow cytometry, the remaining aliquot was stored in TRIzol reagent (Invitrogen-Thermo Fisher Scientific, Milan, Italy) and used for gene expression studies.
Isolation of microglia from adult brains
After i.c.v. treatments, microglia cells were sorted from adult brains (n = 4), as previously described [24]. Briefly, whole brains were dissected and washed in Hank’s balanced salt solution (HBSS; Life Technologies-Thermo Fisher Scientific); after removing the meninges, enzymatic cell dissociation was performed using Neural Tissue Dissociation Kit P (Miltenyi Biotec), with some protocol modifications: after enzymatic digestion with papain, samples were dissociated mechanically, homogenized, and filtered through a 40-μm cell strainer. After extensive washes in HBSS, myelin was removed by suspending samples in 10 ml of cold 0.9 M sucrose solution and centrifuging the dissociated brain cells at 850g and 4 °C for 10 min without braking. Floating myelin and the supernatant were discarded, and cells were processed for microglia magnetic sorting by incubating with CD11b MicroBeads (diluted 1:10 in PBS + 0.5% BSA; Miltenyi Biotec) for 15 min at 4 °C; after washing, cells were suspended in 500 μl of PBS + 0.5% BSA and applied to a magnetic column to purify CD11b+ cells. Immediately after isolation, cells were stored in TRIzol reagent (Invitrogen-Thermo Fisher Scientific) for gene expression.
Primary cell cultures
Peritoneal macrophages
For in vitro assay, peritoneal cells were incubated with ACK solution, as described above, counted, and seeded at the concentration of 1 × 106 cells/ml in RPMI + GlutaMax (Gibco™-Thermo Fisher Scientific) supplemented with 10% endotoxin-free FBS, 1% penicillin/streptomycin, and 1% Na pyruvate (RPMI + 10% FBS). After 45 min and several washes in PBS, medium was replaced with RPMI + 10% FBS for IL-4 and CSF-1 treatment and in RPMI w/o phenol red supplemented with 10% dextran-coated charcoal (DCC)-FBS (RPMI + 10% DCC) for E2 treatment. After 3 h, cells were treated for 16 h with vehicle or 20 ng/ml of recombinant murine IL-4 or 20 ng/ml of recombinant murine CSF-1. For estrogen treatment, cells were treated on the next day for 3 h with vehicle (0.01% ethanol (EtOH)) or E2 105 M.
Astrocytes and microglia cell cultures
Primary cultures of glial cells were prepared from 2-day-old newborn rats as previously described [25]. After meninges removal, brains were mechanically dissociated and digested in a solution of 2.5% trypsin (Sigma-Aldrich) and 1% DNAse (Sigma-Aldrich), filtered through a 100-μm cell strainer, and seeded at the confluence of 5 × 106 in a 75-cm2 flask in minimum essential Eagle’s medium (MEM) supplemented with 10% FBS, 0.6% glucose, 1% penicillin and streptomycin, and 1% L-glutammine (MEM + 10% FBS). Glial cells were grown at 37 °C under a humidified 5% CO2 and 95% air atmosphere, and medium was replaced every 3 days. After 10 days, microglia were obtained by shaking the confluent monolayer of mixed glial cells at 260 rpm for 2 h and seeded in 12-well plates at the confluence of 5 × 105 cells/well. The medium was changed with MEM + 15% FBS or MEM + 5% FBS 30 min after microglia plating in order to remove contaminating cells. In order to purify astrocytes, enriched astroglia cultures following microglia separation were incubated with 5 mM L-leucine methyl ester (Sigma-Aldrich) to eliminate contaminating microglia cells and seeded in six-well plates at the confluence of 5 × 105 cells/well in MEM + 15% FBS or MEM + 5% FBS.
Astrocytes and microglia were treated for 16 h with 20 ng/ml of recombinant rat IL-4, 20 ng/ml of recombinant rat CSF-1 or vehicle. For in vitro proliferation assay, cells were treated with 10 μM BrdU for 2 h before cell processing for flow cytometry analysis.
Flow cytometry analysis
For Ki67 staining, cells were fixed in 4% paraformaldehyde for 15 min, extensively washed with 125 mM glycine in PBS and permeabilized o/n in PBS containing 0.5% Triton X-100 and 1% BSA, at 4 °C. Cells were incubated with rabbit anti-mouse Ki67 antibody conjugated with eFluor660 (Affymetrix eBioscience, Milan, Italy) diluted 1:100 in incubation solution (PBS containing 0.5% Triton X-100 and 0.05% BSA) at room temperature for 1 h. After extensive washes in PBS, cells were analyzed with a flow cytometry system (NovoCyte® 3000 flow cytometer, ACEA Biosciences, San Diego, CA) and analyzed with NovoExpress® Software (ACEA Biosciences).
For BrdU staining, ex vivo peritoneal cells or in vitro primary cells, detached by 0.25% Trypsin-EDTA (Life Technology) for astrocytes or Accutase (Merck-Millipore, Vimodrone (MI), Italy) for microglia, were fixed and permeabilized in 70% EtOH for 30 min at 4 °C and DNA was denaturated with 2 N HCl/0.5% Triton X-100 and incubated 30 min at room temperature. Cells were washed with 0.1 M sodium tetraborate (pH 8.5) and incubated with rat anti BrdU antibody (AbD Serotec—Bio-Rad, Segrate, Italy) diluted 1:100 in incubation solution (PBS containing 0.05% Tween-20 and 1% BSA). After washes in PBS + 1% BSA, cells were incubated with Alexa647-conjugated goat anti-rat secondary antibody (1:200 in incubation solution; Molecular Probes, Monza, Italy) for 1 h at room temperature. After extensively washing with PBS, ex vivo peritoneal macrophages were resuspended in PI solution (H2O containing 10% NP40, 1 mg/ml RNase A and 5 μg/ml PI stock; Sigma-Aldrich), instead primary cells were resuspended in PBS. Samples were analyzed using NovoCyte® 3000 flow cytometer and analyzed with NovoExpress® Software (ACEA Biosciences). Animals with no pulse of BrdU and in vitro samples without BrdU treatment were used for gating strategy to evaluate non-specific signals. Doublets were removed based on FL2 scatter width (FL2-W)/FL2 scatter area (FL2-A).
RNA preparation and expression analyses
Following 24 h of vehicle or IL-4 (250 ng) i.c.v. treatment, brain area (frontal cortex, striatum, and hippocampus) were first homogenized using steel beads and tissue Lyser (Qiagen, Milan, Italy) at 28 Hz, for three cycles of 20 s followed by 30 s, on ice and in RLT buffer. Total RNA from tissue or cells was purified using RNeasy minikit protocol (Qiagen), according to the manufacturer’s instructions, including a step with deoxyribonuclease incubation. For real-time PCR, 1 μg RNA (500 ng for striatum and primary cultures, 100 ng for isolated microglia, 300 ng for ex vivo peritoneal macrophages) was used for cDNA preparation using 8 U/μl of Moloney murine leukemia virus reverse transcriptase (Promega, Milan, Italy) in a final volume of 25 μl; the reaction was performed at 37 °C for 1 h, and the enzyme inactivated at 75 °C for 5 min. Control reactions without the addition of the reverse transcription enzyme were performed (data not shown). A 1:4 cDNA dilution was amplified using GoTaq®qPCR Master Mix technology (Promega) according to the manufacturer’s protocol. The PCR was carried out in triplicate on a 96-well plate using QuantStudio® 3 real-time PCR system (Applied Biosystems-Thermo Fisher Scientific) with the following thermal profile: 2 min at 95 °C; 40 cycles, 15 s at 95 °C, 1 min at 60 °C. Primer sequences are reported in Additional file 1: Table S1. Data were analyzed using the 2−ΔΔCt method.
Immunohistochemistry
Brains were trimmed using a brain matrix (Adult Mouse Brain Slicer Matrix BSMAS005-1, Zivic Instruments, Pittsburgh, PA, USA), and sections were routinely processed, paraffin embedded, and sectioned in 4-μm serial sections. After heat-induced epitope retrieval, performed in Dewax and HIER Buffer H (TA-100-DHBH, Thermofisher Scientific, Waltham, MA, USA) for 40 min at 94 °C, sections were incubated with a 10% normal goat serum for non-specific binding blocking. Sections were immunostained with rabbit polyclonal anti-Ki67 antibody (Clone SP6, Thermo Fisher Scientific, Waltham, MA, USA), incubated with biotinylated goat anti-rabbit secondary antibodies (VC-BA-1000-MM15, Vector Laboratories, Peterborough, UK) and labeled by the avidin-biotin-peroxidase procedure with a commercial immunoperoxidase kit (VECTASTAIN® Elite ABC-Peroxidase Kit Standard, VC-PK-6100-KI01, Vector Laboratories). The immunoreaction was visualized with DAB (Peroxidase DAB Substrate Kit, VC-SK-4100-KI01, Vector Laboratories) substrate, and sections were counterstained with Mayer’s hematoxylin (C0302, Diapath, Italy). Digital image analysis was performed by scoring the number of Ki67-positive cells in three ×400 microscopic fields in the parenchyma of vehicle, IL-4 and CSF-1-treated mice (n = 3); monocyte-like cells were excluded from the analysis. For double immune-fluorescence analysis, after heat-induced antigen retrieval in Dewax and HIER BufferH pH 9 (Thermofisher Scientific) and anti-ki67 antibody (RM-9106, Thermofisher Scientific) incubation, goat anti-rabbit green fluorescent antibody (Alexa Fluor 488, Thermo Fisher Scientific) was used; after washing with PBS, sections were re-incubated with anti-GFAP (Z0334, from DAKO Agilent, Santa Clara, CA, USA) or anti-Iba1 (Wako Chemicals USA, Richmond, VA) for 1 h at room temperature followed by a goat anti-rabbit red fluorescent secondary antibody (Alexa Fluor 555, Thermo Fisher scientific). Sections were mounted on coverslips with ProLong Gold Antifade mountant with DAPI (P36941, Thermofisher Scientific).
Statistical analyses
Unless otherwise stated, all values are expressed as mean ± standard error of the mean (SEM) of n observations. The results were analyzed by the Student unpaired two-tailed t test using GraphPad Prism 5 software, after a normality test (Kolmogorov-Smirnov) [26]. A value of p < 0.05 was considered significant.
Results
Peritoneal macrophage proliferation following the local delivery of IL-4
In order to analyze the proliferative activity of IL-4 in the brain, we first set up in vivo proliferative assays on macrophages in the peritoneum, a peripheral tissue where resident macrophages were shown to increase in number in response to this immune signal [17]. Peritoneal macrophages were collected from the peritoneal lavage of mice 24 h after an i.p. injection of IL-4 and further purified by immunosorting; a control group of mice were injected with vehicle alone. As shown in Fig. 1a, the levels of mRNA coding for proteins related with proliferation (Ki67) and cell cycle (CcnB2 and Cdk1) were increased following IL-4 injection as compared to control mice, suggesting a proliferative effect of IL-4; as expected, the expression of M2 genes, namely Arg1, Fizz1, and Ym1, was also strongly induced by IL-4 (see Fig. 1b).
Fig. 1
figure 1
Expression of cell cycle and M2 polarization genes in peritoneal macrophages following IL-4 treatment in vivo. The expression of genes related with a cell proliferation (Ki67, Cdk1, and CcnB2) and b M2 alternative polarization (Arg1, Fizz1, and Ym1) was analyzed by real-time PCR in peritoneal macrophages isolated from mice treated i.p. with vehicle (veh) or 5 μg IL-4 for 24 h. Data sets for each gene were calculated using the 2-ddCt method with respect to the mean value of the vehicle group. Bars represent mean values ± SEM (n = 2–6). Student’s unpaired t test, *p < 0.05; **p < 0.01; ***p < 0.001 versus veh
In order to confirm the effect of IL-4 on cell cycle entry and DNA synthesis, FACS analyses were conducted on peritoneal macrophages to evaluate Ki67 protein levels and BrdU incorporation, respectively. The results shown in Fig. 2 demonstrate that IL-4 is a proliferative signal for peritoneal macrophages, leading to an increase in ki67-positive and in duplicating peritoneal macrophages of 10 and 6%, respectively. Accordingly, the number of recovered macrophages from peritoneal fluid was more elevated in IL-4-treated mice (data not shown).
Fig. 2
figure 2
Proliferation of peritoneal macrophages following IL-4 treatment in vivo. Ki67 protein expression (a, b) and BrdU incorporation (c, d) were analyzed in peritoneal macrophages isolated from mice treated i.p. with vehicle (veh) or 5 μg IL-4 for 24 h. a, c show representative dot plots depicting gating schemes for Ki67 and BrdU analyses, respectively. Bar charts represent the percentage of macrophages showing a positive signal for Ki67 (b) or BrdU (d) with respect to the total number of macrophages obtained from each mouse following the specified treatment. Bars represent the mean ± SEM of six mice per group. Student’s unpaired t test, ***p < 0.001
Altogether, these results show that locally delivered IL-4 is a proliferative signal for peritoneal macrophages.
Brain delivery of IL-4 has limited effects on brain cell proliferation
We then extended our observation to evaluate the proliferative response of microglia following IL-4 injection in the cerebral ventricles of mice. Cell cycle gene expression was analyzed by real-time PCR in diverse brain areas and, unexpectedly, the mRNA levels coding for Cdk1 and Ki67 were only slightly increased by IL-4, with a twofold induction compared to control samples in the cortex and hippocampus and not in the striatum, while Ccnb2 expression was not modified in any brain areas analyzed (see Fig. 3a). On the other hand, the i.c.v. injection of IL-4 induced the expression of M2 polarization signals, as shown in Fig. 3b: a strong induction of Arg1, Fizz1, and YM-1 mRNAs was generally observed in all brain areas with different region-specific intensities, as already reported [24]. Thus, IL-4-induced polarization is associated with little proliferative effects in the brain.
Fig. 3
figure 3
Brain expression of cell cycle and M2 polarization genes following local delivery of IL-4. Mice were injected i.c.v. with vehicle (veh) or 250 ng IL-4; the cortex, striatum, and hippocampus were isolated and analyzed by real-time PCR for the expression of genes related with a cell cycle (Ki67, CcnB2, and Cdk1) and b M2 alternative polarization (Arg1, Fizz1, and Ym1). Data sets for each gene were calculated using the 2-ddCt method with respect to the mean value of the vehicle group. Bars represent mean values ± SEM (n = 5). Student’s unpaired t test, *p < 0.05; **p < 0.01 versus veh
To further investigate brain cell proliferation following IL-4, we analyzed Ki67 protein expression by immunohistochemistry. The results are reported in Fig. 4 and show that some Ki67-positive cells were present in the cortex and even more in the hippocampus of vehicle-treated mice, while no positively stained cells were detected in the striatum (data not shown); in this experimental conditions, we calculated that Ki67-positive cells are about 1 and 2.7% of total parenchymal cells in the cortex and hippocampus, respectively (see Fig. 4g); IL-4 administration resulted in a statistically significant increase in Ki67-positive cells in the cortex and hippocampus, while no signal was detected in the striatum (see Fig. 4). The morphological appearance of most of the Ki67-positive cells did not recall the microglial cell shape, both in vehicle- and IL-4-treated brains.
Fig. 4
figure 4
Ki67 protein expression in brain areas following local delivery of IL-4 and CSF-1. Following the i.c.v. injection of vehicle (veh; a, d), 250 ng IL-4 (b, e, and h) and 1 μg CSF-1 (C, F and J) brains were processed by immunohistochemistry to visualize Ki67 expression. Images were taken from the cortex (ac) and hippocampus (df) of mice. Histograms in g show the quantification of the percentage of Ki67-positive cells with respect to the total number of cells in brain areas, as specified; h, j monocyte-like cells were detected in brain vessels from IL-4- and CSF-1-treated mice, respectively and excluded from the counting. Bars represent mean values ± SEM (n = 3). Student’s unpaired t test, *p < 0.05 versus veh; ° p < 0.05 versus IL-4. Scale bar, 100 μm
It is known that tissue microenvironment substantially shapes macrophage responsiveness. In order to exclude the possibility that general brain-specific mechanisms could silence proliferative signaling pathways in microglia under non-pathological conditions, we evaluated the activity of CSF-1, the best-known proliferative agent for macrophages. Fig. 4c, f shows that the i.c.v delivery of CSF-1 triggers the proliferation of brain cells, some of which displaying a microglia-like morphology, and results in a fivefold increase in ki67-positive cells in the cortex and hippocampus with respect to vehicle and twofold in the striatum, effects that are also significantly different from those obtained with IL-4 (see Fig. 4g). In addition, some Ki67-positive monocyte-like cells were observed in brain vessels after both IL-4 and CSF-1 treatments (see Fig. 4e, j), suggestive of the recruitment of proliferating monocytes.
Altogether, these data show that, in the adult mouse brain, an increase in IL-4 level does not associate with a proliferative response and suggest that this molecule might not be a proliferative signal for microglia, differently from its effects on peritoneal macrophages.
Proliferative activity of M2 polarization signals on microglia in vivo and in vitro
Since microglia represent only 10% of all brain cells, and considering the restricted percentage of IL-4 responder cells in terms of proliferation in the periphery (see Fig. 2), we evaluated whether the mild proliferative response reported in Fig. 3a could be ascribed to a small subset of microglia. Microglia were purified from the brain of vehicle or IL-4-injected mice and analyzed for proliferative parameters. Notably, Ki67 and cell cycle mRNA levels were not increased in response to i.c.v. IL-4, as shown in Fig. 5a; on the contrary, increased levels of mRNA coding for proteins related with M2 polarization (Arg1, Fizz1, and Ym1) were detected in microglia purified from IL-4 as compared to vehicle-treated mice. These results suggest that brain cells other than microglia are induced to moderately proliferate in response to IL-4.
Fig. 5
figure 5
In vivo effects of M2 polarization signals on microglia gene expression. Microglia were isolated by immunosorting 24 h after a i.c.v. injections of vehicle (veh; open boxes), 5 μg IL-4 (closed boxes) or 1 μg CSF-1 (gray boxes) or b s.c. 17β-estradiol (E2) treatment (5 μg/kg). The expression of genes related with active replication and cell cycle (Ki67; Cdk1, Ccnb2) and M2 alternative polarization (Arg1, Fizz1, Ym1) was analyzed by real-time PCR. Data sets for each gene were calculated using the 2-ddCt method with respect to the mean value of the vehicle group. Bars represent mean values ± SEM (n = 4). Student’s unpaired t test, *p < 0.05; **p < 0.01; ***p < 0.001 versus veh
On the contrary, CSF-1 brain delivery resulted in a significantly increased expression of genes related with proliferation and cell cycle specifically in microglia, as shown in Fig. 5a; as expected since CSF-1 is endowed with M2 polarization effects, we observed a parallel enhancement of M2 polarization genes such as Arg1, Fizz 1, and Ym1.
We then asked whether 17-beta-estradiol (E2), a lipophilic hormone that reduces microglia inflammatory phenotype, could alter microglia proliferation in line with the recent observation on its proliferative effect on peripheral macrophages [22, 23, 27, 28]. Similar to what is observed with IL-4, systemic administration of physiological doses of E2 caused a significant increase in the mRNA coding for Fizz1 and Ym1 in microglia, while cell cycle genes were unaffected (Fig. 5b).
Thus, these data show that under homeostatic conditions, microglia can proliferate in response to some M2-activating signals, such as CSF-1, but not IL-4 and E2.
During the perinatal period, microglia proliferation and development are strongly active processes; we thus asked whether IL-4 might associate with proliferative effects on microglia from this developmental stage. As shown in Fig. 6a, IL-4 treatment of microglia primary cultures from newborn animals did not modify Ki67 and Cdk1 expression, while CSF-1 still resulted in increased Ki67 and Cdk1 mRNA levels. The ability of microglia to proliferate in response to CSF-1 was further demonstrated by BrdU incorporation analyses as a biological evidence of proliferation, while no signs of proliferation were observed following IL-4 under different experimental conditions such as reduced serum concentrations (see Fig. 6b). Gene expression analyses demonstrated that the alternative phenotype is induced in these cells by IL-4 and CSF-1, although with different intensities (see Additional file 2: Figure S1A). Lack of a proliferative response of microglia could not be ascribed to a reduced sensibility of microglia, since the expression of the IL-4 receptor (IL-4Rα) in ex vivo-sorted or in vitro microglia did not vary in response to IL-4 (see Additional file 2: Figure S1B). We also tried to extend our observation to other primary macrophages obtained from adult animals; however, CSF-1 as well as IL-4 and E2 failed to induce proliferation of peritoneal macrophages while still retaining their polarization effects (see Additional file 3: Figure S2), in agreement with recent observation using similar experimental conditions [22, 29].
Fig. 6
figure 6
Proliferative responses of primary cultures of microglia and astrocytes. a The expression of proliferation genes (Ki67 and Cdk1) was analyzed in primary cultures of microglia and astrocytes following vehicle (veh; open boxes), 20 ng/ml IL-4 (closed boxes) or 20 ng/ml CSF-1 (gray boxes) treatments. Bars represent the mean ± SEM of three independent experiments, each performed in triplicate. Data sets for each gene were calculated using the 2-ddCt method with respect to the mean value of the vehicle group. Bars represent mean values ± SEM (n = 3). Student’s unpaired t test, **p < 0.01; ***p < 0.001. b BrdU incorporation was evaluated by flow cytometry in microglia and astrocytes treated with 20 ng/ml IL-4 (closed boxes) or 20 ng/ml CSF-1 (gray boxes) added to culture medium containing high (15%) or low (5%) serum concentrations. Bars represent the mean ± SEM of three independent experiments, each performed in triplicate (n = 3). Student’s unpaired t test, *p < 0.05; **p < 0.01; ***p < 0.001 versus vehicle; °°°p < 0.001 versus vehicle high FBS
In parallel, primary cultures of astrocytes were also assayed for their proliferative response to IL-4; although cell cycle gene expression was unchanged, BrdU incorporation assay revealed a slight yet significant increase in the number of astrocytes in the S-phase of the cell cycle following IL-4, suggesting that the proliferative response observed in the brain following i.c.v. IL-4 (reported in Figs. 3 and 4) can be ascribed, at least in part, to astrocytes. Indeed, double immune staining of brain sections following i.c.v IL-4 shows co-localization of Ki67 signal with about 1% of GFAP-positive cells (see Additional file 4: Figure S3), and not Iba1-positive cells.
Altogether, these data show that microglia in the brain of adult mice are activated by M2 signals, such as IL-4, CSF-1, and E2, to shape their immune phenotype while self-renewal is specifically triggered by CSF-1; IL-4 and E2 brain activities do not correlate with microglia cell expansion, in contrast to what has been observed for peripheral macrophages, as summarized in Fig. 7.
Fig. 7
figure 7
Tissue-specific responses of resident macrophages to polarization signals. Resident macrophages in the peritoneum show proliferative and alternative polarization responses to IL-4, CSF-1, and E2; in the brain, alternative polarization of microglia is induced by the same signals, although with different intensities and target gene-specificity, while cell proliferation is restricted to CSF-1 signaling
Discussion
The present study provides the first evidence to show that microglial cells do not proliferate in response to IL-4, at least in the present experimental conditions; in fact, using molecular and biological assays, we were unable to detect microglia proliferation following IL-4 treatment both in vivo in the mouse brain and in vitro on primary cultures microglia from newborn animals. On the contrary, this immune mediator enhances the proliferation of peripheral macrophages, as shown in this and previous studies [17]. Moreover, also another M2-activating signal, namely E2, showed a similar polarization and non-proliferative activity in microglia of adult mice.
Microglial population is expanded during the pathological course of neurodegenerative diseases and contributes to disease progression [7,8,9,10,11,12]; the activity of IL-4 in brain recently received considerable attention in relation with its anti-inflammatory and pro-resolution effects that are directly mediated by microglia. Expression and secretion of IL-4 is induced by neuroinflammatory insults in activated immune cells and damaged neurons and IL-4-activated microglia produce a series of mediators, including neurotrophic factors, matrix remodeling, and proteolytic enzymes that help reduce neuroinflammation and promote tissue repair, as shown in experimental models of neurodegenerative diseases [18, 21, 30,31,32]. It is thus important to understand whether IL-4 contributes to the expansion of microglia that undergoes an alternative activation phenotype. In this scenario, our results provide an important step forward, as we show that IL-4 activity in the brain, although associated with immunoregulatory and tissue repair phenotype, does not correlate with an increase in microglia number. Analogously, estrogen action in microglia has been proposed to mediate the protective effects observed for this hormone against neurodegenerative diseases in humans and animal models, while the reduction in estrogen levels that occurs at menopause is associated with an increased incidence of neuroinflammatory pathologies [33]. Previous studies reported the effects on microglia polarization when E2 was assayed together with neuro-immune signals [23, 34]; the present study is the first evidence to show that E2 per se promotes microglia alternative polarization.
Our results highlight a substantial difference between microglia and peripheral macrophage biology in their responsiveness to M2-activating signals, as shown in Fig. 7. These two resident macrophage populations have a different developmental origin and acquire both common and specialized functions during life; indeed, a marked difference in the gene expression profiles has been observed in microglia as compared with other macrophage populations [35]. Moreover, it is known that the surrounding microenvironment is crucial to modulate macrophage functions by providing tissue-specific signals and interactions that influence cell phenotype and responsiveness. However, explanations for the lack of microglia proliferation are still missing; one could hypothesize that specific alterations of the IL-4 signaling pathway that converges on cell proliferation are present in microglia as compared to peripheral macrophages; a possible candidate is the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which has been shown to be necessary for the IL-4 activity on the proliferative burst of peripheral macrophages [29, 36]; instead, proliferative responses of macrophages to E2 are still ill defined. On the other hand, our data show that the proliferative signaling of CSF-1R is maintained in microglia, in agreement with previous reports [7, 37,38,39] which also associated CSF-1 activity with the PI3K pathway. Thus, the specific effects of CSF-1 and IL-4 signaling pathways on microglia proliferation might either involve cell-specific mediators of the PI3K pathway or yet undefined PI3K-unrelated processes.
Our study also shows that the in vivo effects of CSF-1 extend to the induction of an M2-like phenotypic activation of brain cells, similar to the response of peritoneal macrophages in vivo, as shown here, or in vitro, as previously reported [40]; interestingly, an opposite effect on Fizz1 expression in brain and peritoneal macrophages was observed, as well as the induction of specific M2 genes in primary cultures of microglia; these features need future investigation, although the experimental procedures and development stage used for culturing primary microglia cells may alter cell responsiveness and limit any comparison with resident microglia of the adult brain. The use of CSF-1R inhibitors in experimental models of neurodegenerative pathologies has been shown to reduce microglia density and to associate with beneficial effects against disease progression, although still unclear are the consequences of CSF-1R inhibition on polarized phenotype effectors, as well as the role of CSF-1R-independent and/or compensating pathways in microglia self-renewal and turnover [5, 7, 11, 41, 42]. Environmental and pathological signals seem to influence the type, timing, and resolution of microglia polarization responses through ill-defined mechanisms that differ between the healthy and injured brain and that need deeper investigation.
Conclusions
The uncoupling of the polarization and proliferative activities of IL-4 and E2 in microglia is unclear; indeed, several aspects of microglia polarization have not been yet investigated, such as the fate of these cells following activation or the existence of local amplifiers of alternative polarization responses, which have only recently been identified for IL-4 in some peripheral tissues [43]. Thus, further studies are needed to understand the molecular mechanisms of microglia proliferation, with the aim of opening novel therapeutic strategies that selectively and timely potentiate alternatively activated microglia while avoiding inflammatory macrophage expansion and monocyte recruitment.
Abbreviations
BSA:
Bovine serum albumin
CNS:
Central nervous system
CSF-1:
Colony-stimulating factor-1
DAB:
3,3′-diaminobenzidine
E2 :
17β-estradiol
FBS:
Fetal bovine serum
HBSS:
Hank’s balanced salt solution
i.c.v. :
Intracerebroventricular
IL-4:
Interleukin-4
MEM:
Minimum essential Eagle’s medium
PBS:
Phosphate-buffered saline
PCR:
Polymerase chain reaction
SEM:
Standard error of the mean
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Acknowledgements
We acknowledge Clara Meda and Monica Rebecchi for the technical support and thank Maria Pia Abbracchio, Barbara Viviani, and Camilla Recordati for their scientific support.
Funding
This work was supported by grants from the European Community (ERC-Advanced Grant Ways 322977), from the European Union’s Seventh Framework Programme (FP7/2007-2013 INMiND 278850), and by CARIPLO Foundation Italy (2011–0591).
Availability of data and materials
Please contact the authors for data requests.
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Authors and Affiliations
Authors
Contributions
GP performed the experiments and participated in the design and discussion of the study and in manuscript drafting. MDM and LM performed the immunohistochemical assays and image analysis. AV contributed to the experimental design. AM contributed to the study design and interpretation of the data. EV conceived and coordinated the study and provided substantial contributions to the design, interpretation, and discussion of the data and manuscript drafting. All authors were involved in revising the manuscript for its methodological and intellectual content. All authors read and approved the final manuscript.
Corresponding author
Correspondence to Elisabetta Vegeto.
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Ethics approval
Experiments were approved by the Italian Ministry of Research and University (#547/2015PR) and controlled by an internal panel of experts.
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The authors declare they have no competing interests.
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Additional files
Additional file 1: Table S1.
Oligonucleotides used in real time PCR assays. (PDF 182 kb)
Additional file 2: Figure S1.
In vitro polarization responses of microglia to IL-4 and CSF-1. A) The expression of M2 polarization genes (Arg1 and Mrc1) was analyzed in primary cultures of microglia following the treatment with vehicle (veh; open boxes), 20 ng/ml IL-4 (closed boxes) or 20 ng/ml CSF-1 (gray boxes). B) The expression of IL-4Rα was analyzed either in microglia cells obtained by immunosorting from the brain of vehicle or IL-4 icv-injected mice (ex vivo) or in primary cultures of microglia (in vitro) as specified above. Bars represent the mean ± SEM of 3 independent experiments, each performed in triplicate. Data sets for each gene were calculated using the 2-ddCt method with respect to the mean value of the vehicle group. Bars represent mean values ± SEM (n = 3). Student’s unpaired t-test, *p < 0.05; **p < 0.01; ***p < 0.001. (PDF 167 kb)
Additional file 3: Figure S2.
In vitro proliferative and polarization responses of macrophages to IL-4, CSF-1 and E2. A) The expression of proliferation (Ki67, Cdk1 and Ccnb2) and M2 polarization (Arg1, Fizz1, Mrc1) genes was analyzed in primary cultures of peritoneal macrophages following treatment with 20 ng/ml IL-4 (black bars) or 20 ng/ml CSF-1 (gray bars). B) The expression of proliferation (Ki67, Cdk1 and Ccnb2) and M2 polarization (Arg1, Vegfα) genes was analyzed in primary cultures of peritoneal macrophages following vehicle (0.01% EtOH) or 10−5 M E2 treatments. Bars represent the mean ± SEM of 3 independent experiments, each performed in triplicate Data sets for each gene were calculated using the 2-ddCt method with respect to the mean value of the vehicle group. Bars represent mean values ± SEM (n = 3). Student’s unpaired t-test, *p < 0.05; ***p < 0.001. (PDF 339 kb)
Additional file 4: Figure S3.
Cellular localization of Ki67 immunostaining in brain astrocytes. Brain sections were analyzed by immunohistochemistry for the expression of Ki67 using antibodies against Ki67 (green labeling) and GFAP (red staining) following the icv administration of 250 ng IL-4. Ki67-positive cells co-localize with GFAP-positive cells (white arrows). Scale bar, 10 μm. (PDF 105 kb)
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Pepe, G., De Maglie, M., Minoli, L. et al. Selective proliferative response of microglia to alternative polarization signals. J Neuroinflammation 14, 236 (2017). https://doi.org/10.1186/s12974-017-1011-6
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Keywords
• Interleukin-4
• Microglia
• Proliferation
• Estrogen | {
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-3,150,149,933,425,885,000 | Why Should I Work Out At All?
It is indeed true that the majority of us have to lead an extremely hectic lifestyle and have no time to even enjoy a hobby of ours much less find the time to hit a gym and start working out. However, engaging in fitness oriented activities can really help you enjoy a maximum level of health along with agility and stamina as well. Here are some of the reasons to help you make up your mind if you are still wondering why going to work and coming home is not enough working out in itself.
It gives your system a serious advantage
Let’s face it, none of us are going to get any younger by the day. Our bodies reach maximum potential when we are in our prime youth and then begin a gradual downhill climb towards our old years. This is why working out will give your body and its internal organs the best chance at fighting back illness and staying healthy. For example a good pilates session will really help you loosen up the tension in your body and reach maximum flexibility which will keep your joints working like clockwork as you gradually get older.
It promotes healthy habits
Working out acts in a psychological manner too where it promotes other healthy habits along with it. If you genuinely enjoy working out it is because you love your health and your body. You will automatically start eating healthy, drinking enough water and getting enough rest while also abstaining from unhealthy habits like alcohol consumption, nicotine intake and eating junk food. On the other hand it can push you towards trying out health improving options like a remedial massage that is great to maintain the healthy condition of your muscles and your joints.
It will help you feel good
Working out releases endorphins which is why even though you get really tired during a workout you feel really great and pumped up afterwards. This release in endorphins is also the chemical substance that is responsible for making you feel good about the way you look and in general as well. This is why working out is also considered a great anger and depression as well as anxiety management technique. Besides, the more you feel better about yourself you will look better too because you will do everything that you must do anyway to ensure that you are taking care of yourself.
It will increase your metabolism and immunity
The majority of food that is available to be bought today are filled with substances like chemicals, preservatives and fatty substances that will make you gain inches around your waistline. Working out promotes the rate of metabolism in an individual. This means that you will no longer have to be overly worried about the weight gain that most people experience with age. Even in the case of immunity, given that the tenacity of bacteria and viruses are increasing by the second, the boost that working out can give your immunity system has certainly never been timelier.
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-9,009,321,179,460,361,000 | What does a Chiropractor do?
Chiropractors work with all of the body but especially with the nervous system and the bones and nerves of the spinal column and spinal cord, respectively.
Chiropractors spend years of highly specialised training in order to locate where poorly functioning spinal vertebrae are irritating or impinging the nerves which travel down the spinal cord and out through the spinal column to the muscles, organs and glands of the body.
These poorly functioning vertebrae are called Subluxations. The nerves of the body act like telephone cables through which the brain communicates it’s orders to all of your body’s parts. Vertebral Subluxation can interrupt these messages resulting in poor functioning of the body part supplied by the irritated nerve. This may be experienced as a body signal such as pain, numbness, tingling or often no pain is felt at all.
What Causes Subluxations?
Physical stresses – such as falls, traumas and accidents, lifting, poor posture, birth trauma.
Chemical stresses – eg. smoking, alchohol, pharmaceuticals, food additives, pesticides, pollution.
Emotional stresses – It is well known that what we think and feel can have huge impact on our health and even on specific organs within the body.
The first possible time to suffer a subluxation is at birth! This is one of the most physically traumatic events that a person experiences.
Anyone can become subluxated as a result of the stresses of daily work and life. Those with heavy physical work are often more likely to experience subluxations. | {
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820,399,124,608,693,500 | Juvenile Asian snake Rhabdophis tigrinus from the toad-rich island of Ishima, Japan. The present study aimed to clarify these issues. Get the latest research from NIH: https://www.nih.gov/coronavirus. | Beolens, Bo; Watkins, Michael; Grayson, Michael (2011). Many sources, though not ITIS, recognize one subspecies, Rhabdophis tigrinus formosanus of Taiwan. Epub 2013 Sep 10. Venom-induced consumption coagulopathy (VICC), which is sometimes reported as disseminated intravascular coagulation (DIC), subsequently improved rapidly. 2013 Jul;11(7):1310-8. doi: 10.1111/jth.12218. Rhabdophis tigrinus, the tiger keelback, kkotbaem, or yamakagashi, is a venomous colubrid snake found in East and Southeast Asia.Many sources, though not ITIS, recognize one subspecies, Rhabdophis tigrinus formosanus of Taiwan. Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. At 5.5 h after envenomation, APTT and PT-INR increased beyond a measurable range, and fibrinogen levels dropped below the detection limit. Although this snake is reluctant to bite, even defensively, the bite has been known to cause fatalities in humans. Snake antivenom for snake venom induced consumption coagulopathy. While the term "poisonous snake" is often incorrectly used for a wide variety of venomous snakes, some species of Rhabdophis are in fact poisonous. USA.gov. Point-of-care derived INR does not reliably detect significant coagulopathy following Australian snakebite. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. The venom acts very slowly, inhibiting the ability of the blood to clot and causing death by hemorrhage: Although rTM was effective in this case, further studies are necessary to prove its safety and efficacy. Rhabdophis lateralis, a colubrid snake distributed throughout the continent of Asia, has recently undergone taxonomic revisions.Previously, Rhabdophis lateralis was classified as a subspecies of R. tigrinus (Yamakagashi) until 2012, when several genetic differences were discovered which classified this snake as its own species. Thromb Res. It is present throughout Russia and Eastern Asia, including China, Taiwan, Korea, and Japan, but excluding Ryukyu Islands . Rhabdophis is a genus of snakes in the subfamily Natricinae of the family Colubridae. "QI: Quite Interesting facts about deadly poisons", https://en.wikipedia.org/w/index.php?title=Rhabdophis&oldid=983684046, Creative Commons Attribution-ShareAlike License, This page was last edited on 15 October 2020, at 17:03. COVID-19 is an emerging, rapidly evolving situation. Species in the genus Rhabdophis are generally called keelback snakes, and are found primarily in Southeast Asia. | {
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-3,767,039,450,314,250,000 | Better Help Rates Canada 2022
Yes so we will be discussing Better Help Rates Canada…When a costly in-office session with a therapist was the only way to get assistance, gone are the days. Online therapy is now among the leading ways individuals receive individual, couples, and group counseling. Not just is it typically more convenient, however it’s also a more comfortable setting for many clients.
Thankfully, online platforms like BetterHelp make it more practical to look for aid. Keep checking out to discover out how we assessed it on the important considerations for quality online therapy.
How much will BetterHelp therapy expense? Can advantages usually cover any of that expense? How do the expenses compare to what you ‘d spend for rivals’ services or for conventional, in-person treatment? Are there opportunities to get discount rates or monetary help?
How much does BetterHelp cost monthly?
Expenses compare favorably both to in-person therapy and to equaling services, particularly when you consider the value of weekly live sessions consisted of for each customer (not just offered at a premium rate). Pricing details on the site is more opaque than we ‘d choose; generally, you would not understand your likely expenses prior to completing the questionnaire unless you have actually read our evaluation here. We’ll set out the significant pricing information and aspects below so that you can understand BetterHelp’s range of possible costs and discount rate choices.
hi my name is hey sue and today we’re gon na be discussing high functioning depression so for those of you that are really familiar with mental health and some of the disorders that we can discover in the DSM you might understand this as dysthymia so we’re gon na talk a bit more about signs that you could be looking for whether you might be experiencing high operating depression or somebody that you know and appreciate is going through this difficulty and struggle
so initially let’s think about anxiety in general when you consider somebody that’s depressed what enters your mind for me I’m thinking of someone that has a hard time rising has a hard time leaving their house maybe they have actually disliked things they utilized to really take pleasure in like hobbies or specific kinds of food restaurants things that they liked to do with their downtime perhaps they’re not truly so proficient at maintaining relationships with their household their pals perhaps they’ve lost their task due to the fact that they’ve lost motivation and this will in this drive to live their life so on the flip side let’s think about individuals in your life that are very high-functioning you might have a co-worker for instance or have had a co-worker that seems to in some way manage to get up early every day prior to work to work out maintains
Insurance coverage also will not be an option. But, unless you have excellent insurance coverage with a low deductible, the cost of treatment will likely be a terrific value to you compared to options.
Client care and privacy
Grade: 9
Good, attentive service and a healthy devotion to customer privacy are two procedures of a business’s regard for its customers. How does BetterHelp stack up? Does it supply dedicated client service specialists who provide efficient and prompt aid when issues develop? How well does the company protect your information and honor your desire for personal privacy? What steps does BetterHelp require to secure your sensitive information?
In a nutshell, BetterHelp is committed to security, quality, and personal privacy– and it reveals. The customer service group replies quickly to problems you raise– appealing to reply within 24 hr but, in our experience, responding in far less time than that– and responses your questions with the suitable level of customized care. And the business makes sure that its therapists stick to HIPAA policies and safeguard your confidentiality. You can even more safeguard your privacy utilizing a nickname with your therapist. Given that BetterHelp does not work with insurance coverage or employers, there isn’t even a basic level of information-sharing between such entities, which indicates optimal privacy for you.
What is the BetterHelp debate? Better Help Rates Canada
BetterHelp is the biggest online therapy platform worldwide. Ad tech professional, Alon Matas, established the company in 2013 after looking for therapy for anxiety. He discovered that most people who need it weren’t getting aid. Factors such as absence of gain access to, availability, expense, trouble, and fear make in-person treatment challenging for many people. Online treatment platforms like BetterHelp strive to use a simpler, more comfortable, and more inexpensive method to get help.
The demand for online treatment has escalated in the last few years. According to the CDC, 40% of American grownups experienced mental health or substance abuse problems throughout the coronavirus pandemic. It took a substantial toll on more youthful grownups, important employees, people of color, and caregivers. While online therapy ended up being the only alternative for a lot of during this time, favorable experiences helped many individuals recognize that it’s a feasible choice in a post-pandemic world, too.
Everybody can take advantage of talking with a therapist. Everybody deals with challenges in life that can get in the way of our happiness or become obstructions to our objectives. And in some cases, when objectives themselves alter, we require help coping and navigating with challenging feelings.
BetterHelp therapists are all extremely qualified to help you as you seek to enhance your life. The business also works with therapists who specialize in specific areas of issue, consisting of however not restricted to:
Depression
Tension
Stress and anxiety
Self-esteem
Life modifications
Parenting
Relationships
Religion
Sexuality
Identity
Anger
Dependency
Eating
Sleep
PTSD
Grief
Household dispute
Attempt BetterHelp
Additional services
In addition to private treatment, the BetterHelp homepage lists Couples and Teenager therapy choices. Each of these services sends you to a sis website when chosen– Regain.us for couples and TeenCounseling.com for teens. Prices for these services resembles BetterHelp, and all therapists fulfill the exact same high requirements and go through the exact same extensive screening. Better Help Rates Canada
Better help reviews
BetterHelp has a different site dedicated to LGBTQIA counseling, called Pride Therapy. Its services are just as cost effective and structured as the parent company, however therapists with Pride Therapy focus on providing treatment to people in the LGBTQIA community. Pride Counseling likewise secures your privacy and privacy as rigorously as BetterHelp.
maybe somebody else that you’ve understood in the past great work ethic actually an assertive communicator simply appears generally like he understands what’s going on with life has whatever figured out so now that we have these images in mind of somebody with depression and somebody that seemingly doesn’t wish to move gears a bit to speak to you about a functioning alcoholic we’ve all heard this term so what does it suggest when we state someone’s an operating alcoholic or generally referring to someone that probably does have some type of issue with alcohol however they have the ability to keep their task they have the ability to preserve relationships family but the problem I think is that in some cases they’re unable to maintain those things in healthy ways and it’s very hard sometimes to recognize a functioning alcoholic due to the fact that they are able to keep some aspects of their life together so leaping back to the initial subject here of someone with high working depression otherwise called dysthymia it’s truly hard to determine these individuals often and often it’s us sometimes we can’t even recognize when it’s us that we’re suffering from these things so today again we wish to speak about things that you can be trying to find or things that you might have seen in yourself that could be an indication that you’re experiencing high-functioning anxiety so people with high-functioning depression or experiencing dysthymia are often difficult to identify we’re not seeing these overt traits of an extremely depressed person no catatonic states in fact individuals with high-functioning depression are typically able to keep actually healthy way of lives great relationships with other individuals and that and it vertically practically makes the threat a little bit scarier in a different kind of method why someone with overt symptoms of anything we can discover them we can get them into some sort of services or attempt to help them as best as we can for individuals flying under the radar for individuals experiencing signs that we don’t see it’s truly hard to determine them and after that get them help it’s truly challenging to interact to them that perhaps they need to think about finding help on their own so when we think about mental health services in general there already is a quite big preconception around this a lot of individuals out there adults in the United States for instance have a difficult time looking for treatment because of you understand the idea that if you look for treatment you’re crazy or you can’t deal with things on your own or something
Is BetterHelp legit?
Yes, BetterHelp is a legit, trustworthy company and a leader in online therapy with over 22,000 therapists and almost two million clients so far. Lots of individuals prefer it to their standard in-person treatment.
A safe and safe platform
Complete compliance with HIPAA law
Greater cost for some individuals, compared to in-person therapy
The choice of privacy
High requirements for its therapists
A straightforward experience whether you use the app or the site
Who are the therapists?
The most essential resource BetterHelp offers is its wide array of highly qualified therapists. Although it was obtained by Teladoc, Inc. in 2015, the business continues to use the exact same strenuous therapist application process in order to veterinarian therapists and preserve quality. BetterHelp reports that just 15% of therapists who apply to the platform are authorized.
The therapist application process consists of:
A review of each therapist’s background, experience, and references
Confirmation of qualifications
A case study test assessed by a licensed clinician; a video interview
A platform skills test
Therapists are likewise subject to continuous quality improvement, customer, and tracking feedback throughout their tenure at BetterHelp.
higher for them since they do not want to idea people in their lives in to the reality that they might be battling with something or that they may need help with something therefore for people experiencing this we have a tough time finding them and they have a difficult time finding help because you understand possibly some part of them doesn’t actually want to be recognized where this other part does however we don’t know how to find them so what are we trying to find in order to identify whether we ourselves are having a tough time with this or somebody that we care about might be going through a hard 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 challenge with high functioning depression so one of the first things to search for is this basic sense of sadness going back to this image you may have of this depressed individual you could be thinking somebody sobbing throughout the day just having a tough time with life plunged over catatonic even maybe not moving very much you’re not going to really see this with somebody with high functioning depression but rather like I stated a subtle and basic sense of unhappiness the majority of the time practically every day if not every day and it’s a bit inexplicable in some cases you can’t actually inform where this feeling is coming from or pinpoint any particular trigger that harmed your sensations or anything like that some other things to be searching for and thinking about is the failure or you understand the loss of ability to experience delight loss of interests and things that you utilized to truly discover to be something that makes you feel great or bring some kind of fulfillment to your life you may also observe decreased energy so like Better Help Rates Canada.
I said not always not being able to get out of bed but simply decreased you feel fatigued a lot of the time where perhaps prior to you didn’t experience it that way other things to be trying to find is being really self-critical which results in perfectionism which can also 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 having problem with high operating anxiety experienced these things like I said actually self-critical feeling a great deal of regret and pity about the past and even the future things that haven’t even took place yet this is something that a lot of individuals couldn’t be struggling with you may likewise be thinking about this depressed individual who seems sad all the time however there’s other sensations involved in anxiety. | {
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A B C D E F G H I J K L M N O P Q R S T U V W X Y Z A-Z Listings Contact Us
BiPap
What is BiPap?
Some medical problems can make it hard for you to breathe. In these cases, you might benefit from bilevel positive airway pressure. It is commonly known as BiPap or BPap. It is a type of ventilator—a device that helps with breathing.
During normal breathing, your lungs expand when you breathe in. This is caused by the diaphragm, which is the main muscle of breathing in your chest, going in a downward direction. This causes the pressure to drop inside the tubes and sacs of your lungs. This decrease in pressure sucks air into your lungs. They fill with oxygenated air.
If you have trouble breathing, a BiPap machine can help push air into your lungs. You wear a mask or nasal plugs that are connected to the ventilator. The machine supplies pressurized air into your airways. It is called “positive pressure ventilation” because the device helps open your lungs with this air pressure.
BiPap is only one type of positive pressure ventilator. While using BiPap, you receive positive air pressure when you breathe in and when you breathe out. But you receive higher air pressure when you breathe in. This setting is different from other types of ventilators. For instance, continuous positive airway pressure (CPAP) delivers the same amount of pressure as you breathe in and out. Different medical problems may respond better to BiPap versus CPAP.
Why might I need to use BiPap?
BiPap may help you if you have a medical problem that impairs your breathing. For example, you might need BiPap if you have any of the following:
• COPD (chronic obstructive pulmonary disorder)
• Obstructive sleep apnea
• Obesity hypoventilation syndrome
• Pneumonia
• Asthma flare-up
• Poor breathing after an operation
• Neurological disease that disturbs breathing
BiPap may not be a good option if your breathing is very poor. It may also not be right for you if you have reduced consciousness or problems swallowing. BiPap may not help enough in these situations. Instead, you may need a ventilator with a mechanical tube that is inserted down your throat. Or you may benefit from a tracheostomy. This is a procedure that creates an airway in your windpipe.
In some cases, people can move off such ventilator support to BiPap as their breathing improves. People who don't want a breathing tube but want some assistance with breathing may also use BiPap.
What are the risks of BiPap use?
BiPap is usually very safe. It has a lower risk of complications, such as infection, compared with ventilator support or tracheostomy. Most problems from BiPap involve the facemask. It may fit too tightly. Some other risks include:
• Local skin damage from the mask
• Mild stomach bloating
• Dry mouth
• Leaking from the mask, causing less pressure to be delivered
• Eye irritation
• Trouble clearing phlegm
• Sinus pain or sinus congestion
Your own risks may differ depending on your age, the amount of time you need BiPap, and your medical problems. Talk with your healthcare provider about any concerns.
How do I get ready for BiPap use?
You should be familiar with the parts of your BiPap machine. They include:
• A face mask, nasal mask, or nasal plugs
• The machine’s motor, which blows air into a tube
• The tubing that connects the machine’s motor to the mask or plugs
Your BiPap machine might also have other features, such as a heated humidifier.
If you are buying a BiPap machine for home use, you may want to talk with a professional who sells home medical equipment. This person can help you pick the type of BiPap machine best suited to your needs. He or she can also give you instructions about how and when to clean the masks, tubing, and other parts of the machine.
You might want to try several types of masks before deciding on the one you like best. If your mask feels tight, you may need to have it refitted.
Before you start BiPap therapy, your machine may need to be calibrated. Someone from your medical team will adjust the settings. That person is often a respiratory therapist. The settings need to be correct so that you receive the appropriate therapy. You may also get other instructions on how to prepare for your BiPap therapy.
What happens during BiPap use?
You might receive BiPap therapy while at the hospital for a breathing emergency. You also might use it at home for a chronic condition.
Follow your healthcare provider’s instructions about when to use BiPap. You might need to use it only while you sleep. Or you might need to use it all the time. You will not receive the full benefits from your BiPap therapy if you don’t use it as directed.
When you first start using BiPap, you may feel uncomfortable. It may feel odd wearing a mask and feeling the flow of air. Over time, you should get used to it. If you feel like you really can’t breathe while using BiPap, talk with your healthcare provider. He or she may need to adjust the pressure settings on your machine.
It’s important not to eat or drink anything while using BiPap. You might inhale food or liquid into your lungs if you do so.
The noise from most BiPap machines is soft and rhythmic. If it bothers you, try using ear plugs. If the device is very loud, check with the medical supplier to make sure it is working correctly.
Talk with your healthcare provider if you are having any symptoms or problems while using BiPap. He or she can help you figure out how to address them. Here are some general tips:
• A humidifier may help reduce nasal dryness. Using a facial mask instead of a nasal mask may also help lessen any eye or sinus symptoms. If you get headaches, they could be due to sinus congestion. In some cases, your healthcare provider might prescribe an antihistamine or nasal steroid spray for these symptoms.
• If you have a leaky mask, skin irritation, or pressure lines, you may need a different size or type of mask. You may also find that adjusting the straps around your mask helps.
• Your healthcare provider may be able to help you avoid stomach bloating by reducing the pressure setting on your machine.
Your healthcare provider may give you other instructions about the best way to use your machine.
What happens after BiPap use?
If your health problem gets better, you may be able to start using less pressure on your BiPap machine. Or you might be able to use the machine less frequently. Work with your healthcare team to help get the best treatment.
Next steps
Before you agree to the test or the procedure make sure you know:
• The name of the test or procedure
• The reason you are having the test or procedure
• What results to expect and what they mean
• The risks and benefits of the test or procedure
• What the possible side effects or complications are
• When and where you are to have the test or procedure
• Who will do the test or procedure and what that person’s qualifications are
• What would happen if you did not have the test or procedure
• Any alternative tests or procedures to think about
• When and how you will get the results
• Who to call after the test or procedure if you have questions or problems
• How much you will have to pay for the test or procedure
Online Medical Reviewer: Alan J Blaivas DO
Online Medical Reviewer: Daphne Pierce-Smith RN MSN CCRC
Online Medical Reviewer: Paula Goode RN BSN MSN
Date Last Reviewed: 3/1/2019
© 2000-2020 The StayWell Company, LLC. 800 Township Line Road, Yardley, PA 19067. All rights reserved. This information is not intended as a substitute for professional medical care. Always follow your healthcare professional's instructions.
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Can you get your period while you’re pregnant?
Q: Hi there! I had sex last month when I was on my period and we only realized the condom broke after my bf came. I did a preg test and it was negative, and I had bleeding last week that was maybe my period but I’m not sure. Can you still get your period if you’re pregnant?
The short answer is no, you can’t get your period while you’re pregnant.
If an egg isn’t fertilized and doesn’t implant into the wall of the uterus, then the body is like “Well, we don’t need this uterine lining we’ve been building up all month,” and you have a period. All of the uterine lining is then shed from the body out of the vagina (that’s what period blood actually is). If a fertilized egg does implant into the uterus (aka pregnancy happens), then the body is like “Whoa, I need all this uterine lining to nourish the egg!” and you don’t have a period.
Bleeding can happen while a person is pregnant, it’s just not a period. Reasons for this could include:
Spotting, Implantation Bleeding and Ectopic Pregnancy are the three that we get asked about the most, so we’ve got more info on those below. It should be noted that Implantation Bleeding and Ectopic Pregnancy bleeding are generally uncommon.
It can also help to remember that using hormonal birth control or emergency contraceptive pills (like Plan B) can also cause bleeding different than what you’re used to. Hormones can change what bleeding is like during your period, and using something like Plan B can make your next period early or even up to 2 weeks late.
The only way to know for sure if you’re pregnant is to do a pregnancy test. It’s not possible to tell from missed or irregular periods alone. Pregnancy tests are accurate if taken 14 days after you had sex where there was a risk of pregnancy. And they’re very accurate! Please see one of our recent blog posts for more info:
Going off the scenario described above, there really isn’t a risk of pregnancy when someone’s on their period. Eggs can only be fertilized between 24-48 hours after ovulation. Ovulation typically happens 11-16 days before someone is expecting their period. When a period is happening, the egg and uterine lining aren’t usable and are getting flushed out. Even if sperm were introduced to the equation at this point, they wouldn’t be able to do anything (since sperm die within 5 days). Now if someone has a really short cycle, like under 25 days between periods, then there could be a potential risk of pregnancy from sperm leftover after sex during a period. For more info, please check out our post What is Risk: Pregnancy Edition.
Spotting
Spotting is light bleeding that happens between periods. Where period bleeding is generally a heavy enough flow that people use various period products to absorb it, spotting is more likely going to show as just some light spots of blood that you might notice in your underwear or when wiping in the bathroom. These spots tend to be a different colour (often red, dark red, or brownish) and a different consistency than your regular period blood as well. Causes for it can include hormonal birth control, emergency contraceptive pills, urinary tract infections, STIs, pelvic inflammatory disease, polyps, ovulation, early pregnancy, or even particularly rough sex.
Implantation Bleeding
This is a small amount of bleeding that some people experience 6-12 days after an egg is fertilized. While it can happen when you’d potentially be expecting your period, implantation bleeding is not the same kind of bleeding the you’d likely experience during your period. The table below is a general comparison:
Regular Period Implantation Bleeding
How long does it last? 3+ Days 24-48 Hours
What is the flow? Heavier bleeding first, then lightening up Light to medium spotting
What does it look like? Darker blood first, then lighter Dark brown, black, red or pink
What kind of cramps? More severe before bleeding, lasting for 2-3 days Mild or none at all
Ectopic Pregnancy
An ectopic pregnancy is where a fertilized egg attaches itself somewhere outside of the uterus (commonly in a fallopian tube). An early symptom of this is early vaginal bleeding. Other more serious symptoms include:
If you’re experiencing any of these, it is generally recommended that you check in with a clinician as soon as possible.
Resources
Please note that as with many resources around periods and pregnancy, the following links use gendered language around bodies and experiences.
If you have questions about this topic, feel free to contact one of our peer educators. [Link]
Last Updated: April 2020
• What do you do if you don’t have sex?
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What do you do when you get a positive STI test *after* a break up? How do you tell your fresh new ex? Here are some tips!
• LGBTQQIA2SPGNCNBGQ
People have lots of different terms and definitions when it comes to understanding their sexual orientations or gender identities. This post helps lay out some of the more widely mentioned definitions, and talks about how we can improve our resources to be more inclusive! | {
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7,779,784,114,770,364,000 | gammagraphy
Also found in: Medical.
Translations
gammagraphie
gammagraphy
n. gammagrafía, registro de rayos gamma después de la administración de isótopos radioactivos.
English-Spanish Medical Dictionary © Farlex 2012
Mentioned in ?
References in periodicals archive ?
The diagnosis of thrombosis was based on doppler ultrasonography, tomography, magnetic resonance, arteriography, phlebography, pulmonary gammagraphy and plethysmography.
It may be asymptomatic or manifest with dyspnea, cough, chest pain, decreased amount of drainage or simulate a deficit of ultrafiltration.There is a relationship between increased intraperitoneal pressure (IP) and the appearance of hydrothorax.The diagnosis is made by chest X-ray, thoracentesis and gammagraphy. It is a serious and rare complication that usually causes the abandonment of techniques while the realization of chemical pleurodesis with sclerosing agents (talc, tetracyclines, blood) can be an effective treatment to solve the pleuroperitoneal communication.
The Brazilian gammagraphy accident that occurred in May 2000 involved an operator performing routine exposures with a [sup.60]Co apparatus containing a 2.11 TBq source.
The [sup.131]I metaiodonebenzylguanide gammagraphy (131I-MIBG), despite its low image quality and definition, has 83.5% sensitivity and, in combination with platelet normetanephrine, it reaches 100% sensitivity.
Diagnostic images: renal ultrasound, voiding cystogram and renal gammagraphy. | {
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6,564,830,730,348,353,000 | Innocent Heart Murmurs
Helping Hand Logo
Blood flow in a normal heart
A heart murmur is an extra sound heard while listening to the heart. An innocent heart murmur is harmless. It's caused by blood flowing through the heart, not by heart disease (Picture 1).
Innocent heart murmurs are common in children and usually go away before they become adults. These murmurs can also be called functional murmurs, physiological murmurs, or vibratory murmurs.
Diagnosis
Innocent heart murmurs are usually diagnosed based on your child's history and a physical exam. Sometimes other tests are needed.
What This Means
• A child with an innocent murmur has a normal heart and doesn't need to limit any activity.
• An innocent murmur may get louder with activity, exercise, or sickness. It won't hurt your child.
• Your child doesn't need treatment or medicine.
• Your child’s doctor, health care provider, or our clinic staff can answer other questions.
Innocent Heart Murmurs (PDF), Somali (PDF), Spanish (PDF)
HH-I-357 • ©2017, revised 2023 • Nationwide Children's Hospital | {
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1,641,650,415,797,972,700 | Essential Dietary Minerals
Calcium
Requirement: 1,300 mg. for women 18 years and younger, 1,000 mg for women 19+ years.
Needed for: helps build bones for baby and helps maintain mother’s bones, teeth, may prevent pregnancy-induced high blood pressure, inhibits lead mobilization from the bones.
Sources: Lowfat milk products, soymilk, sardines, canned salmon (with bones), tofu, dark leafy green vegetables, dried beans and peas.
Deficiency:
Toxicity:
Chromium
Requirement: 50 to 200 mg.
Needed for: Regulation of blood sugar. Helps build proteins in baby’s developing tissues. Might aid in baby’s growth and reduce pregnancy-induced diabetes (gestational diabetes.
Sources: Whole grains, wheat germ, orange juice.
Deficiency:
Toxicity:
Copper
Requirement: 1.5 to 3.0 mg.
Needed for: normal pregnancy outcome, energy metabolism, connective tissue, and red blood cell formation. Aids in development and maintenance of baby’s heart, arteries, and blood vessels; skeletal system and nervous system.
Sources: Chicken, fish, extra-lean meats, whole grains, nuts and seeds, soybeans, dark leafy green vegetables.
Deficiency:
Toxicity:
Fluoride
Requirement: 3.0 mg.
Needed for: For strengthening bones and teeth, reducing risk for cavities in mother and baby. It increases the bioavailability of calcium and helps to buffer acids present in the mouth.
Sources: Not found in nature, but is found in the body through combining with other constituents in the body. There are 3-12 mg. of fluorine per liter of untreated water.
Toxicity: Dental fluorosis, also called mottling of tooth enamel, is a developmental disturbance of dental enamel caused by excessive exposure to high concentrations of fluoride during tooth development.[i]
Iodine
Requirement: 175 mcg.
Needed for: Essential for thyroid gland function
Sources: iodized salt, seafood, and sea vegetables.
Deficiency:
Toxicity:
Iron
Requirement: 30 mg.
Needed for: prevention of Anemia, helps baby develop and gain weight, prevents premature delivery.
Sources: Extra-lean meats, fish, poultry, cooked dried beans, dark leafy green vegetables, raisons , prunes, whole grains.
Magnesium
Requirement: 350 mg. for women who are 19+ years, 400 mg. for women 18 years and younger.
Needed for: Energy metabolism, blood-sugar regulation, helps normal muscle contraction and nerve transmission, maintains uterine relaxation during pregnancy and aids contractions during labor.
Sources: Low-fat milk, peanuts, bananas, wheat germ, whole grains, cooked dried beans and peas, dark leafy green vegetables, oysters.
Manganese
Requirement: 2.0 to 5.0 mg.
Needed for: It is a component of several enzymes.
Sources: Whole grains, fruits, vegetables, tea
Deficiency:
Toxicity:
Molybdenum
Requirement: 75 to 250 mcg.
Needed for: It is a component of several enzymes.
Sources: Whole grains, beans, milk.
Deficiency: jaundice, nausea, and fatigue, due to liver disfunction; headaches, tachypnea, tachycardia, vomiting, nausea and coma, due to sulfide toxicity (created by lack of Molydenum)[ii]; certain genetic disorders.
Toxicity: Liver damage, Kidney damage, weight loss
Selenium
Requirement: 65 mcg.
Needed for: Essential for growth, protects tissues in baby and mother from free-radical damage.
Sources: Whole grains, seafood, lean meat, low-fat milk products.
Potassium
Requirement: Pregnant women: 4,700 milligrams (mg) per day
Nursing moms: 5,100 mg per day.[iii]
Needed for: helps in maintaining fluid and electrolyte balance, sending nerve pulses, helping muscles to contract, releasing energy from proteins, fats and carbohydrates.
Sources: fruits and vegetables, red meat and chicken, fish, milk and yogurt, nuts, and soy.
Deficiency: weakness, fatigue, muscle cramps, constipation, and abnormal heart rhythms.
Toxicity: rhabdomyolysis, insulin deficiency, metabolic acidosis or extensive tissue or red blood cell damage, and kidney failure.[iv]
Zinc
Requirement: 15 mg.
Needed for: It is essential for conception, reduces the risk for spontaneous abortions, helps prevent birth defects, aids normal growth, helps development of bones, vision, and taste.
Sources: Extra-lean meats, turkey, cooked dried beans and peas, wheat germ, whole grains.
Deficiency: dry skin, hair loss, acne, spots on nails, poor wound healing, poor immunity.
Toxicity: nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches[v]
[i] Dental fluorosis: http://www.cdc.gov/fluoridation/safety/dental_fluorosis.htm#a2
[ii] http://voices.yahoo.com/molybdenum-deficiency-symptoms-causes-4735632.html
[iii] http://www.babycenter.com/0_potassium-in-your-pregnancy-diet_655.bc
[iv] http://www.livestrong.com/article/24690-symptoms-potassium-overdose/
[v] http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/
Caffeine, Tobacco, and Alcohol
Caffeine
Caffeinated beverages do not seem to cause birth defects or preterm labor and delivery in people…but there are other risks. Such as: fetal growth retardation, miscarriage, and low birth weight.
Woman who drink more than 300mg of caffeine are at the highest risk. That would be about three, five ounce cups. Those that both smoke and drink caffeine are at even a higher risk for babies with stunted growth.
Coffee (5 oz. cup) 60-180 mg
Tea (5 oz. steeped 4 minutes) 38-77 mg.
Cocoa (5 oz. cup) 2-20 mg.
Chocolate milk (8 oz.) 2-7 mg.
Cola drinks (Jolt, Mr. Pibb, Mountain Dew, etc.) 36-72 mg.
Non-prescription drugs (Excedrin, Anacin, etc.) 30-65 mg.
Tobacco
Cigarette smoke is full of chemicals. Many of these migrate to the sperm cells when they fertilize the ovum, and then continue to bombard the fetus when the mother smokes or is exposed to tobacco smoke.
Women who smoke are more likely to experience preeclampsia during pregnancy, preterm labor, premature rupture of the membranes, and premature delivery. The baby born to a smoking woman tends to be lower in birth weight, and more likely to die soon after birth than those who do not smoke.
The damage to the baby can persist into later life. They are at more risk for cancer as an adult, susceptible to middle-ear infections, asthma, chronic bronchitis, and wheezing.
If raised in a household where smoking is allowed children are more likely to develop hypertension, as well as neurological and behavioral problems such as attention deficit disorder. They also tend to score lower in intelligence tests later in life.
Men who smoke have a considerable higher risk of having children with birth defects and childhood cancer. This is probably due to the lowering of vitamin C levels in seminal fluids and sperm. Not even the best of nutrition can make up for the damage done by smoking!
Alcohol
Alcohol freely enters the placenta and directly exposes the developing baby to its toxic effects. It travels in the baby’s blood stream at the same concentration as that of the mother. If mother is “buzzed”, so is the baby!
Some babies born develop a condition called “Fetal Alcohol Syndrome” or FAS. They are shorter in length, lighter in weight, than other babies. They do not “catch up” eve with special postnatal care. They also have abnormally small heads, irregularity in their faces, limb abnormalities, heart defects, and poor coordination. Many are mentally retarded and may develop behavioral problems as they grow up (such as hyperactivity).
No one knows how much alcohol it would take to damage a baby. Since it causes permanent physical and mental birth defects and no “safe” amount is known, the best bet is to abstain from alcohol.
Be aware of the alcohol in certain foods. Such as Irish Coffee, wine coolers, rum and fruit cakes, liquor-laced desserts, and cough medicines.
A Good Question
What needs to happen, in order to fix a broken system? Your probably wondering what I mean by a broken system. I am talking about the care of women, and especially birthing.
In a nation that has been considered “advanced” we are so far behind the eight-ball that it becomes shameful. Our c-Section rates were seriously through-the-roof, and although some improvement has been made, the United States is still higher than most “civilized” countries! The average being around 31%.
Along with that outrageous number of c-Sections are the ever-climbing mortality rates of women in birth, predominately women of color. This is shameful in a country that is supposed to be “advanced”!
On top of both high c-Section rates, and high mortality rates for birthing, is the across-the-racial-board birth trauma. It should NEVER happen! But, we have nurses and doctors who force women into procedures, who intimidate and threaten.
The media (film and television) makes it seem that birth is both dangerous and extremely painful. When that consciousness is embedded in the psyche of women, and you have a medical field that relies on mechanical means to monitor births… the stage is set. We have normalized bad birthing practices, and outdated concepts about birth.
That is without discussing the current political scenarios.
The next few blogs will address the history behind, and the current information about birthing in the United States. The outdated concepts surrounding birth practices need debunking. The normalization of bad birthing practices needs to have a light shown upon it, in order to make it STOP.
It is time to become educated,
get angry,
and create a change!
NOTE: I am still doing research, the next two topics are valuable as well, and allows me time to get things done.
Also published at my sister site: Hoksiyuhab Oti
Anemia
blood-75302_1280
Normal Red Blood Cells
What is it?
Anemia is a condition of the blood in which there are less red blood cells (hemoglobin) than what would be considered normal. This would indicate a low amount of iron in the blood. The main function of the red blood cells is to carry oxygen to the lungs and body tissues and remove carbon dioxide. The symptoms of this condition reflect the lack of oxygen and build-up of carbon dioxide.
There are three classifications: excessive blood loss, excessive red blood cell destruction, and low red blood cell production. To identify which of the classifications, a series of labs are necessary. Just in the “excessive blood loss” classification are many causes, such as a slow-bleeding ulcer or excessive menstruation. Deficient production is the most common cause, but even it can have different causes. It could be due to iron deficiency, low B12, or lack of folic acid.
Symptoms
If the deficiency reaches appoint of concern, it has already become serious. The symptoms often do not get recognized.
• Loss of appetite
• Constipation
• Weakness
• Fatigue
• Coldness of extremities
• Pallor
• Pale and brittle nails
• Soreness in the mouth
• Cessation of menstruation
Anemia often is the indication of an underlying health issue. It should always be investigated, lab tests will assist in determination of the classification of deficiency and the treatment used. It is not recommended that you self-diagnose due to the problems that arise from iron supplementation when not necessary. Too much iron will damage the liver, heart, pancreas, and the activity of immune cells, it has been linked to cancer.
Recommendations
Certain foods bolster the levels of iron in the blood. These are: calves liver, Blackstrap molasses (at least one tablespoon twice a day), broccoli, egg yolks, asparagus, red raspberries, plums, prunes, purple grapes, bananas, kelp, whole grains, yams, and squash.
Oxalic Acid in certain foods will block or interfere with absorption of iron. The foods high in Oxalic Acid are almonds, cashews, chocolate, cocoa, rhubarb, soda, spinach, swiss chard, and most nuts and beans. Eliminate these foods or at the very least, limit their consumption.
Note: eating fish with vegetables high in iron will increase the absorption of iron. As does the elimination of sugar from the diet. When taking iron supplements, avoid taking calcium, vitamin E, zinc or antiacids…these will interfere with absorption.
The Following Herbs Are Also Helpful[1]
• Alfalfa (as a tea)
• Bilberry
• Cherry
• Dandelion
• Mullein
• Nettle (tea)
• Red Raspberries
REFERENCES
James F. Balch, M.D. and Phyllis A. Balch, C.N.C. Prescription for Nutritional Healing, 2nd Ed. (1997) Avery.
Michael Murray, N.D. and Joseph Pizzorno, N.D. Encyclopedia of Natural Medicine, Revised 2nd Ed. (1998) Three Rivers.
[1] Other herbs that are not listed may helpful, but not recommended in pregnancy.
How to Maintain Your Gynecological Health
Women tend to leave all the charting of our gynecological health in the hands of our doctors, no one at all. We can, and we should, and we need to keep our own records for ourselves, at home.
This would entail a few moments a day, at most, of inputting information. I will be creating a down-loadable blank chart you can use for this purpose.
Much of what we see in our charts at the doctor’s office, may seem to be a problem, only because we women do not understand or are not taught about normal feminine health. We can understand them better when we see what would be our “true” gynecological conditions.
These would be:
• Vaginal infections
• Abnormal bleeding
• Premenstrual syndrome
• Breast lumps
• Endometriosis
• PCOS[i]
• Nabothian (cervical) cysts
“…charting enables a woman to understand her body in a practical way (Wescheler, 230)”. A woman who charts every day is so aware of what is normal for her own body, that she can actually assist her doctor in determining what is not normal based upon her symptoms. Keeping the chart of her menstruation cycle assists In well-being, and working with the doctor.
Normal Healthy Cervical Fluid VS. Real Vaginal Infections
We live in a culture that advertises douche and sprays for vaginal “discharge” giving women the idea that they are “dirty” all the time. Douching and sprays only act to confuse the identity of healthy cervical fluid and what would be a real infection.
Wescheler explains in her book, that doctors say you don’t need either. On a talk show she watched, she says that the doctor stated that the infections from these products were “…enough to send his children to college (Wescheler , 231)”. Then there is also the yeast infection products that women self-diagnose and take every month for a “recurring” problem.
But, using the chart, detection of an actual infection will be easier, and discovered earlier. You can get treatment before discomfort sets in. Secretions mid-month are normal, but late in the month may indicate infection.
Symptoms of Vaginal Infections That Can Be Distinguished from Normal Cervical Fluid
Once you have routinely charted your normal cervical fluid, an infection can be distinguished by the unpleasant symptoms that set them apart from what is normal. Vaginal infections can range from STIs (See: The Effects of Sexually Transmitted Infections on Pregnancy) to a variety of forms of Vaginitis and of course the generic “yeast infection”.
• Abnormal discharge
• Itching, stinging, swelling, and redness
• Unpleasant odor
• Blisters, warts, and chancre sores
Avoiding Infections
Besides the consequences of douching, you should not wear clothing that is damp or too tight, as these create an unhealthy vaginal environment. Also you should wear cotton underwear, or at least cotton crotch underwear as these allow your body to breathe.
Normal VS Abnormal Bleeding
Normal menstruation lasts about five days and usually will follow a pattern, here are two variations:
Light –> heavy –> medium –> light –> very light
Heavy –> heavy –> medium –> medium –> light
Also, some women may spot (ordinarily brownish) or bleed at other times in their cycle besides actual menstruation. Spotting is one of the most misunderstood aspects of a woman’s cycle. A common mistake is to assume any type of bleeding episode is menstruation. True menstruation occurs after ovulation, about 12 to 16 days after. Any other type of bleeding is either anovulatory bleeding, what is considered normal spotting, or is symptomatic of a problem.
[i] Polycystic Ovary Syndrome
Based upon: Weschler, Toni. Taking Charge of Your Fertility. Rev. (2006) William Morrow.
Plains Paleo-Vegetarian Nutrition for Pregnancy
(this information was taken from my sister site hoksiyuhaboti)
The first thing you should know is that there are many types of vegetarians and styles of eating vegetarian. The two most common are Lacto-Ovo (milk and eggs) and Ovo (eggs). There are also “semi-vegetarians” who mostly eat a vegetarian diet, with occasional additions of chicken, or fish. My vegetarian cookbook mentions crusto-vegetarians who eat shell fish; mollo-vegetarians who eat clams, scallops, oysters or mullosks; repto-vegetarians who eats snakes and other reptiles…as examples of the few of many variations on the vegetarian diet.
For the Lakota, your diet could be called a Paleo-Vegetarian diet.
alaska from scratch on pinterest
from Alaska From Scratch on Pinterest
What??
As Lakota people, consider this: your fore-mothers gathered tinpsila (wild turnips), beans (there is story about this vegetable and the importance of “giving back”), blo (wild potatoes), berries, corn (wagmeza), squash (wagmu) and many other fruits and vegetables. There were healing plants that would have also found its way into the pot, as well.
The people gathered eggs when possible, traded for corn and squash, and gathered wild rice (before coming out to the plains). In the old stories about the first Huƞka “making of relatives” ceremony, with the Arikira. Corn was given in the ceremony, by the Arikira. Corn is used in soup with Tinpsila and Tripe (buffalo guts). This soup is used in ceremony.
Since many of you do not gather up your fruits and vegetables in the old way, what can you do? First, get fresh fruit and vegetables whenever possible, when in season (less expense). Next to that would be dried or frozen.
Unfortunately, most of the dried foods found in stores around Native country are sulfured. “Organically made” dried foods are hard to find, and disproportionately expensive.
You can create a garden. To do so you would need to use an old traditional practice of “the three sisters” for planting. The garden would consist of beans, corn and squash. You can create low mounds with the squash at the center of the top, a circle of corn surrounding it interdispersing some bean bush plants. The center of the top would have a slight indent to catch water from the summer thunder storms.
Grains are not a part of the Paleo diet, with an exception of wild rice by the northern bands of the Oċeti Ṡakowiƞ. Baked or fried bread never was a part of the old traditional diet, not even unleavened flat breads. But I was told that there was a dumpling made from starchy vegetables and formed into balls then placed into the soup.
Nuts were also gathered when the people were encamped. So you can add some nuts to your diet for protein. The best nut is the almond, and of course walnuts would have been gathered a long time ago, from the walnut trees. If you choose to use acorns, make sure you understand the method to process them into edible food. Pine nuts are excellent, too.
The Benefits of a Vegetarian Diet
If you have Diabetes, obesity, kidney or heart disease you can be assured that the vegetarian diet will help you to build your way back to good health. Too much meat eaten at a meal is hard for the digestive system, and often is transformed into acids.
“Most digestive disorders, such as indigestion, nausea, bloating, gastric reflux, are symptoms caused by excess acid in the gastric region and not enough alkaline minerals in the intestinal tract.[i]
Can you go Paleo AND do vegetarian? Why, yes. Remember there are many types of vegetarian diets. You can play with the type of meats you use… but, always remember you need to purchase grass-fed, free-range, and you will be much healthier!
If you add eggs, these too should be free-range. Milk should not be raw, but you should consider this: it was not a part of the Lakota/Dakota/Nakota diet. Women breastfed their babies sometimes until 7 years of age, and then no other milk was consumed.
Acid/ Alkaline pH Considerations
Many diseases are caused by pH imbalance. Such as: diabetes, heart disease, arthritis to name a few. Also disorders can be healed by eating correctly such as: acid reflux, morning sickness, migraines, and constipation.
A vegetarian diet is mostly alkaline in nature. This is due to the ratio of vegetables and fruits in the diet to proteins. Meats (red meats, beef, mutton, pork, salmon, herring, mackerel, lobster, shrimp and crayfish), millet, white rice, couscous, semolina, white breads, soda crackers, white refined sugars and items coated with it, lard and some lard-like products (Crisco) used for cooking, are all foods high in acid forming elements.
In general, a good rule of thumb is to plate your food with 2/3 alkaline foods, and 1/3 acidic. Of the alkaline types of foods, you should choose any leafy green vegetables, but the ones highest in minerals and vitamins for re-building and maintaining good health are Kale, Bok Choy, and spinach. In the Orange to yellow vegetable bracket are squashes, pumpkins, and carrots. Citric fruits should be eaten early in the day for better digestion.
Foods to avoid:
Refined sugar, all processed foods (white bread, rolls, etc.), any of the typical sweetening substitutes such as Sweet and Low (a carcinogenic) except for stevia (which is plant-based). Even though you may love your fry bread (as I do) that needs to be very limited (only at ceremony or special occasions). Most of the canned fruits used for Wojapi have an additional amount of corn syrups, so use fresh fruits instead.
REFERENCES:
Goodman, Ronald. Lakota Star Knowledge.
Vasey, Christopher. Acid Alkaline Diet for Optimum Health, The. (1999) Healing Arts Press.
[i] How to Balance Your pH to Heal Your Body. http://www.mindbodygreen.com/0-6243/How-to-Balance-Your-pH-to-Heal-Your-Body.html.
Symptoms of Marginal Nutrient Deficiencies
• Tiredness or fatigue
• Stressed
• Irritability
• Trouble with concentration or remembering
• Numbness or tingling of extremities
• Low immunity or prone to colds or the flu
• Depression / Anxiety
• Cravings for sweets
• Morning Sickness
DEPRESSION OR ANXIETY: Deficiencies in vitamin B1.
Whole grains, wheat germ, peanuts, green peas, dark leafy green vegetables, lean pork, cooked dried beans and peas.
CRAVING SWEETS/MORNING SICKNESS: Deficiency in Vitamin B6
VERY PALE SKIN: Deficiency in Folic Acid
FATIGUE: deficiency in iron
Before becoming fatigued, remember that many foods are packed with iron. So begin eating these foods even before becoming pregnant. These foods are: Black Strap Molasses, Spinach, Kale,
INCREASED COLDS AND SUSCEPTIBILITY TO FLU: Deficiency in copper, iron, selenium, zinc, Vitamin A & Beta Carotine, Vitamin E, Vitamin C, or any of the B vitamins (especially Folic Acid)
DISORIENTATION/NUMBNESS OR TINGLING OF EXTREMITIES/MOODINESS/IRRITABILITY/DIZZYNESS: Vitamin B12 deficiency which causes macrocytic anemia, or if the cause is by a lack of digestive factor, pernicious anemia. These two are not the same as an iron deficiency.
Found mostly in food of animal origin, i.e. meats, milk and eggs. If found in plant form it usually is due to fermentation such as Miso.
Note: B12 deficiency may put you at risk for a preterm delivery, or a low-birth-rate baby.
FOLIC ACID
Folic Acid is one of the B Vitamins.
It is found in:
• leafy green vegetables
• wheat germ
• molasses (especially blackstrap)
• nutritional yeast
• whole grains
• root vegetables
• beans
• milk
• spirulina
• The liver contains high concentrations of environmental and systemic toxins / not recommended for pregnant women.
For the maximum use of folic acid from foods, eat them: raw or steamed. You can sautee the vegetables, but remember to do so lightly. If you boil the vegetables, the vitamin will be leached out of the vegetable into the water.
Eat at least two large portions a day. Also eat the other listed items as well.
SYMPTOMS OF DEFICIENCY
• The “mask of pregnancy” and other pigment changes
• Loss of appetite
• Vomiting
• Persistent vaginal infections
• Because other B complex vitamins may also be deficient: various nervous system complaints
Babies are more likely to to have neural tube defects (such as Spina Bifida) when mothers are deficient in Folic Acid early in pregnancy. Low day intake of folic acid and /or low blood folic acid levels in the third trimester doubled the chances of preterm delivery and low birth-rate babies.
Pregnancy Diet For Baby
Plan your meals, AND SNACKS around fresh veggies and fruit, grains and legumes, and ample calcium-rich / protein-rich foods.
Whats-the-Paleo-Diet-3
For those who eat Paleo with Meat
Start your day with a good breakfast:
-Helps energy levels
-maintains optimum weight
-Even just a small meal with some protein and carbs will be beneficial
Eat meals and snacks every 3 to 4 hours
-snacks should include one fruit or vegetables with one serving from another food group.
– Fruit, or vegetable juice (non-sweetened preferably) can substitute for a fruit or vegetable serving.
THE 5-MINUTE MEAL
The trick to preparing a quick, low-calorie meals and snacks are advanced planning, having a basic inventory of ingredients and the right kitchen tools/appliances.
Tools/appliances: microwave oven, slow-cooker, wok or non-stick skillet and a blender
Plan your meals using fresh vegetables and fruit, whole grains and legumes (beans), along with protein rich food. Try not to have canned fruits packed in syrup, eat oatmeal instead of granola bars, steamed broccoli instead of the packaged broccoli with creamed cheese…
SUPER FOODS
Spinach
kidney beans
Tofu
Wheat germ
Broccoli
Papaya
Salmon
Non-fat Milk
Eat fresh fruits and vegetables that are in season, when they are not in season chose frozen before canned.
You can add Nuts such as: almonds, cashews, peanuts, pecans, pistachios, walnuts, and peanut butter.
Also add seeds such as:
pumpkin, sesame, or sunflower seeds.
PROTEIN RICH FOODS
Proportion size should be three ounces of extra-lean meat, skinless chicken, fish or one cup of cooked dried beans, lentils, split peas or chickpeas.
~Limit eggs to just one per day.
CALCIUM RICH FOODS
Cooked black-eyed peas
Bok Choy
Broccoli
Low-Fat Cheese
Collard greens
cottage cheese
Rice Dream
Kale
Yogurt
GREAT GRAINS:
Whole wheat bagel
Whole wheat breads
Sourdough bread
Cornbread
Whole wheat Pita
Rice, preferably brown
white basmati rice
Whole grain Total cereal Noodles or pasta
Kellog’s, Eggo Homestyle waffles
Cooked cereal: Oatmeal, barley, farina
QUENCHERS: Sparkling water, apple cider, apple juice, apricot nectar, carrot juice, grapefruit, grape, orange, papaya nectar, passion fruit nectar, peach nectar, pineapple juice, prune, tomato juice, V8 juice.
If you eat well, the occasional treat will not be a problem, so long as it is not a substitute for whole nutritious foods.
Drink at least 32 ounces water (by itself), a day.
Dehydration is one of the main factors of early labor in women.
Drink tea instead of drinking coffee (it dehydrates).
You should try to drink these teas, at least two cups a day:
Red Raspberry Leaf / Nettle tea.
Upcoming Topics
Trust the Process
Diet for a Healthy Baby
Vegetarian Diet for Pregnant Women
Symptoms of Marginal Dietary Deficiencies
Folic Acid
Anemia
How to Maintain Your Own gynecological Health
You can suggest topics to me, as well: | {
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-2,981,005,459,930,825,000 | What Are the Dangers of Excessive Nutrients?
The nutrients you take in each day not only give you energy to carry out your activities but also provide biological and chemical molecules to support your health. Balancing your daily nutrients assures you have sufficient material to meet your needs but not so much it negatively impacts your well-being. Excessive nutrients can, over time, lead to unwanted weight gain, affect your metabolic processes and increase your risk of nutritional toxicities.
Weight Gain
Maintaining your weight depends on both your food intake and your activity level. Taking in as many calories as you burn allows you to stay at your current weight, but, if you routinely consume more calories than you need, you will increase your body fat. Carbohydrates, proteins and fats all contribute calories to your diet, with carbs providing your primary fuel source. However, once your energy needs are met, excess carbohydrates can convert to fatty acids for storage in your adipose tissue. Your dietary proteins and fats supply amino acids and fatty acids to your body, and, once the requirements for these nutrients are met, the excess can also convert to fat tissue.
Metabolism
Excessive protein intake can impact several aspects of your metabolism. For example, consuming greater levels of this nutrient than your body needs can affect insulin sensitivity and potentially increase the risk of developing diabetes. High dietary protein is contraindicated if you have kidney disorders, and it may be associated with the onset of renal cancer. It may also cause calcium to be leached into your urine, affecting bone health, or predispose you to metabolic acidosis. In this condition, your body’s protein synthesis decreases while protein breakdown accelerates.
Toxicity
Nutrients that do not supply calories to your diet can be dangerous if you take in too many of them. Fat-soluble vitamins are especially prone to causing adverse effects because you store them in your adipose tissue. Toxic levels of vitamin A, for example, can cause birth defects, while too much vitamin D can increase your blood level of calcium and eventually cause calcium deposits in your soft tissues. Minerals can also accumulate to toxic levels and cause problems. For instance, excess dietary calcium may lead to kidney stones, and it affects the absorption of phosphorus, iron, zinc and magnesium. High sodium intake can impact your cardiovascular system, too much copper can cause liver damage and excess manganese can result in neurotoxicity.
Hyponatremia
Water can be an overlooked nutrient, yet it is essential for your body to function properly. Although taking in too little water can cause dehydration and even life-threatening effects, overloading on water can be equally damaging. Hyponatremia is a condition in which your tissues are flooded with so much water it dilutes the sodium surrounding your cells. In its mild form it can cause headache, muscle cramps and fainting, but the condition can rapidly escalate, leading to seizures, brain damage and even death.
About the Author
A writer since 1985, Jan Annigan is published in "Plant Physiology," "Proceedings of the National Academy of Sciences," "Journal of Biological Chemistry" and on various websites. She holds a sports medicine and human performance certificate from the University of Washington, as well as a Bachelor of Science in animal sciences from Purdue University.
Photo Credits
• two obese people wearing union jack waistcoats image by david hughes from Fotolia.com
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5,607,157,541,551,663,000 | Nutritional Dietary supplements
The treatment for most cancers remains to be some way off but it is one thing that science expects to happen possibly within the next few a long time; medical research continues to advance in it’s warfare with this disease that plagues humanity. Our Health and Fitness articles aid you develop a life-style that keeps you up and about, bodily and mentally. Medical and psychological analysis has proven that video video games affect one’s physical and psychological health. Exercise is any bodily activity that enhances physical health and general health.
Various medicine includes healing, therapeutic, and preventive health care practices and treatments that won’t fall inside the realm of typical medicine. Many food retailers, quick meals joints, vitamins and dietary dietary supplements might see an increased demand of their merchandise on account of the developments in health and wellness.
Preserving issues cleaner around the house, opting to minimize or stop smoking altogether, or exercising extra are just a few of the many other ways taught in public health education to fight sickness and enhance one’s life-style. Since we are healthy, exercise and eat proper, we look for high deductible catastrophic coverage.
The significance of health and wellness has definitely come to the forefront of the health industry within the last decade. The federal government regards any kind of incentive for a referral as a potential violation of this legislation because the chance to reap monetary advantages may tempt providers to make referrals that are not medically needed, thereby driving up healthcare prices and probably placing patient’s health in danger.
And, based on recent analysis, there’s a hyperlink between good intestine health and healthy psychological status. Rather than be an imposing and daunting challenge to know, the result will be development of risk administration systems to guide the delivery of health care.
Social health, together with mental and bodily health, is likely one of the key features to determine the final …
Vitamins And Dietary supplements
Many medical studies show positive health results from increased vitamin levels. If the expiration is old-fashioned, it does not imply that the product is dangerous for you, it simply signifies that the vitamins may need misplaced their efficiency. Stress, sugar, caffeine, tobacco, alcohol, drugs, and poor digestion are simply a number of the points that enhance your want for vitamins.
This makes it just about impossible to separate the impact of vitamins from the influence of these different variables. Large amounts of beta-carotene will not make folks sick, but they’ll flip the skin yellow or orange. Fat-soluble vitamins are simpler to retailer than water-soluble ones and might stay within the physique as reserves for days, some of them for months.
Even if they have a baby-proof cap, it is simply not worth the risk as a result of vitamins taken in high doses can be poisonous. The vitamin links lead to progressive JPEG photographs of vitamins and their derivatives and precursors that vary in dimension from about 35 Kb as much as about eighty five Kb.
The Molecular Expressions Vitamins Assortment accommodates all the known vitamins and many biochemicals that had been as soon as thought and claimed to be vitamins. I’ve seen two dermatologists and they each assured me there’s nothing unsuitable with my scalp, the hair is popping out on the follicle and can finally grow back.
Fat-soluble vitamins are absorbed into the body with the use of bile acids, that are fluids used to absorb fat. Fresh fruits and vegetables and whole grains are the first sources of vitamins, carotenoids, and vitamins, in addition to of fiber and vital minerals.…
Dietary Supplements
The significance of health and wellness has definitely come to the forefront of the health industry in the final decade. The Environmental Health profession had its trendy-day roots in the sanitary and public health movement of the United Kingdom This was epitomized by Sir Edwin Chadwick, who was instrumental in the repeal of the poor laws and was the founding president of the Chartered Institute of Environmental Health.
Obviously, when the ailment is life – threatening, resembling cancers, severe organ issues (equivalent to pneumonia, liver problems, and so forth), they want rapid, dramatic therapy, while, at other times, it would make more sense, to make use of, another strategy.
Organized interventions to improve health primarily based on the principles and procedures developed by means of the health sciences are offered by practitioners educated in medicine , nursing , vitamin , pharmacy , social work , psychology , occupational therapy , bodily therapy and other health care professions Medical practitioners focus primarily on the health of people, while public health practitioners consider the overall health of communities and populations.
HealthConventional Chinese health beliefs adopt a holistic view emphasizing the significance of environmental elements in growing threat of disease. The A to Z index of medical ailments comprises hyperlinks to topics with information about that individual health situation. Whereas life have been by far the main factor in untimely deaths, environmental components is the second main cause and has been rising in its importance for health over the past several many years.
Common exercise also improves psychological health, helps prevent despair and improves one’s self worth. After all, each person is totally different, but the one factor that basically stood out was that regardless that these individuals have been through extremely robust occasions they’re also residing interesting and unique lives.
The time period health and wellness are frequently used interchangeably, but the meanings are slightly completely different from one another. Exercise keeps …
Dietary Supplements
HealthThe commonest theme of most cultures is fitness but there are totally different ideas of health as a part of their culture. Though the health benefits of milking the prostate is essential, one has to be very careful in doing so. It’s often beneficial for many males yet it’s imagined to be executed with precautions since it may possibly trigger a different set of issues once finished incorrectly.
For most people, good health care means having a main-care physician, knowledgeable who assists you as you assume responsibility in your total health and directs you when specialised care is critical. New philosophy of health regard health as a fundamental right, it’s an essence of productive life, it is an integral a part of growth and it is the central to the idea of high quality of life and is a world large social objective.
By way of public health training, even simple issues comparable to carrying a flu masks in particularly affected areas, or knowing when to take vaccines for a selected illness that is prominent at that time of the yr, at all times proves very efficient in limiting the number of individuals affected yearly.
Do you know that sweet smelling pineapple is filled with vitamins and minerals? Public health has been described as “the science and artwork of preventing disease, prolonging life and selling health by way of the organized efforts and knowledgeable decisions of society, organizations, public and private, communities and people.” fifty two It is involved with threats to the overall health of a neighborhood based mostly on population health evaluation.
The following checklist is an example of few recognized data assets for an EHR: Repute of EHR, the EHR knowledge, contracts with internet hosting service providers, bodily and logical components of the system, health care professionals, public customers and the procedures of EHR utilization.
A hospital is pushed by the goal of saving lives. 2. More …
Dietary Dietary supplements
Health is a term that refers to a combination of the absence of illness , the ability to manage stress effectively, good vitamin and physical health, and prime quality of life. Prostate therapeutic massage is said to advertise a lifelong prostate health in addition to set off a soothing and erotic feeling. Prolonged psychological stress might negatively affect health, and has been cited as a factor in cognitive impairment with aging, depressive illness, and expression of illness.
The federal government regards any type of incentive for a referral as a potential violation of this regulation as a result of the chance to reap monetary benefits may tempt suppliers to make referrals that are not medically necessary, thereby driving up healthcare costs and doubtlessly placing affected person’s health in danger.
As medical science continues to level to the indeniable benefits of standard train and following a healthy weight loss plan, many people have begun instituting each day routines designed to make us feel healthier and assist us live longer. Healthy body leads to healthy thoughts, and healthy thoughts results in constructive ideas, and positive ideas results in ideas that bring positive change on the planet and make world a better place.
HealthConventional Chinese language health beliefs undertake a holistic view emphasizing the importance of environmental factors in rising threat of illness. Clearly, when the ailment is life – threatening, comparable to cancers, extreme organ points (such as pneumonia, liver problems, and many others), they want immediate, dramatic therapy, while, at different times, it would make more sense, to use, an alternate approach.
Common train additionally improves psychological health, helps stop melancholy and improves one’s self worth. In fact, every particular person is totally different, but the one thing that actually stood out was that regardless that these people have been through extremely powerful occasions they’re also residing interesting and unique lives.
The healthcare discipline is the topic of a bunch of …
Nutritional Dietary supplements
A hospital is driven by the goal of saving lives. When away from dwelling, it is easy to let stress get the perfect of you, however, by including a few of these foods into your food plan, you may be serving to your thoughts to extend your overall effectively being and psychological health. Too much intake of alcohol would cause sure illnesses like brain damage, liver problems, diabetes, high blood pressure and even cancer.
The past ten years or so have been seen a proliferation of various terms, titles, and systems of massage reminiscent of: Therapeutic, Holistic, Swedish, Sports, Neuromuscular, Bodywork, Oriental, Shiatsu, Acupressure, Esalen, Reichian, Polarity, Reflexology, and so forth.
Exercise keeps the body healthy and robust. Also, many hospitals provide incentives to recruit a physician or different health care skilled to hitch the hospital’s medical staff and supply medical services to the surrounding group. To respect private privacy and supply sufficient heat, the client is roofed or draped with a sheet or towel so that solely the part of the body labored on is uncovered at any given time.
With school crammed with exams, homework, and countless other annoying conditions, it’s extremely helpful to eat meals that assist improve your mental health and wellness. And, according to latest analysis, there is a link between good gut health and healthy mental status. Quite than be an imposing and daunting challenge to know, the outcome may be improvement of danger administration techniques to guide the delivery of health care.
Majority of the links offered below direct you to matters and articles on completely different mental and bodily health situations, including asthma, most cancers, arthritis, diabetes, epilepsy, eating disorders, substance abuse, sexually transmitted illnesses, ailments associated with pregnancy, childhood, and far more.
Health has been the newest factor to care about. Pineapple is revered for its anti-inflammatory properties, digestive health advantages and potential anti-cancer properties. Obstetricians and gynecologists, who specialise in … | {
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985,222,536,792,040,800 | Tuesday, September 10, 2024
What Is The Strongest Benzodiazepine For Anxiety
Don't Miss
Are There Different Types Of Benzodiazepines
Should You Take Xanax For Anxiety? (Benefits/Side Affects)
There are 2 different types of benzodiazepines. These are hypnotics and anxiolytics.
Hypnotics are shorter acting. They are mostly used for treating sleep problems such as insomnia.
Anxiolytics are longer lasting. They are mostly used for treating anxiety.
Below is a table of benzodiazepines and their trade names.
Hypnotic Benzodiazepines
You can find more information about Anxiety Disorders by clicking here.
Can Benzos Make Anxiety Worse
In short, benzos are very easy to get on, almost impossible to get off. The anxiety and panic experienced by people stopping benzos is usually much worse than the anxiety and panic that initially led to their use. Other common symptoms are irritability, insomnia, tremors, distractibility, sweating, and confusion.
Is Benzodiazepine Addiction A Problem In Your Life
Benzodiazepine addiction can be incredibly powerful. For many, it completely overtakes their life. This not only impacts the user, but can impact their entire family as well. The addiction may worsen to the point where it seems like all hope is lost, but nothing is further from the truth. Help is out there.
You or your loved one can transform from a life of addiction and dependence to a life of purpose and passion. No one is beyond redemption with the proper love and connection. You know the dangers of waiting too long to get help. Dont take that risk. Contact a treatment provider now for rehab-related support.
Also Check: Which Of The Following Represents A Negative Symptom Of Schizophrenia
Quick Answer: What Is The Strongest Benzodiazepine For Anxiety
• Can Benzos make anxiety worse?
• Ativans strength makes it very addictive, and the drug carries a very high risk of dependence.
• Halcion. Halcion is one of the fastest acting of all Benzos, and it is also processed by the body faster than other Benzos.
• Klonopin. Klonopin is one of the longest acting of all Benzos.
• Librium.
Is There A Non Addictive Anxiety Medication
List Of Benzodiazepines From Strongest To Weakest ...
Examples include desvenlafaxine, duloxetine, and venlafaxine. BenzodiazepinesBenzodiazepines are fast at reducing anxiety, but they are not usually considered the first course of treatment for anxiety. Hydroxyzine is also prescribed to treat anxiety because it works quickly and is non-habit forming.
Also Check: What Is The Phobia Of Clowns Called
How Does Benzodiazepine Work For Anxiety
Benzos do their job by affecting the gamma-aminobutyric acid, or GABA, receptors within the brain. GABA is a neurotransmitter that works by sending messages throughout the spinal cord and the brain. When benzos are taken, it inhibits or slows down those messages from being sent and relaxes your system.
Benzos are very fast acting and relieve symptoms of anxiety in a very short amount of time. Unfortunately, this also means they are typically only prescribed for the short term and used in emergent situations. That is why they are so helpful when anxiety or panic attacks arise because they can calm you dont and stop it within minutes.
Are Alprazolam And Temazepam Safe To Use While Pregnant Or Breastfeeding
Alprazolam
• Benzodiazepines, such as alprazolam, can cause fetal abnormalities and should not be used in pregnancy.
• Alprazolam is excreted in breast milk and it can affect nursing infants. Therefore, women who are should not take alprazolam while breastfeeding.
Temazepam
• Temazepam and other benzodiazepines have been associated with fetal damage, including congenital malformations, when taken by pregnant women in their first trimester. Temazepam should be avoided during pregnancy.
• Use by nursing mothers has not been adequately studied.
Read Also: What Is The Phobia Of Clowns Called
What Is Usually Prescribed For Panic Attacks
Several types of medication have been shown to be effective in managing symptoms of panic attacks, including: Selective serotonin reuptake inhibitors . Generally safe with a low risk of serious side effects, SSRI antidepressants are typically recommended as the first choice of medications to treat panic attacks.
Common Side Effects Of Ativan Vs Xanax
How to get XANAX
Side effects of Ativan and Xanax tend to be greater at higher doses. The most common side effects of Ativan are sedation, dizziness, and weakness. Patients taking Xanax often experience sedation, dizziness, and weakness.
Other side effects that may occur with either drug include fatigue, lightheadedness, drowsiness, amnesia/memory impairment, confusion, disorientation, depression, euphoria, suicidal ideation/attempt, incoordination, lack of energy, dry mouth, tremor, convulsions/seizures, vertigo, visual disturbance , slurred speech, change in libido, impotence, decreased orgasm, headache, coma, respiratory depression, apnea/worsening of sleep apnea, worsening of obstructive pulmonary disease, and gastrointestinal symptoms including nausea, constipation, or diarrhea.
Other side effects may occur. Consult a healthcare professional for a complete list of side effects.
Ativan
Source: DailyMed , DailyMed
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How Do I Know If I Have Generalized Anxiety Disorder
The first step is to rule out the possibility that your symptoms are being caused by a medical condition that is not psychiatric. Among the conditions that produce symptoms similar to those of anxiety are hyperthyroidism or other endocrine problems, too much or too little calcium, low blood sugar, and certain heart problems. Certain medicines also can sometimes cause anxiety. A thorough evaluation by your health care provider will determine if any of these conditions are the cause of your symptoms.
If no other medical culprit can be found and the symptoms seem out of proportion to any situation you are facing, you may be diagnosed with an anxiety disorder.
Which Drug Is Safer Long Term
Although Klonopin is indicated for the treatment of panic disorder, and for certain types of seizures, few trials have evaluated its use long-term. Experts advise doctors monitor the usefulness of Klonopin periodically, and consider gradual discontinuation if the drug appears ineffective.1 Xanax should only be used short-term.1,2,3
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Which Drug Is More Likely To Cause Dependence
Both Klonopin and Xanax have the potential to cause both physical and psychological dependence. Susceptibility to dependence varies depending on dose taken, regularity of consumption, and genetic factors. It is not clear whether risk of dependence is higher with some benzodiazepines compared with others.7
Some people can form dependencies to benzodiazepines after as few as 14 days of regular use. Following six months of continuous use, more than 50% of people are classed as dependent. Benzodiazepines should not be stopped suddenly dosages need to be slowly tapered off over several weeks to months to avoid withdrawal reactions. All addiction-prone individuals should be under careful surveillance if they need to be prescribed benzodiazepines.4,7
Can Strong Benzodiazepines Cause Immediate Overdose
FDA to require strongest warning label for common anxiety ...
Benzodiazepines suppress the central nervous system by increasing the effectiveness of the gamma-aminobutyric acid neurotransmitters in the brain, which leads to some nerve impulses being blocked.
When this type of medication is used properly, the central nervous system still functions well. However, high doses of any type of benzodiazepine can cause an overdose. Excess of these drugs in the system can lead to trouble breathing, confusion, slowed heart rate, weakness, coma, and death.
Injecting these drugs or consuming them with other central nervous system depressants can increase the risk of an overdose, and so can taking more than the doctor-recommended dosage.
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Are Withdrawal Symptoms More Severe With Xanax
Yes. Reviews suggest discontinuation from Xanax is particularly difficult and is associated with more serious rebound and withdrawal symptoms.5 Compared to Klonopin, Xanax has a much shorter half-life .4,5,6 Half-life is a technical term for the time it takes for 50% of an administered drug to leave your body it is not the same as duration of effect. The blood levels of drugs with longer half-lives tend to remain relatively more constant in the body, and tend to cause much less severe withdrawal symptoms than dramatic fluctuations seen with benzodiazepines with a shorter half-life such as Xanax.
Withdrawal symptoms may include agitation, convulsions, hallucinations, tremor, abdominal and muscle cramps. More severe withdrawal symptoms are likely in people who have taken larger dosages over an extended period of time.
List Of Commonly Abused Benzodiazepines
Benzodiazepines are drugs prescribed to treat anxiety disorder, panic attacks, and insomnia. Theyre often abused because of their sedative-hypnotic properties and the pleasurable sense of relaxation they can produce.
There are many types of benzodiazepines. Some are stronger than others, and some last longer. Which one a doctor prescribes depends on your personal needs.
The strength of a benzodiazepine depends on its potency as well as its half-life. Half-life is how long it takes for your body to metabolize and excrete half of the drug dose.
Long-acting benzodiazepines take effect gradually and stay in your system for a prolonged period. Theyre typically prescribed for anxiety.
Short-acting benzodiazepines take effect quickly but dont last as long. Theyre often prescribed for insomnia .
Read Also: Does Pristiq Help With Anxiety
Does Xanax Cause Rebound Anxiety
Those who were prescribed Xanax for generalized anxiety disorder, panic disorder, or insomnia can experience rebound symptoms after quitting use of the drug. Rebound effects are intensified symptoms of a pre-existing psychological disorder and may include anxiety, panic attacks, and inability to sleep.
Are There Any Side Effects
Top 5 Strange Facts about XANAX
Not everyone who takes benzodiazepines will get side effects. Talk to your doctor if you are worried about side effects.
Addiction
You should only be prescribed benzodiazepines for the shortest amount of time possible. Taking benzodiazepines regularly for a few weeks or more can lead to addiction. Doctors recommend that you only take them for 2-4 weeks.
Intermittent use may help to avoid addiction. Intermittent means that you dont take it regularly. For example, you dont take it every day.
The risk of addiction is higher if you have a history of drug or alcohol abuse. Or if you have a personality disorder.
Common side effects
• Hallucinations. This is when you see, her, smell or feel things that are not there.
• Delusions. This is where you have beliefs that dont match reality
When will withdrawal side effects stop?
Your withdrawal side effects will usually stop after a few weeks. But they can last longer for a small amount of people. You may not get withdrawal side effects when you stop your benzodiazepine medication.
You should talk to your doctor or local pharmacist if you are worried about the withdrawal effects of benzodiazepines.
Is there anything that can help with my symptoms through withdrawal?
Antidepressant and mood stabilizing drugs may help with the withdrawal effects of benzodiazepines.
If you have insomnia you may benefit from treatment with melatonin.
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Conditions And Durations With No Evidence Of Efficacy
Even in the conditions for which BZDs have proven efficacyPD, GAD, SAD and insomniathere is no evidence of long-term efficacy.
Aside from PD, GAD, SAD and insomnia, no other mental disorders have an evidence-basis for BZDs. To the contrary, PTSD and phobias have evidence of ineffectiveness or even harm. Biological explanations for BZD-induced anxiety include discontinuation symptoms and/or worsening of underlying anxiety pathophysiology . BZDs have demonstrated the ability to interfere with fear extinction , which is critical for the improvement of anxiety and is likely why BZDs have been found to increase fear conditioning with phobias and to have fear-sensitizing effects in response tostress . For many, BZDsespecially when used long-termactually worsen anxiety.
List Of Benzodiazepines From Strongest To Weakest
Benzodiazepines are all created with different levels of potency and efficacy, and their half-life, or how long they last, will vary based on how they are made and their intended uses. Keep in mind, of course, that even the lowest-strength benzodiazepine medications can still be highly addictive.
Although most individuals who use benzos to get high prefer the more potent, shorter-acting drugs, all of them are rated as Schedule IV controlled substances and should be considered dangerous outside of a carefully monitored prescription use.
Here is a list of benzodiazepines in order from strongest to weakest.
Strongest Benzodiazepines:
• Valium
• Dalmane/Dalmadorm
No matter the strength, the potency, how long the benzodiazepine lasts, or how fast it takes effect, they are all capable of causing dependency and addiction, and this is where Allure Detox can help.
The health threat posed by withdrawal is one of the main reasons a benzo detox is necessary. Our team performs benzo detox on a medical basis, prescribing replacement drugs on a decreasing schedule until the withdrawal symptoms dissipate. It is challenging for a long-term benzo users to stop on their own.
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The Risks Of Dependence After Benzo Use
The biggest risk associated with benzos is dependence, abuse, and addiction. Some people may develop a dependence without doing it on purpose. Over time, your body becomes adjusted to having it in your system. This may cause you to take higher doses to achieve the same effect. Other people abuse and become addicted to benzos in order to feel high.
According to NIH:
Among past-year benzodiazepine misusers, 46.3% reported that the motivation for their most recent misuse was to relax or relieve tension, followed by helping with sleep . About 5.7% reported experimentation as their main motivation for misuse, and 11.8% reported using them to get high or because of being hooked.
These numbers are very high and alarming, but no matter why you have become dependent upon benzodiazepines, there is help available to get you off of them.
What Are The Main Differences Between Klonopin Vs Ativan
FDA to require strongest warning label for common anxiety ...
Klonopin is the brand name for clonazepam. It is used to treat panic disorder and seizures. Klonopin stays in the body relatively long with a half-life of 30 to 40 hours. This means that a person can still feel the lingering effects of Klonopin for some time after its taken.
Ativan is the brand name for lorazepam. It can be used to treat anxiety and seizures. The injectable form can also be used for anesthesia before certain procedures. Ativan has a half-life of around 20 hours in the body.
Main differences between Klonopin vs. Ativan
Klonopin
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Is Lorazepam Stronger Than Diazepam
Diazepam is better absorbed after oral than after i.m. administrations but this does not apply to lorazepam. The clinical effect and amnesia begin more rapidly with diazepam, but last longer following lorazepam. Lorazepam is more effective than diazepam in blocking the emergence sequelae from ketamine.
What Are Ssris And Snris
Selective serotonin reuptake inhibitors like Zoloft and Prozac, and serotonin and norepinephrine reuptake inhibitors like Effexor and Pristiq are antidepressant medications, but they can help with anxiety symptoms as well. For this reason, many providers will prescribe an SSRI or SNRI if you have a combination of depression and anxiety.
SSRIs and SNRIs are not an instant fix for symptoms associated with an anxiety disorder, nor do they even provide immediate relief, Alonzo said. They work by interacting with the neurotransmitters and receptors in your brain, which can help regulate mood, sleep and energy levels. It is important for patients to understand that these medications may take four to six weeks for full effect.
Some patients may respond better to one of these medications than others. If after taking the medication for two weeks and symptoms have not improved, talk to your provider to have your medication regimen adjusted. Treatment trials with more than one medication are not uncommon.
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Does Anxiety Worsen With Age
Anxiety doesnt necessarily get worse with age, but the number of people suffering from anxiety changes across the lifespan. For example, phobias are more common in children, panic disorder is more common in middle-aged adults, and older adults are more likely to experience generalized anxiety disorder.
Do Benzodiazepines Affect Other Medication
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Tell your doctor about any medicines you are taking before you start to take benzodiazepines. This includes any supplements or herbal medicines you take. Benzodiazepines can react with other types of medication and cause more side effects such as extra tiredness or low blood pressure. Medication that can react with benzodiazepines includes:
• antidepressants,
• beta-blockers.
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Do I Need This Treatment
A certain amount of anxiety or insomnia is a normal reaction to what is happening in your life. You may worry or feel stressed, and sometimes these feelings can keep you up at night. Most often, these feelings pass and are not a problem. However, these feelings can become a problem when they continue over a longer term, cause severe distress, make you feel physically ill and affect your behaviour. This kind of anxiety may be triggered by a challenging life event. It can also be a symptom of a mental health problem.
The ability to fall asleep and to sleep through the night can be affected by many types of health problems. These include physical conditions that cause pain or trouble breathing, as well as mental health problems. When sleep is disrupted, health can be further affected.
While each situation is unique and different treatment approaches may be called for, benzodiazepines can help to provide relief.
Get On The Path Of Recovery From Benzo Dependence
We believe that quality clinical care should be readily available to everyone who needs it, especially those struggling with a drug addiction that can be fatal, like a benzodiazepine addiction. Many people mistakenly believe that because a knowledgeable professional prescribes prescription drugs, they are always safe to use. While they are typically safe to use when theyre used as directed, if they are abused, they can lead to a range of serious issues like physical dependence, overdose, and fatality. Call us today to receive the addiction treatment you both need and deserve.
24/7 Confidential Treatment Helpline
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What Is Alprazolam What Is Temazepam
Alprazolam is an anti-anxiety medication used to treat anxiety disorders and panic attacks. Alprazolam is a benzodiazepine, the same drug class that includes diazepam , clonazepam , lorazepam , and flurazepam . Alprazolam and other benzodiazepines act by enhancing the effects of the neurotransmitter gamma-aminobutyric acid that inhibits activity in the brain. It is believed that excessive activity in the brain may cause anxiety or other psychiatric disorders.
Temazepam is a drug used to treat anxiety. Temazepam also increases total sleep time and is used to treat insomnia. It is a benzodiazepine, the same class of drugs as diazepam , alprazolam , clonazepam , flurazepam , and lorazepam . Temazepam and other benzodiazepines act by enhancing the effects of the neurotransmitter gamma-aminobutyric acid that inhibits activities of the brain. It is believed that excessive activity in the brain may lead to anxiety or other psychiatric disorders and temazepam reduces the activity.
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-7,426,506,076,037,518,000 | 138 Views
Health
What does it mean to have anaemia?
Dr. Sylvester Ikhisemojie
Dr. Sylvester Ikhisemojie
Anaemia is a unique phenomenon that often represents a range of effects around the body. It usually represents the fact that the total red blood cell count is lower than normal or that the protein compound called haem, which is responsible for the binding of oxygen to the red blood cell is less than it should be.
When either fact is the true position of things, the person is said to have anaemia. The average red blood cell count in an average sized adult weighing about 70 kilogrammes is between 5.5 and 6 million red blood cells. When taken together with the plasma and the other components of the blood, they usually bring the total average blood volume to the average of 5.5 to 6 liters. More accurately, this figure is assumed to be the case when the blood of any person is spun in a tiny capillary tube in a centrifuge and a figure expressed as a percentage is obtained. That figure is known as the packed cell volume, or PCV.
The PCV varies with age. In the newborn child, it is usually between 45 and 50 per cent and may occasionally reach 55 per cent. This figure gradually diminishes over the first three months of life as the blood from the mother which still circulates in the baby gradually gets whittled down as the cells die off and are replaced by the native ones produced by the baby. When the level falls below 30 per cent, as is often the case, a state of anaemia is declared. With the passage of time and in the absence of illness, this figure begins to creep upwards again and should reach a figure between 44 and 48 per cent for males at the end of the first year of life. For female infants, the figure is slightly less at between 40 and 44 per cent. For much of the first decade of life, this is maintained.
The specter of anaemia is a very broad field. The most dramatic cause is usually bleeding. The blood loss may be dramatic and rapid with serious consequences. We can often see such results from the scenes of an accident, from serious burns and from major operations in the theatre. Sometimes, the source of the bleeding is equally dramatic and may not be evident. This is the case in those persons who sustain internal injuries and therefore bleed into their body cavities. This can also be observed from major injuries as seen in the emergency rooms of various hospitals where the people who sustain major fractures such as the thigh bone can lose up to half of their blood volume into the soft tissues of the thigh and go into a status known as shock. When people are shot in their abdomen, they can lose similar quantities of blood into the large spaces within that cavity with similar consequences.
The most common cause of anaemia in Nigeria and elsewhere in the world, however, is nutritional and the most prominent of these is iron deficiency. In our country alone, as many as 1.5 million people could be suffering from this problem in any given year. It is therefore a huge burden that can be substantially ameliorated with the judicious use of iron supplementation in the diet. In addition, all possible causes of iron deficiency must be identified and treated. That usually means some serious laboratory blood work. The stool will also have to be examined in order to exclude the possibility of worms so that when malaria has been treated, bacterial infections cured and worms killed and expelled from the body, the blood count should improve. In many cases, there are other contributing factors such as poor nutrition and chronic malnutrition.
People who are trapped in this kind of vicious cycle often do not have any meaningful, tangible disease other than illiteracy and poverty. For such people, proper education is the key to getting out of this kind of cycle. Many others will need specific treatment to address their deficiency and some are ill enough to be hospitalised. People in this category include those who do not have evident, dramatic bleeding but who bleed all the same. Some of these people have ulcers from which they bleed a little at a time over a long period of time. Others have problems like diverticula disease from which they could similarly bleed. A good number are knowledgeable enough to tell that they are carrying some burden but will have no way of even realizing that they are bleeding internally. Some of the people who have bleeding ulcers will often pass black stools that resemble tar. They will not know that it signifies internal bleeding unless they complain at a hospital and are told.
In summary, bleeding can be open and torrential. It can also be concealed and severe. In the same way, bleeding can be slow and may occur over a period. Finally, it can be open and also slow over a long time frame. This is seen in women who have problems like fibroids and from benign prostatic hypertrophy in men who can also bleed in severe cases. Such cases tend to cause blood loss over time. And even though they can often be severe as well, it is never anything close to what one can see at an accident scene or in a gunshot injury. Sometimes, certain catastrophes are known to occur even in the absence of some illness and these are fortunately uncommon things. In that regard, we remember here and now major problems like a ruptured aneurysm which involves the explosion, so to speak, of a blood vessel whose wall is weakened to the extent that it gets torn. When this happens, depending on what part of the body is involved, the person can lose almost their entire blood volume before it is realised that something is wrong. If the abdominal aorta is the culprit, such an individual is unlikely to even get to the hospital before death ensues.
The major aspects of anaemia we have looked at today cover only two aspects; there are several others and we shall be looking at those ones as well over time. What we have explored today are two major causes – blood loss anaemia and nutritional anaemia. What is important is to know that sometimes, whatever may be the cause of a particular type of anaemia, the effects on the body are similar. If someone has been shot in the abdomen, or has an accident in which the spleen gets ruptured or is a pregnant woman who suffers from a ruptured ectopic pregnancy, the blood loss in each case is catastrophic and the effects are the same ultimately. We will have time to look at those effects ultimately when we explore the effects of anaemia on our body and our lives in the subsequent essay.
Ask the doctor
Dear doctor, I have mouth odour. It started with gum bleeding. Any time anything touches it, there is bleeding. I want you to recommend any drug or health tips to get rid of it totally. Thanks. 0705xxxxxxx
Thank you very much for that question because it is one that has been asked on this page repeatedly over a long time. If your gums bleed at any touch, you need to see a dental surgeon for proper examination and treatment. Your problem may go beyond just taking care of the mouth odour but let the dentists first give you their opinion.
Dear doctor, I have been addicted to bread and beans. In fact, for the past two years, 95 per cent of my food has been bread and beans. Now, I am worried because it is getting too much. Is it something I should be worried about? Thanks. 0703xxxxxxx
You should have nothing to worry about at this point. As far as I see, you also take some other types of food it is not that bread and beans is your exclusive diet. Perhaps for the time being, that combination is what catches your fancy. Enjoy it while it lasts. Bread has carbohydrate and sugar. Beans has protein, plant protein for that matter. That is a balanced diet in every respect.
Dear doctor, I saw your article about bald head in SUNDAY PUNCH. Please, do you know any remedy for bald head? I am just 30 years old and baldness troubles me a lot. 0805xxxxxxx
The available remedies were mentioned in that article. We talked about hair transplant which is not available in Nigeria and we also talked about Minoxidil cream. The latter is available in some pharmacies as a two per cent cream and can be applied to the bald area two times a day over a period of six weeks to three months before you assess if anything has been gained.
I am a 34-year-old man. I am experiencing serious baldness. I am from Lagos. Please what should I do? 0902xxxxxxx
You can visit any of the major pharmacies in Lagos where you can ask for Minoxidil cream and apply it as described above. That should help but progress might be slow.
Dear doctor, I am an 18-year-old virgin but sometimes I feel like having sex. I take comfort in the pillow most times because I don’t want to have sex with any man for now because I am still young. Please sir, does it have any effect on me? 0810xxxxxxx
It is good to hold yourself as you are doing. Your feelings are normal but the pillow cannot have any effect on you.
Dear doctor. Please I have facial twitch. What can be the cause and how can I be cured of it? I am 70 years old. Thank you. 0803xxxxxxx
It may not have a cause at your age to put it very directly. Sometimes, though, it may be caused by a tumour which is an abnormal growth within the face especially if the growth gets to the point at which it is able to touch any of the branches of the facial nerve and provoke it to cause muscle twitching.
In a similar way, when a blood vessel touches a branch of the facial nerve, it can also provoke a similar response. The best thing for you to do is to see a physician who will examine you and be able to determine what will be the most likely cause of your facial twitch. When that is done, treatment is possible.
Dear doctor, I am 56-year-old woman with two kids. I am a healthy woman really and do not have either high blood pressure or diabetes. I do not take alcohol too but of late, I have found myself getting very tired with any small physical activity I do. I have done some tests recommended by our family doctor mainly PCV (packed cell volume), fasting, blood sugar and malaria parasites. I was also tested for typhoid. Only malaria parasite was present and I had treatment but the symptoms remain. What do you think I should do? 0703xxxxxxx
I believe you have not done enough tests to determine what the problem is. Perhaps you should see a physician who will then conduct a more comprehensive examination on you which will include hormone profiles such as thyroid function and the sex hormones. When all that has been done, I am certain that a solution to the weakness you complain of will be found. Above all, that will be a determination of whether the feelings you are suffering are due mainly to having arrived at the age of menopause. Those tests will help unveil what the cause is and that is half way to solving the problem.
Dear doctor, I have been experiencing some degree of internal heat off and on for the past five months. I first complained at the National Hospital, Abuja where my doctors asked me to run some blood tests and they assured me that there was nothing to worry about. However, about three months ago, I observed that I was losing weight rapidly and was sweating quite profusely even when an air-conditioner was on. I complained again and was asked to run another series of tests. I was then informed that what I am suffering from is known as a toxic goiter. However, I do have a niece who suffered from similar problems and I know you were instrumental in getting her treated. I have no swelling as such on my neck and I do hope to avoid doing an operation like she did. What do you suggest I do now and how do I go about it? I am very disturbed about this. Thank you very much. 0817xxxxxxx
First of all, I must thank you for your faith in what we are doing here. The most important thing as I see it now is to make a diagnosis regarding your condition. You can have a toxic goiter even in the absence of a neck swelling and there is a distinct terminology for that and it is then known as an occult kind of disease. You will need to have thyroid function tests done at intervals over time to monitor your level of improvement of lack of it as well as X-rays of the chest and neck and possibly an ultrasound scan. After all of that, a more certain diagnosis is usually made and treatment can then be started. Your doctors will be able to advise you as required or you can also reach out to us here for further directions. But the very first thing to do now is a confirmation of the clinical diagnosis that has been reached.
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-7,155,789,626,748,296,000 | Diabetes complications
Having type 1 diabetes does not prevent you from living a normal life. People with type 1 diabetes can and do become elite athletes, corporate high-flyers, trapeze artists, medical professionals, teachers and everything in between. But having type 1 diabetes does mean you have to balance your diabetes management with your day to day life to avoid complications.
Complications can occur because over time persistent high blood glucose levels can damage the body’s organs. This damage is referred to as diabetes-related complications. It may be frightening to think about complications but it is important to understand all you can about living with type 1 diabetes and the affect your management has on your overall health.
If you can manage to keep your blood glucose levels, cholesterol and blood pressure within the normal range, the risk of damage to your body is reduced. With the support of your healthcare team you will be able to develop a daily self-management program that includes setting goals, taking responsibility and making positive lifestyle choices.
Effective diabetes care means taking charge of your diabetes management. Ask questions and request more information if you need to. The more you know the more confident you will become and the easier it will be to manage your diabetes. It is important that you follow the annual cycle of care to ensure you are constantly monitored for any complications.
When diabetes is left undiagnosed or unchecked for too long, it can be responsible for a number of diabetes related complications such as eye disease (diabetic retinopathy), nerve damage (diabetic neuropathy), kidney disease (diabetic nephropathy), heart disease and stroke. See below for more information on complications.
Complications
Hypos and hypers
Diabetes is a manageable condition, but key to successfully living with diabetes is balancing medication and insulin injections with food and activity. When that balance isn’t right, one of two things will happen: either blood glucose drops too low and hypoglycaemia (a hypo) results, or blood glucose rises too high and hyperglycaemia (a hyper) occurs. No matter how much you know about diabetes or how careful you are, if you are living with type 1 diabetes you are likely to experience some hypos or hypers.
Kidney disease
Your kidneys help to clean your blood. They remove waste from the blood and pass it out of the body as urine. Over time, diabetes can cause damage to the kidneys (diabetic nephropathy). You will not notice damage to your kidneys until it’s quite advanced, so it is important that you have the recommended tests to pick up any problems early.
If the kidneys fail, toxic waste products stay in the body, fluids build up and the chemical balance is upset. If the kidneys are unable to function properly, dialysis treatments or a kidney transplant will be needed. The risk of developing kidney problems is reduced by managing your blood glucose levels, having regular kidney and blood pressure checks and leading a healthy lifestyle. Early signs of kidney problems can be detected through a urine test. Finding out about early kidney damage is simple and painless. Treatment at this time can prevent further damage. Read more here.
Nerve damage and lower limb complications
Diabetic neuropathy is the medical name given to progressive damage to the nervous system caused by type 1 diabetes. Diabetic neuropathy can lead to a loss of feeling in the hands and feet. Reduced circulation resulting from high blood glucose impairs normal wound healing in the extremities, so minor damage can linger and develop into permanent injury. Personal daily foot checks and thorough annual foot examinations conducted by your doctor or podiatrist will help to reduce your risk of lower limb complications. For more information read here.
Heart disease and stroke
People with diabetes are at increased risk of heart disease and stroke due to raised blood glucose levels (BGLs), in association with high blood pressure and cholesterol. To read more follow this link.
Eye disease (diabetic retinopathy)
Diabetes can damage the back of the eye and affect vision. The development of diabetic retinopathy is strongly related to the length of time diabetes has been present and the degree of blood glucose control. Regular checks and treatment can prevent serious eye problems and blindness caused by retinopathy. Learn more here.
Oral health
Dental problems are more common in people with diabetes. Dental problems can include gum inflammation (gingivitis), infection and inflammation of the ligaments and bone that support the teeth (periodontitis), tooth decay (dental caries), dry mouth (xerostomia), fungal infections (oral thrush) and disturbances in taste.
Oral problems can occur in people with diabetes for a number of different reasons, which is why it is especially important to visit a dentist regularly and tell them about your diabetes. People with diabetes who have persistent high blood glucose levels are more likely to have dental problems. For more information on looking after your teeth and gums click here.
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Lipohypertrophy
Lipohypertrophy is a condition where there is a build up of fatty tissue under the skin which is known to commonly occur if insulin is repeatedly injected into the same site. For more information click here.
Coeliac disease
Type 1 diabetes and coeliac disease are both known as autoimmune diseases – conditions where the immune system attacks parts of the body. While the cause of both coeliac disease and type 1 diabetes is not fully known, there is a relationship between the two conditions. Between 4-10% of people with type 1 diabetes also have coeliac disease. To find out more click here.
Sexual health
While most people with diabetes, both male and female, are able to lead completely normal sex lives, diabetes may contribute to sexual problems for some people. To read more click here
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Hearing
While it unknown exactly why hearing loss is more common among people with diabetes some researchers believe prolonged high blood glucose levels may lead to hearing loss by affecting the supply of blood or oxygen to the tiny nerves and blood vessels of the inner ear. Over time, the nerves and blood vessels become damaged, affecting the person’s ability to hear.
Diabetic ketoacidosis (DKA)
Consistently high blood glucose levels can lead to a condition called diabetic ketoacidosis. This happens when a severe lack of insulin means the body cannot use glucose for energy, and the body starts to break down other body tissue as an alternative energy source. Ketones are the by-product of this process.
Ketones are poisonous chemicals which build up and, if left unchecked, and will cause the body to become acidic – hence the name ‘acidosis’. DKA generally develops over 24 hours but can develop more quickly particularly in young children. DKA develops when blood glucose levels are extremely high – often as a result of illness. For information on how to look after yourself when you are feeling unwell click here. DKA can develop rapidly and should be treated as a medical emergency at hospital.
Depression, distress and burnout
The demands of managing type 1 diabetes are considerable and diabetes burn-out, diabetes distress and diabetes depression are very real and recognisable problems. It is important that you don’t ignore your emotional wellbeing. Diabetes NSW has developed several useful information sheets that will provide you useful tips.
Persistent infections
Ongoing infections that don’t appear to clear up can lead to more serious consequences for people living with diabetes. If you get an infection, it is important that you contact your doctor or call Diabetes NSW and ask to speak to a diabetes educator on 1300 136 588. | {
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2,878,757,537,833,401,300 |
• Robert Danziger
The P-Value Controversy And Why It Matters to a Determined Patient
As a determined patient checking out conclusions of any medical research study, you will want to figure out whether the conclusions the study has drawn apply to you and your unique health situation. That’s why you should look at something called “P” values.
A “P” value, or probability value, is a term used by statisticians and in research to show whether the results of a study are due to an actual, significant difference in treatments or the difference is mostly likely due to some random factor. For example, let’s say a study showed that a group being treated with a particular drug had fewer symptoms compared to another group being treated with a different drug. In the summary of the results of a research study, it may be reported that drug A was better than drug B and give a P value for the results of less than (“<”) 0.05. This means that there is less than a 5 percent chance that you should dismiss the results showing that drug A was better than drug B and more than a 95 percent chance the results can be relied on. That's good news.
The lower the P value, the more unlikely that the results are due to a random factor that might not show up if the study were to be repeated. Thus, if the P value were <0.005, there would be less than 5/1000 (or 0.5 percent) chance that the results showing drug A was better than drug B are unreliable. That sounds even better, doesn't it?
The determined patient looks for a lower P value in studies because this means the conclusions are more likely to be correct. The controversy is how low the P value should be for a study to have value. By convention, it has been 0.05 but with the new call for a P value that is ten times lower, or 0.005, researchers are being pressured to make sure their studies are even more reliable than ever before.
#Pvalue #determinedpatient #medicalresearchstudies #understandingresearchstudies #researchstudies
23 views0 comments
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8,168,489,082,917,024,000 | beach massage
luxury Thai spa
Another type is myofascial release therapy. It involves releasing stiffness and adhesions in the fascia. Your therapist can massage areas that are tight with light pressure and stretch them.
A 2021 analysis of 17 studies showed that MLD early in breast cancer surgery can help to prevent the progression to clinically significant lymphedema. But, it may not prove to be any benefit to patients with moderate or severe lymphedema.
Cranial sacral therapy, also known as craniosacral massaging, is a form of bodywork that relieves compression in the spine, low back and head bones.
The massage will include work on your entire body, though your therapist will focus on specific areas that need to be released. You can wear lightweight clothing for the massage, or you can be fully or partially undressed.
The most common type of massage is Swedish massage therapy. It involves soft, long, kneading strokes, as well as light, rhythmic, tapping strokes, on topmost layers of muscles. This is also combined with movement of the joints. By relieving muscle tension, Swedish therapy can be both relaxing and energizing. And it may even help after an injury.
In a traditional Thai massage, practitioners use their hands, thumbs, elbows, forearms, and sometimes even their feet to reduce tension in your muscles.
luxury Thai spa
luxury Thai spa
luxury Thai spa
Cupping therapy is a treatment that uses the body's own energy. Keep reading to learn more about this alternative treatment, and what to expect during treatment.
According to 2014 research lymphatic drainage massage was found to be more effective in improving the quality-of-life of fibromyalgia patients than connective tissues massage.
If a massage therapist is pushing too hard, ask for lighter pressure. Occasionally you may have a sensitive spot in a muscle that feels like a knot. It's likely to be uncomfortable while your massage therapist works it out. But if it becomes painful, speak up.
walk in massage places
Pressure points are sensitive parts of the body that correspond with different aspects of your mental and physical well-being. How to use five pressure points.
It is also a good idea for you to speak briefly with your therapist prior to starting your session. This allows you to share your expectations and ask questions.
Typically, massage practitioners use either oil or talcum powder to allow their hands to slip over a person's skin. Sometimes, a sheet or thin piece of cloth might be used for the same effect.
walk in massage places
my Thai massage
my Thai massage
Myofascial Release Therapy is another type. This involves relaxing stiffness in the fascia (the connective tissue system that holds each muscle in the body), and releasing it. With light pressure, your therapist will massage or stretch tight areas.
Massage is perhaps one of the oldest healing traditions. Many ancient peoples – including the Ancient Greeks, Egyptians, Chinese and Indians – were convinced of the therapeutic properties of massage and used it to treat a variety of ailments.
Cranial sacral therapy is a gentle manipulation of bones in the skull and spine that can improve the flow cerebrospinal fluid. It can also result in deep relaxation.
How often should I get a Thai massage?
Deep tissue massage uses more pressure than a Swedish massage. It’s a good option if you have muscle problems, such as:
Before prescription medication, prostatic therapy was the main treatment for ED. Prostatic massage is still used today by many men. Learn...
There are some instances where massage and myotherapy may not be recommended, or a GP or specialist referral should be obtained, including (but not limited to):
walk in massage places
How long should you get a Thai massage for?
You need to decide what massage style you prefer before you can make a decision. Are you looking for relaxation or stress management? Do you need to relieve symptoms or treat a specific health condition? Let the therapist know your needs before you book a massage. Ask the therapist which style they use. Many people use multiple styles. The therapist can also customize your massage to suit your needs and goals, such as your age or condition.
During a Thai massage, the therapist uses their body to move the client into a variety of positions. This type of massage includes compression of muscles, mobilization of joints, and acupressure.
Abhyanga is a type of oil massage from the system of Ayurvedic medicine. The oil is warmed and gently massaged all over the body. This type of massage focuses on nourishing the skin rather than deeply massaging the muscles.
How long should you get a Thai massage for? | {
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-4,521,054,713,537,836,000 | Keratitis
Also known as: bacterial keratitis, viral keratitis, inflammation of the cornea.
What is keratitis?
The cornea is the clear domed-shaped surface in the front of the eye. It provides protection to both the iris and pupil of the eye. Keratitis is an inflammation or infection of the cornea.
What causes keratitis?
Keratitis can occur after an eye injury, a bacterial/viral/parasitic or fungal infection or due to lack of Vitamin A. Wearing contact lenses increases the risk of keratitis because of poor hand hygiene with its use.
What are the symptoms of keratitis?
Common symptoms include; a painful red eye, swelling, discomfort when the child looks at light (light sensitivity or photophobia), teary watery eye or discharge, blurry vision, and the feeling of something being in the eye.
What are keratitis care options?
Treatment is a medical emergency and the child should see an ophthalmologist as soon as possible. Potential treatments for keratitis include protecting the cornea, eye drops and/or oral medications.
Reviewed by: Jack Wolfsdorf, MD, FAAP
This page was last updated on: 3/23/2018 2:13:25 PM | {
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-1,217,869,440,473,742,000 | Clinical Review
Emergency and early management of burns and scalds
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b1037 (Published 08 April 2009) Cite this as: BMJ 2009;338:b1037
1. Stuart Enoch, specialty registrar in burns and plastic surgery1,
2. Amit Roshan, specialty registrar in burns and plastic surgery2,
3. Mamta Shah, consultant burns and plastic surgeon3
1. 1University Hospitals of Manchester, Manchester M23 9LT
2. 2Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge CB2 8QE
3. 3Central Manchester and Manchester Children’s Hospitals NHS Trust, Manchester
1. Correspondence to: M Shah, Regional Paediatric Burns Unit, Booth Hall Children’s Hospital, Manchester M9 7AA mamta.shah{at}cmmc.nhs.uk
Summary points
• Most minor burns can be managed in primary care
• Appropriate first aid limits progression of burn depth and influences outcome
• Assessment of area and depth is crucial to formulating a management plan
• Burn depth may progress with time, so re-evaluation is essential
• All major burns require fluid resuscitation, which should be guided by monitoring of the physiological parameters
• A multidisciplinary approach is crucial for a successful clinical outcome
Burn injuries are an important global health problem. Most simple burns can be managed by general practitioners in primary care, but complex burns and all major burns warrant a specialist and skilled multidisciplinary approach for a successful clinical outcome. This article discusses the principles behind managing major burns and scalds using an evidence based approach and provides a framework for managing simple burns in the community.
Sources and selection criteria
We searched Medline, Ovid, Burns, and the Cochrane Library until June 2008 for randomised controlled trials, systematic reviews, evidence reports, and recent evidence based guidelines from international burn associations.
What is the burden of burns injuries?
Annually in the United Kingdom, around 175 000 people attend accident and emergency departments with burns from various causes (box 1).1 This represents 1% of all emergency department attendances, and about 10% of these patients need inpatient management in a specialist unit.2 A further 250 000 patients are managed in the community by general practitioners and allied professionals. Of patients referred to hospital, some 16 000 are admitted, and about 1000 patients need active fluid resuscitation. The number of burns related deaths average 300 a year.1
Box 1 Some important causes of burns and scalds
• Flame burns
• Scalds (hot liquids)
• Contact burns (hot solid)
• Chemicals (acids or alkalis)
• Electrical burns (high and low voltage)
• Flash burns (burns resulting from brief exposure to intense radiation)
• Sunburns
• Friction burns
• Radiation burns
• Burns from lightning strike
Globally, the World Health Organization estimates that 322 000 people die each year from fire related burns.3 This could be an underestimate, however, because we have no valid comprehensive statistics from developing countries, where >95% of these deaths occur.3 4 High population density, illiteracy, poverty, and unsafe cooking methods contribute to the higher incidence in developing countries.4
How is the area of a burn estimated?
In adults, Wallace’s “rule of nines” is useful for estimating the total body surface area—18% each for chest, back, and legs apiece, 9% each for head and arms apiece, and 1% for the perineum. It is quick to apply and easily remembered, although it tends to overestimate the area by about 3%.5 The Lund and Browder chart takes into account changes in body surface area with age (and growth). It is useful across all age groups and has good interobserver agreement.5 Another useful, but rather subjective, guide is to use the surface area of the patient’s palm and fingers, which is just under 1% of the total body surface area. This method is useful for estimating small burns (<15%) or large burns (>85%). In large burns, the burnt area can be quickly calculated by estimating the area of uninjured skin and subtracting it from 100.6 A common mistake is to include erythema—only de-epithelialised areas should be included in these calculations.
How is the depth of a burn assessed?
Clinical estimation of burn depth (fig 1) is often subjective—an independent blinded comparison among experienced surgeons showed only 60-80% concurrence.7 Burn wounds are dynamic and need reassessment in the first 24-72 hours, because depth can increase after injury as a result of inadequate treatment or superadded infection.8 Burn wounds can be superficial in some parts but deeper in other areas (fig 2). The table shows some characteristic features of burns of varying depth.
Characteristic features of burns of different depths
View this table:
Figure2
Fig 2 Tea scald over the chest and shoulder of a child showing heterogeneity of burn depth. S=superficial, I=intermediate, D=deep
A blinded rater comparison of laser Doppler imaging, which assesses skin blood flow, with clinical assessment and histopathology found that imaging was 90-100% sensitive and 92-96% specific for estimating burn depth.7 However, the high outlay costs for this equipment preclude its use outside specialist burns units. Other methods such as transcutaneous videomicroscopy (direct visualisation of dermal capillary integrity) and infrared thermography (temperature gradient between burnt and intact skin) remain largely experimental.9 10
The terms “partial thickness” or “full thickness” burns describe the level of burn injury and indicate the likelihood and estimated duration for healing to occur. Superficial burns usually heal (by epithelialisation) within two weeks without surgery, whereas deeper burns probably need excision and closure of the area, often with skin grafts. Hypertrophic scarring is more common in deeper burns treated by surgery and skin grafting than in superficial burns.11
What factors influence outcome?
Logistic regression analysis of survival data from 1665 burns patients from the Massachusetts General Hospital identified three risk factors for death: age over 60 years, more than 40% of body surface area injured, and inhalation injury.12 As survival outcomes have improved (mortality about 5-6% in resourced centres),13 however, assessment of outcome has shifted from mortality to quality of life measures.14 Thus, the current focus in burns patients is the preservation of function, reconstruction, and rehabilitation.13
How are minor burns managed?
Flowchart 1 (web fig 1 on bmj.com) provides a guideline for managing a “minor” burn in the community. The European working party of burns specialists recommends cleaning burns with soap and water (or a dilute water based disinfectant) to remove loose skin, including open blisters.15 Although the clinical evidence for “deroofing” of blisters is poor, without deroofing burn depth cannot be assessed. All blisters should therefore be deroofed, apart from isolated lax blisters <1 cm2 in area, which can be left alone.16 A simple non-adhesive dressing, such as soft silicone (for example, Mepitel), padded by gauze is effective in most superficial and superficial dermal burns. However, biological dressings such as Biobrane are better, especially for children, because they reduce pain, and the wound bed can be inspected through the translucent sheet.17 New non-animal derived synthetic polymers such as Suprathel look promising for treating partial thickness burns, but further studies are needed. Silver sulfadiazine can be used for deep dermal burns. Dressings should be examined at 48 hours to reassess depth and the wound in general, and dressings on superficial partial thickness burns can be changed after three to five days in the absence of infection. If evidence of infection exists, daily wound inspection and dressing change is indicated. Deep dermal burns need daily dressings until the eschar has lifted and re-epithelialisation is under way, after which dressings can be changed more often.
When is referral to a specialist burns unit needed?
Box 2 shows the criteria for referring a “complex” burn to the specialist burns unit. Small area burns that take more than 14 days to heal; become infected; or are likely to lead to considerable aesthetic, functional, or psychological impairment (face, hands, feet, across flexures, genitalia) may also need to be referred.1
Box 2 National burn injury guidelines for referral to a burns unit
All complex injuries should be referred. Such injuries are likely to be associated with:
• Extremes of age (<5 or >60 years)
• Site of injury
• Face, hands, or perineum
• Any flexure including neck or axilla
• Circumferential dermal burns or full thickness burn of the limb, torso, or neck
• Inhalation injury (excluding pure carbon monoxide poisoning)
• Mechanism of injury
• Chemical burns >5% total body surface area (except for hydrofluoric acid when >1% area needs referral)
• Exposure to ionising radiation
• High pressure steam injury
• High tension electrical injury
• Hydrofluoric acid burns >1%
• Suspected non-accidental injury in a child (if delayed presentation, unusual pattern of injury, inconsistent history, discrepancy between history and clinical findings, multiple injuries, or old scars in unusual anatomical locations)
• Large size
• Child (<16 years old) >5% total body surface area
• Adult (≥16 years) >10% total body surface area
• Coexisting conditions
• Serious medical conditions (such as immunosuppression)
• Pregnancy
• Associated injuries (fractures, head injury, or crush injuries)
How should major burns be managed?
All major burns should be managed initially according to trauma resuscitation guidelines.8 Box 3 shows a consensus summary on first aid management (prehospital care) for burns,18 and box 4 shows the principles for managing any large burns.
Box 3 Consensus guidelines for prehospital management of burns18
• Approach with care and call for help
• Stop the burning process
• Help the person to “drop and roll” if the clothing is alight
• Turn the power off if electricity is involved
• Assess patient as per guidelines for emergency management of severe burns (see box 4) and manage appropriately
• Cool the area but prevent hypothermia
• Assess burn severity
• Cover or dress the area with clingfilm or cellophane
• Suspect inhalation injury in burns sustained in an enclosed area, facial burns, or when nasal hair has been singed
• Early intubation may be needed if there is evidence of inhalation injury
• Cannulate and administer fluids (Hartmann’s solution or Ringer’s lactate)
• Provide adequate analgesia
• Transfer to appropriate hospital or burns care centre
Box 4 Emergency management of severe burns approach (adapted from the Australian and New Zealand Burns Association)
Order of management priority in patients with severe burns
• A. Airway with cervical spine control
• B. Breathing and ventilation
• C. Circulation with haemorrhage control
• D. Disability—neurological status
• E. Exposure preventing hypothermia
• F. Fluid resuscitation
Adults
Resuscitation fluid alone (first 24 hours):
• Give 3-4 ml (3 ml in superficial or partial thickness burns, 4 ml in full thickness burns or those with associated inhalation injury) Hartmann’s solution/kg body weight/% total body surface area. Half of this calculated volume is given in the first eight hours after injury. The remaining half is given in the second 16 hour period
Children
Resuscitation fluid as above plus maintenance (0.45% saline with 5% dextrose, the volume should be titrated against nasogastric feeds or oral intake):
• Give 100 ml/kg for first 10 kg body weight plus 50 ml/kg for the next 10 kg body weight plus 20 ml/kg for each extra kg
Prompt irrigation with running cool tap water for 20 minutes provides optimal intradermal cooling.19 Ice and very cold water should be avoided because they cause vasoconstriction and worsen tissue ischaemia and local oedema.20 Hypothermia should be avoided, especially in children. Patients with chemical burns may need longer periods of irrigation (up to 24 hours), and specific antidote information should be obtained from the regional or national toxicology unit.
The prehospital consensus guidelines emphasise that dressings help relieve pain from exposed nerve endings and keep the area clean.18 Polyvinylchloride film (such as clingfilm) is useful, but remember that circumferential wrapping can cause constriction. Cellophane films can worsen chemical burns, so the area should be irrigated thoroughly until pain has decreased and only wet dressings should be applied. Intravenous opiates or intranasal diamorphine should be used for analgesia.
All patients with facial burns or burns in an enclosed area should be assessed by an anaesthetist and the need for early intubation ascertained before transfer to a specialist unit. In full thickness circumferential burns—especially to the neck, chest, abdomen, or limbs—escharotomy may be needed to avert respiratory distress or vascular compromise of the limbs from constriction. Flowcharts 2 and 3 (web figs 2 and 3 on bmj.com) show the management of patients in the emergency department or the specialist burns unit.
What is the role of fluid resuscitation?
Effective fluid resuscitation remains the cornerstone of management in major burns. If more than 25% of the body is burnt, intravenous fluids should be given “on scene,” although transfer should not be delayed by more than two attempts at cannulation.18 The aims are to maintain vital organ perfusion and tissue perfusion to the zone of stasis (around the burn) to prevent extension of the thermal necrosis. In the UK, expert consensus recommends that fluid resuscitation be initiated in all children with 10% burns and adults with 15% burns; children who had early (within two hours) fluid resuscitation had a lower incidence of sepsis, renal failure, and overall mortality.8 21
How much fluid?
Several formulae, based on body weight and area burnt, estimate volume requirements for the first 24 hours. Although none is ideal, the Parkland formula (3-4 ml/kg/% burn of crystalloid solution in the first 24 hours, with half given in the first eight hours) and its variations are the most commonly used. Resuscitation starts from the time of injury, and thus any delays in presentation or transfer to the hospital or specialist unit should be taken into account and fluid requirement calculated accordingly. Resuscitation formulae are only guidelines, and the volume must be adjusted against monitored physiological parameters.
Historically, under-resuscitation was an important cause of death from major burns, but reports suggest that the pendulum may have swung towards over-resuscitation. Resuscitation volumes greater than two to three times the estimated requirements have been used, with associated complications of volume overload, such as pulmonary oedema.w1 Volume overload, also known as “fluid creep,”w2 may be made worse by the relative unresponsiveness of fluids during the first 24 hours. Studies using invasive monitoring in burns resuscitation have shown that the rate of intravascular volume replacement is independent of the volume of crystalloid infused.w3 Studies have therefore looked at using smaller volumes as long as resuscitation is early and suitably monitored—an approach termed permissive hypovolaemia.w4 Although early studies have been encouraging, randomised controlled trials (RCTs) are lacking.
Which fluid?
The preferred resuscitation fluid varies greatly. Currently, the most popular one is crystalloid Hartmann’s solution, which effectively treats hypovolaemia and extracellular sodium deficits. Sodium chloride solution (0.9%) should be avoided because it causes hyperchloraemic metabolic acidosis.
The early phase after burn injury is characterised by increased capillary permeability, so large volume crystalloid resuscitation may lead to a decrease in the plasma protein concentration and egression of the fluid into the extravascular space. Capillary integrity may be sufficiently restored by about 12-24 hours, however, and many burns units manipulate the intravascular oncotic pressure by adding a colloid (albumin or plasma) after the first 12 hours in large area burns.22
A recent Cochrane meta-analysis of 67 RCTs of trauma, burns, and post-surgery patients found no evidence that colloid resuscitation reduces mortality more effectively than crystalloids.23 Although the addition of colloids in burn resuscitation may decrease total volume requirements, RCTs are needed to evaluate its other benefits.24
How should resuscitation be monitored?
The use of urine output alone to assess adequate fluid resuscitation in burns has been challenged.5 w1 Invasive haemodynamic monitoring with central venous pressure or pulmonary artery catheters are not recommended for routine monitoring of fluid replacement in burns because of the risk of infection. Less invasive monitoring using thermodilution methods to measure intrathoracic blood volume, cardiac output, and cardiac index have recently received attention. Although preliminary studies have suggested that this may aid resuscitation, one RCT failed to support these findings in burns.w6
What is the role of nutrition?
The role of nutritional support in major burns has shifted from one of preventing malnutrition to one of disease modulation.w6 Nutritional requirements are dynamic, and early debridement and skin cover result in a 50-75% increase in energy expenditure. Thus, a nutritional plan—that takes account of factors such as the extent and depth of the burn, the need for repeated surgical interventions, the appropriateness of the enteral or parenteral route, and the pre-injury health status of the patient—should be implemented within 12 hours.
Psychosocial aspects
The psychological requirements of patients and their carers change over the early resuscitative phase, acute phase, and rehabilitation phase. The prevalence of depression is estimated to be high (up to 60%) in burns inpatients, and up to 30% have some degree of post-traumatic stress disorder.w7 All burns centres offer specialist advice on long term psychosocial adjustment in burns patients. Changing faces in the UK and the Phoenix society in the United States provide excellent support for burns survivors.
How are scar and burn areas managed after healing?
A retrospective cohort study of 337 children with up to a five year follow-up found hypertrophic scarring in less than 20% of superficial scalds that healed within 21 days but in up to 90% of burns that took 30 days or more to heal.11 Appropriate treatment must therefore be instituted early and infection prevented to encourage rapid healing. Healed burns do not have adnexal structures, and are therefore dry, sensitive, and irregularly pigmented. Hence the area should be moisturised and massaged to reduce dryness and to keep the healed area supple. A sun cream, with a sun protection factor of 30, is advised to prevent further thermal damage and pigmentation changes.
New directions in burn wound management
Although autografting is the gold standard for skin replacement in burns, limited availability of donor skin precludes this option in large area burns. Hence, various tissue engineered skin substitutes (fig 3) have been developed to provide temporary or permanent wound coverage.
Figure3
Fig 3 Newer tissue engineering directions in burns management. Cultured epidermal autografts (right), staged dermal acellular substitutes (bottom), single application dermal cellular substitutes or allogenic composites (left)
Autologous keratinocyte grafts (obtained after biopsy and culture of the patient’s own keratinocytes) and or allogenic keratinocyte grafts have been developed for large area superficial burns. Other developments include a keratinocyte suspension in a fibrin sealant matrix aimed at increasing the adherence of keratinocytes to the wound bed (keratinocyte-fibrin glue suspension) and a total lysate of cultured human keratinocytes made up of growth factors, cytokines, and matrix molecules in a hydrophilic gel.w8
Processed skin from human cadavers—in which the cells are removed to leave a non-antigenic dermal scaffold—is used as a dermal replacement for treating deeper burns. Allogeneic fibroblasts, obtained from neonatal human foreskin and cultured in vitro, seeded on a biologically absorbable scaffold or on a nylon mesh, have also been developed. The proliferating fibroblasts secrete collagen, matrix proteins, and growth factors and aid healing. Composite skin substitutes comprising allogeneic keratinocytes (epidermal equivalent) and fibroblasts (dermal equivalent) are also available.w9
Although a recent meta-analysis of 20 RCTs has shown these substitutes to be safe, their efficacy could not be determined on the basis of current evidence.w9
Additional educational resources
Resources for healthcare professionals
• Burn Surgery (www.burnsurgery.org)—Good resource for health professionals regarding all aspects of burns
Resources for patients
Notes
Cite this as: BMJ 2009;338:b1037
Footnotes
• Contributors: SE and AR designed the paper, carried out the literature search, collated the up to date evidence, and prepared the manuscript. SE created the flow charts and AR created fig 3. Both authors contributed equally in the development and completion of this article. MS is the senior author who proofread the article, provided invaluable suggestions, did the necessary corrections and amendments, and provided the expert advice. SE is guarantor.
• Competing interests: None declared.
• Provenance and peer review: Commissioned; externally peer reviewed.
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8,185,105,692,306,626,000 | ID: 7604
Image of a hernia in the abdomen region of a man
Hernia
A hernia is the bulging of an organ through a tear in the tissue or muscle that is supposed to hold it in place. Most are found in the abdomen, however, they can also be found in the groin and even upper thigh area. Surgery is nearly always recommended to avoid further complications, such as strangulation, when the organ makes its way through the tear and blood supply is cut off.
Did you know?
Hernias are most common in men and can develop at any age. In fact, babies have been known to be born with hernias. When a baby is born with a hernia, it is usually fixed as soon as possible to avoid further complications while the baby grows. Strangulation is a particular risk for infants.
What are the symptoms of a hernia?
A hernia is usually pretty easy to spot, and although it can be diagnosed by oneself, it’s always important to get to the doctor as soon as possible. Hernias are characterized by bulging, swelling, or pain in the area in which they are present.
What are some of the most common hernias?
Incisional hernias are commonly seen in overweight individuals. It occurs when the intestines bulge outside of the intestinal wall at a site where previous abdominal surgery was performed.
Umbilical hernias are commonly seen in newborns and occur when the intestines bulge through the abdominal wall near the belly button.
When will I know if I need surgery?
More often that not hernias are monitored to see if they progress. If the doctor notices a change in it, such as it growing or not resolving on its own, they will typically decide to perform surgery. More often than not the surgery will be done laparoscopically, to avoid large incisions. Oftentimes a mesh will be used to patch the area in which a hernia has occurred.
Mesh offers the highest chance of success and decreases the probability of a recurrence.
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2,049,369,727,167,981,600 | The Best Advice About Home I’ve Ever Written
Considerations to Make When Buying Home Health Test Kits
When you are sick, there is nothing you can do because you are weak and that is why taking care of your health is always an important and primary thing to do. Nowadays the hospitals are full of people who are sick from diseases some that can be cured others cannot be cured. There are many things that can affect your health and the most important thing is to master them early so that you can avoid such issues later such as bad eating habits and lifestyles that can be avoided stay healthy. If you are living now, in this generation, you have no excuse of not taking care of your health because many developments have taken place to ensure that you are safe. For example, as you may learn, today, you can conveniently purchase home test kits which you can be using on yourself to measure your health and therefore eliminating the need to always go to see a specialist for regular checkups. Discussed in this article are some guidelines to help you purchase home health test.
It is important to understand that your health and your body is very complex and that is why you will find that there are different health test kits you can buy in the market today. The best thing you can do is invest in all of them because anything can happen and complications can arise but most importantly, if you have been struggling with a specific area of your health, it is important to buy the specific health test kit. For example, can decide to buy, kits that you want such as cholesterol test kit, heart test kit, typhoid, blood pressure test kit to name but a few.
When it comes to the manufacturing of the health test kits, there are rules and regulations and also governing bodies that overlook to ensure that you purchase quality products. One of the governing bodies is the FDA and visiting the FDA’s website can help you in the purchasing process so that you can buy from the appropriate company. The best way to ensure that you are purchasing the appropriate material is by engaging a certified dealer. You need to engage more info so that you can understand the cost of getting the home health test kits because they vary from one company to another, even as you look for quality.… | {
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-896,392,995,080,820,700 | Search all medical codes
Drug screen, any number of drug classes from Drug Class List A; single drug class method, by instrumented test systems (eg, discrete multichannel chemistry analyzers utilizing immunoassay or enzyme assay), per date of service
CPT4 code
Name of the Procedure:
Drug Screen, Any Number of Drug Classes from Drug Class List A; Single Drug Class Method, by Instrumented Test Systems (e.g., Discrete Multichannel Chemistry Analyzers Utilizing Immunoassay or Enzyme Assay)
Summary
A drug screen using instrumented test systems to detect the presence of specific drugs or drug metabolites in a sample (usually urine). This method utilizes advanced analyzers such as immunoassays or enzyme assays to identify and measure drugs from a predefined list.
Purpose
This procedure is used to detect and measure the presence of drugs in the body. It is commonly used for medical diagnostics, employment screening, legal cases, and substance abuse programs. The goal is to identify individuals using specific drugs and to monitor or diagnose potential drug misuse issues.
Indications
Specific symptoms or conditions that may warrant this procedure include:
• Suspected drug overdose
• Monitoring compliance with prescribed medications in chronic pain management or addiction treatment programs
• Employment or pre-employment screening
• Legal or forensic investigations
• Pre-surgical assessments or routine health evaluations
Preparation
• Patients may be instructed to avoid certain foods or medications that might interfere with test results.
• Patients might be asked to provide a fresh urine sample at the clinic or testing site.
• No specific fasting or extensive preparation is typically required.
Procedure Description
1. Sample Collection: A urine sample is usually collected from the patient in a sterile container.
2. Sample Processing: The sample is then processed using an instrumented test system such as a discrete multichannel chemistry analyzer.
3. Testing: The analyzer uses immunoassay or enzyme assay methods to detect and measure drug metabolites.
4. Result Analysis: Results are reviewed and interpreted by healthcare professionals to determine the presence of drugs from the drug class list A.
Duration
The procedure, including sample collection and processing, generally takes about 30-60 minutes.
Setting
This procedure is typically performed in an outpatient clinic, laboratory, or hospital setting.
Personnel
Healthcare professionals involved include:
• Laboratory technicians to process and analyze the sample
• Medical or clinical staff to assist with sample collection
• Physicians or medical staff to interpret the results
Risks and Complications
• False positives or negatives due to sample contamination or interference
• Misinterpretation of results due to cross-reactivity with other substances
• Minimal physical risk from the sample collection process
Benefits
• Accurate detection of drug use, contributing to appropriate medical treatment and intervention.
• Valuable for legal, employment, and monitoring purposes.
• Rapid and reliable results typically available within a few hours.
Recovery
• No recovery time needed post-test.
• Patients are usually able to resume normal activities immediately.
• Follow-up appointments if further evaluation or treatment is needed.
Alternatives
• Saliva or blood drug testing: less common, more invasive, and usually more expensive.
• Hair follicle drug testing: can detect longer-term drug use but may not be as immediate.
• Point-of-care (POC) drug testing kits: quick and often done in non-laboratory settings but may have varying accuracy.
Patient Experience
• The patient might experience minimal discomfort during the urine sample collection.
• Usually, no pain or significant side effects.
• Results are typically reviewed with the patient soon after the test, with additional guidance or next steps provided as needed.
Similar Codes | {
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-5,103,514,982,162,966,000 | Computational Discovery of Picomolar Q o Site Inhibitors of
Jun 12, 2012 - Its application yielded the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex, an important membrane protein for d...
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Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex Ge-Fei Hao,†,∥ Fu Wang,†,∥ Hui Li,†,‡,∥ Xiao-Lei Zhu,† Wen-Chao Yang,† Li-Shar Huang,§ Jia-Wei Wu,*,‡ Edward A. Berry,§ and Guang-Fu Yang*,† †
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ‡ MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, P. R. China § Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, United States S Supporting Information *
ABSTRACT: A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (Ki = 881.80 nM, porcine bc1), the most potent compound 4f displayed 20 507-fold improved binding affinity (Ki = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (Ki = 83.00 pM) bound to the chicken bc1 at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a highthroughput drug discovery method, independent of biophysical screening techniques.
INTRODUCTION High potency that should be balanced with other properties is a sought-after characteristic of drug molecules. The challenge of discovering high-potency membrane protein inhibitors is of great interest, since about 60% of currently marketed drugs target this type of protein.1 The cytochrome bc1 complex (EC 1.10.2.2, bc1) is an essential and central component of the cellular respiratory chain and of the photosynthetic apparatus in photosynthetic bacteria; it catalyzes the electron transfer (ET) from quinol to a soluble cyt c, with concomitant translocation of protons across the membrane to generate a proton gradient and membrane potential for ATP synthesis.2,3 Its critical importance in life processes makes the bc1 a promising action target for numerous antiparasitic agents, antibiotics, and fungicides.4 Three subunits containing prosthetic groups are essential for ET function: the cyt b subunit bearing two b-type hemes (bL and bH heme), cyt c1 with a c-type heme, and the iron−sulfur protein (ISP) having a 2Fe−2S cluster.5,6 The “proton-motive Q-cycle” is a favored mechanism for electron and proton transfer in this complex,7 suggesting the existence of two discrete reaction sites: a quinone reduction site near the negative side of the membrane (Qi or QN) and a quinol oxidation site close to the positive side of the membrane (Qo or QP). © 2012 American Chemical Society
Based on inhibition patterns and the crystallographically observed inhibitor binding sites in the bc1, the existing bc1 inhibitors can be divided into three classes (Figure 1, Supporting Information):2 (1) class P inhibitors bind at the Qo site and include azoxystrobin, kresoxim-methyl, famoxadone, stigmatellin, and UHDBT; (2) class N inhibitors target the Qi site and include antimycin A and diuron; and (3) class PN inhibitors can bind to both the Qo and Qi sites and include NQNO and possibly funiculosin. The most potent bc1 inhibitor that has been identified is antimycin A, a natural Qi site inhibitor that binds to bovine heart mitochondrial particles with a dissociation constant of 32 pM.8 Although Qo site inhibitors have attracted great interest as antifungal agents, no picomolar range Qo site inhibitor has yet been reported. Therefore, discovering new ultrapotent Qo site inhibitors is of great interest, not only for the functional study of bc1 but also for potential antifungal applications. Fragment-based drug discovery (FBDD) has recently been rapidly developed as an alternative to traditional methods of hit identification, such as high-throughput screening (HTS).9 Compared with HTS, FBDD has several significant advantages.10 First, compared to larger drug-like molecules, fragments Received: January 13, 2012 Published: June 12, 2012 11168
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usually exhibit higher ligand efficiency (LE), which is defined as the binding free energy (ΔG) divided by the heavy atom count (HAC).11,12 Comparison based on LE rather than potency alone could be useful in determining the potential of drug candidates. Second, the hit rate from fragment screening is typically much higher than that observed with HTS13 because the property space covered by fragments is much broader and more extensive than that covered by drug-like molecules.14 Third, in most cases, there are more opportunities to optimize fragments to high quality leads with relatively low molecular weight and better drug-like properties. However, FBDD also poses challenges. First, FBDD often relies on the detection of fragment binding via sensitive biophysical methods, such as NMR spectroscopy, X-ray diffraction, isothermal calorimetry (ITC), surface plasmon resonance, and mass spectrometry,15,16 that require specialized equipment, personnel with specific expertise, and supporting informatics infrastructure. Second, due to the much weaker binding affinity of fragments, excellent solubility is required to enable screening at high concentrations. Furthermore, large amounts of purified protein (>10 mg) are always essential, which are very difficult to achieve in most cases, especially for membrane proteins.17,18 The low-throughput nature of FBDD has prompted several attempts to develop a computational screening method for fragment identification from the much larger commercially available library.19−21 However, fragment docking is also very challenging; since fragments may be more promiscuous in the binding pocket than larger drug-like molecules, it is very difficult to predict the binding mode of a fragment and accurately estimate its binding affinity. Based on the X-ray diffraction structures of bc1 bound to various methoxyacrylate (MOA)-type inhibitors,2,22 we found that the conformation of the MOA pharmacophore in the binding pocket was highly conserved. This observation prompted us to hypothesize that computational screening of the side-chain fragment without changing the pharmacophore should be an effective way to discover new high-potency bc1 inhibitors. In the present work, we developed a new approach named pharmacophore-linked fragment virtual screening (PFVS) by integrating the advantages of FBDD and docking methods. Using this new approach, we successfully discovered a series of new bc1 inhibitors with picomolar potencies. To our knowledge, this is the first application of the FBDD method in the computational discovery of ultrapotent inhibitors of membrane proteins. To verify the simulated binding mode, we also determined the crystal structure of chicken bc1 in complex with one of the picomolar inhibitors.
Figure 1. The workflow of PFVS. During the computational virtual screening, each fragment from a small library containing 1735 fragments was set to link with the MOA pharmacophore via a sulfur atom. The energies of the complexes were optimized step by step in a three-step cycle, and candidates were finally determined.
Compound 1 was successfully synthesized but was eventually abandoned because this compound and its N-methylated derivatives were determined to be unstable. The synthesis of compound 5 was unsuccessful, but its analogue, 5a, was obtained with a Ki of 94.97 nM against porcine bc1. Further optimization of compound 5a did not significantly improve its potency. We successfully synthesized compounds 2−4, with Ki values against porcine bc1 of 31.10, 316.09, and 881.80 nM, respectively. Initially, we focused on the structural optimization of the two more prominent compounds, 2 and 3; however, this did not result in development of a compound with significantly improved potency. Unexpectedly, structural optimization of compound 4, which contained a side-chain moiety of quinoxaline and exhibited relatively lower inhibitory activity, resulted in several compounds with greatly improved potency (see the following text and Figure 3). We previously established that improving the Ar−Ar interactions between the side chain of an inhibitor and the hydrophobic residues in the binding pocket (e.g., Phe274) can effectively improve the potency of bc1 inhibitors.23 Furthermore, the presence of electron-donating and electron-withdrawing groups can increase the Ar−Ar dimer interaction energies, as can increasing the number of heavy atoms in the dimers.24 The quinoxalinyl group of compound 4 was surrounded by a hydrophobic pocket formed by the side chains Phe274, Phe127, Ile146, Pro270, Glu271, Ala277, Leu294, Met124, and Ile298 (Figure 4a, numbered according to the cyt b subunit of the bovine bc1). First, we introduced a hydrophobic methyl group onto the 3-position of the quinoxaline ring, creating compound 4a; this greatly improved the potency (Ki = 41.00 nM) as expected due to the increased Ar−Ar interaction energies between the quinoxalinyl group and its surrounding hydrophobic residues (Figure 4b). Additionally, the LE of compound 4a was improved to 0.37, higher than that of compound 4 (LE = 0.32). On the other side, we replaced the bridge sulfur atom in compound 4 with an oxygen atom; the resultant compound 4b also exhibited much higher potency against porcine bc1 with a Ki value of 51.50 nM and LE of 0.38, which was likely due to the conformational change-induced improvement of the Ar−Ar interaction between the quinoxalinyl ring and the phenyl group of Phe274 (Figure 4c). Combining the above two strategies led to compound 4c (Figure 4d), whose potency (Ki = 28.00 nM) was further improved. Interestingly, introduction of an additional methyl group onto the 6-position of the quinoxaline ring resulted in
RESULTS Hit Identification through PFVS and Hit Optimization. The workflow of PFVS is shown in Figure 1. During the computational screening, each fragment from a small library containing 1735 fragments was set to link with the MOA pharmacophore via a sulfur atom, since the nucleophilic substitution reaction between the E-methyl 2-(2-chloromethylphenyl)-3-methoxyacrylate pharmacophore and the mercaptocontaining fragment is highly active and easy to perform. After performing a 3-step computational screening (see the Experimental Section), we obtained 10 hits with the most favorable binding free energies (Table 1, Supporting Information). By setting the criterion of LE over 0.28, five candidates (Figure 2) were selected for chemical synthesis and further evaluation of bc1 complex−inhibition activity. 11169
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Figure 2. Chemical structures of five final candidates. The fragments determined by PFVS are shown in blue boxes. 5a is a synthetic analogue of compound 5. Ligand efficiency (LE) value is defined as the calculated binding free energy (ΔGcal) divided by the HAC, LE = −ΔGcal/HAC.
Figure 3. The process of structural optimization of compound 4. Under the guidance of computational simulation, different fragments were introduced as side-chain moieties onto positions 3, 6, and 7 of quinoxaline; the bridged sulfur atom was also replaced with an oxygen atom. As a result, the potency was improved step by step. Compound 4a was designed by introducing a hydrophobic methyl group onto the 3-position of the quinoxalinyl ring of compound 4. Compound 4b was designed by replacing the bridged sulfur atom with an oxygen atom. Compound 4c was designed by the combination of the above two strategies. Compound 4d was designed by introducing an additional methyl group onto the 6-position of compound 4c. Compound 4e was designed by replacing the methyl group at the 3-position of compound 4d with a trifluoromethyl group. Compound 4f and its isomer 4g were designed by introducing trifluoromethyl groups to positions 6 and 7 of the quinoxaline ring. The experimentally determined Ki values are marked, and LE values are calculated according to the binding free energies (ΔGexp) derived from Ki values.
compound 4d (Figure 4e) with a much improved potency (Ki = 0.75 nM). These results led us to carefully analyze the interactions between the substituted quinoxalinyl ring and its surrounding residues. The methyl group at the 3-position of the quinoxaline ring penetrated into a groove lined by hydrophobic side chains of Pro270, Ile146, Tyr278, and Phe274. Replacing this methyl
group with a trifluoromethyl group introduced several C−F···H bonds between the trifluoromethyl and the above-mentioned residues, which is believed to greatly improve the binding free energy.25 As expected, the resultant compound 4e formed two C−F···H bonds with Pro270, three with Ile146, and two each with Tyr278 and Phe274; distances between the F and H atoms ranged from 2.45 to 2.98 Å (Figure 4f). The Ki value of 11170
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Figure 4. The simulated binding modes of eight different compounds. (a) Side view of the quinoxalinyl group of compound 4 surrounded by a hydrophobic pocket formed by the side chains Phe274, Phe127, Ile146, Pro270, Glu271, Ala277, Leu294, Met124, and Ile298. (b) The potency of compound 4a is improved greatly due to the improvement of the Ar−Ar interaction energies between the quinoxalinyl group and its surrounding hydrophobic residues. (c) The potency of compound 4b is improved by the conformational change-induced improvement of the Ar−Ar interaction between the quinoxalinyl ring and the phenyl group of Phe274. (d) The Ar−Ar interaction between the quinoxalinyl ring of compound 4c and the phenyl group of Phe274 is further improved. (e) The hydrophobic interaction energies between the quinoxalinyl group of compound 4d and its surrounding hydrophobic residues are further improved. (f) Compound 4e was designed by replacing the methyl group at position 3 with a trifluoromethyl group, which resulted in two C−F···H bonds with Pro270, three with Ile146, and two each with Tyr278 and Phe274. (g) Additional trifluoromethyl at position 6 of compound 4f resulted in more C−F···H bonds with F121, M124, and I298. (h) The additional trifluoromethyl at position 7 of compound 4g resulted in more C−F···H bonds with M124 and A125. The pink lines show the hydrogen and the C−F···H bonds. The F···H distances range from 2.38 to 3.00 Å.
Table 1. Binding Free Energies (kcal/mol) of Compounds 2−4, 4a−g, and 5a
a
no.
ΔH
−TΔS
ΔGcal
ΔGexpa
Ki (nM)
LEb
MW
2 3 4 4a 4b 4c 4d 4e 4f 4g 5a
−43.94 −40.57 −45.74 −49.68 −45.48 −47.45 −48.76 −49.92 −52.55 −51.12 −45.16
33.89 31.82 37.46 39.63 36.20 36.37 36.47 37.22 39.30 37.96 35.39
−10.05 −8.75 −8.28 −10.05 −9.28 −11.08 −12.29 −12.70 −13.25 −13.16 −9.77
−10.26 −8.89 −8.28 −10.10 −9.97 −10.33 −12.48 −13.78 −14.18 −13.93 −9.60
31.10 ± 0.90 316.09 ± 10.71 881.80 ± 33.92 41.00 ± 3.60 51.50 ± 1.30 28.00 ± 0.53 0.75 ± 0.23 0.083 ± 0.013 0.043 ± 0.006 0.065 ± 0.018 94.97 ± 3.82
0.41 0.32 0.32 0.37 0.38 0.38 0.45 0.44 0.42 0.41 0.36
371.48 411.50 366.44 380.46 350.37 364.39 378.42 432.39 486.36 486.36 381.46
ΔGexp = −RTln Ki. bLE is defined as the experimental binding free energy (ΔGexp) divided by the HAC, LE = −ΔGexp/HAC.
It should be noted that the optimization of compound 4 summarized in Figure 3 is based on the above-mentioned computational strategy. The experimental and calculated binding free energies (ΔG) of compounds 2−4, 4a−g, and 5a (Table 1) showed a good linear correlation with a correlation coefficient of r2 = 0.95, further confirming the reliability of this computational strategy. Inhibitory Kinetics of Compounds 4 and 4e. Kinetic properties are of great importance for understanding the molecular mechanism of bc1 function. We therefore examined the inhibitory effects of compounds 4 and 4e on porcine succinate-cytochrome c reductase (SCR, mixture of respiratory complex II and bc1 complex). As previously described,23 we measured the complex II activity of SCR using succinate and DCIP as substrates, we used decylubiquinol (DBH2) and cyt c as substrates to measure the bc1 complex activity, and we used
compound 4e was 0.083 nM, improved 10 624-fold compared to compound 4; its LE was also greatly increased to 0.44. We further designed two ditrifluoromethyl derivatives, compound 4f and its isomer, 4g. As shown in Figure 4g,h, the 6- or 7position CF3 group formed several additional C−F···H bonds with the surrounding residues Phe121, Met124, Ile298, and Ala125; the F···H distances ranged from 2.66 to 2.93 Å. The potencies of compounds 4f and 4g were further improved 20 507- and 13 566-fold, respectively, compared to the original hit compound 4; their LE values were still over 0.4. The synthetic routes for compounds 2−4, 4a−g, and 5a are summarized in Scheme 1, Supporting Information. Their chemical structures were characterized by 1H and 13C NMR and HRMS. The crystal structure of compound 4f (CCDC 831447) was further confirmed by X-ray diffraction analyses (Figure 2, Supporting Information). 11171
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succinate and cyt c as substrates to measure SCR (both complex II and bc1 complex) activity. Both compounds 4 and 4e significantly inhibited bc1 complex activity as well as the SCR activity. Neither compound exhibited any effect on the activity of complex II, even with inhibitor concentrations as high as 20 μM. These results indicated that compounds 4 and 4e are effective bc1 complex inhibitors. Compound 4 displayed a linear product versus time relationship (Figure 3, Supporting Information), similar to that of the classical reversible inhibitor azoxystrobin. However, compound 4e exhibited typical characteristics of a slow, tightbinding inhibitor, with the product formation versus time showing curvilinear functions (Figure 4, Supporting Information). In the presence of compound 4e and saturated substrate concentrations, the product formation curves started linearly in the initial phase, but the slopes decreased with increasing time, approaching steady states; more dramatic slope reduction was observed with increasing compound 4e concentrations (Figure 5a). We calculated the observed first-order rate constant (kobs) and found it to be proportional to the concentrations of the inhibitor 4e (Supporting Information). Slow-tight binding inhibitors can be further classified as competitive, noncompetitive, or uncompetitive, as ascertained by studying the effect of substrate concentration on kobs. With an increase in the substrate concentration, kobs decreases for a competitive inhibitor, increases for a uncompetitive inhibitor, or is constant for a noncompetitive inhibitor. We next monitored the time courses of bc1 complex inhibition with different cyt c concentrations and a fixed compound 4e concentration (Figure 5b). The independence of kobs on [cyt c] clearly indicated that compound 4e was a noncompetitive inhibitor with respect to cyt c; the inhibition constant can therefore be calculated as Ki = k−0/k+0 = 0.083 ± 0.013 nM (Supporting Information). To assess the effect of the substrate ubiquinol on compound 4e, we conducted inhibitory kinetic studies of SCR, using DBH2 and cyt c as substrates. In the presence of compound 4e, the progress curves appeared similarly curvilinear (Figure 6). However, in contrast to the previous observation for cyt c, kobs decreased with increasing DBH2 concentration at a fixed compound 4e concentration, clearly demonstrating that compound 4e was a competitive inhibitor with respect to the substrate ubiquinol. To further unravel the inhibitory mechanism, we performed different sets of inhibitory experiments with various concentrations of substrate DBH2 and inhibitor compound 4e (Figure 5, Supporting Information). Through detailed kinetic analyses, the inhibition constant Ki was calculated to be 0.974 ± 0.024 nM, approximately 12-fold higher than that derived from the succinate-cyt c system. We believe that this discrepancy is largely owing to the presence of the nonionic detergent lauryl maltoside in the assays using DBH2 as substrate.23 Crystal Structure of Chicken bc1 in Complex with Compound 4e. We determined the crystal structure of the representative compound 4e bound to chicken bc1 complex at a resolution of 2.70 Å and found it to be similar to that seen with other MOA-type inhibitors, with the Rieske iron−sulfur protein in the c1 position.2 Electron density in the Qo site (Figure 7a) promoted unambiguous positioning of the inhibitor. As shown in Figure 7b, the pharmacophore of this new inhibitor bound in the fashion of typical MOA inhibitors; the planar methoxyacrylate was inserted into a slot bounded by Phe128, Tyr131, Phe274, and Glu271, with an H-bond between the carbonyl
Figure 5. Inhibitory kinetics of bc1 complex with cyt c as substrate by compound 4e. The enzyme activity was measured using succinate and cyt c as substrates. Each reaction mixture contained 100 mM PBS (pH 7.4), 0.3 mM EDTA, 20 mM succinate, and various concentrations of cyt c and compound 4e. The reaction was initiated by adding 0.1 nM SCR to the reaction mixture, and the time course of the absorbance change at 550 nm was recorded continuously for cyt c reduction. Experimental data are shown as dots, and theoretical values as lines. (a) Effect of the concentration of 4e on the inhibition of bc1 complex. The assays were carried out in the presence of 60 μM of cyt c and various concentrations of compound 4e (1, 0 nM; 2, 0.5 nM; 3, 1 nM; 4, 1.5 nM; and 5, 2.5nM). Inset: Secondary plot of kobs against concentrations of compound 4e. (b) Effect of cyt c concentration on the inhibition of bc1 complex by compound 4e. The assays were carried out in the presence of 2 nM of compound 4e and various concentrations of cyt c (1, 20 μM; 2, 28 μM; and 3, 60 μM). Inset: Secondary plot of kobs against concentrations of cyt c.
oxygen of the methoxyacrylate and the backbone N of Glu271. The bridging phenyl ring was nearly at right angles to the plane of the methoxyacrylate and was inserted between residues Pro270 and Gly142 (Figure 7c,d). The side chain extended from the bridging ring past the ring of Phe274, in loose contact with Met124, toward an opening to the bulk lipid phase between helices αC and αF. This was presumably the entry path for lipophilic substrates and inhibitors from the lipid phase. The quinoxaline ring stacked with Phe274, and this interaction, predicted by the modeling, has been shown to be important for tight binding. As also predicted by the modeling studies, the trifluoromethyl substituent inserted into a space between Ile146, Phe274, Ala277, and Leu294, capped at the end by Tyr278 (Figure 7c). The fit was quite close, with 10 contacts having less than 3.5 Å between the fluorine atoms and these residues, 4 of them closer than 3.3 Å. While the rotational position of the trifluoromethyl group may not be accurately determined by the data at this resolution, it is clear from the dimensions of the pocket that any rotamer would make numerous contacts. 11172
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nature of fragment screening continues to raise critical questions about both fundamental and practical aspects of this approach. The present work successfully developed a new PFVS approach, providing a solution to this shortfall of FBDD. When using computational docking for fragment screening, the biggest challenge lies in predicting the binding mode and accurately estimating the binding affinity, due to the promiscuous conformation of a fragment in the binding pocket. However, in our study, when the fragment was linked with the pharmacophore, it became a “drug-like” molecule, making it easy to predict the binding mode and accurately calculate its binding affinity. Using the rational design of bc1 inhibitors to test our approach, herein, we determined the Ki value of the pharmacophore E-methyl-2-(2-methylphenyl)-3-methoxyacrylate to be 4065.12 ± 206 nM, corresponding to a ΔG of −7.37 kcal/mol. Therefore, the contribution of the fragments to the binding free energies of compounds 4a−g varied from 0.91 to 6.81 kcal/mol. We also estimated the binding energies of the hit fragments of compounds 4a−g. When keeping the bridge atom invariant except for compounds 4f and 4g, the calculated binding energies (ΔH) of these hit fragments were qualitatively consistent with the ΔG values of their corresponding pharmacophore-linked virtual ligands (Figure 8, Supporting Information). Thus, it is practicable to identify the fragment through evaluation of the pharmacophore-linked virtual ligand. Of course, the pharmacophore used in the present work has a highly conserved conformation, which made it much easier to determine the binding mode of the pharmacophore-linked fragments. When using the PFVS approach to design inhibitors of proteins with a conformationally flexible pharmacophore, sufficient energy minimization might be needed to ensure that a rational binding mode will be obtained for the pharmacophorelinked fragments. Compounds 4e−g, discovered by PFVS, are the first reported picomolar inhibitors of the bc1 Qo site. Compared to that of the original hit compound 4, the potencies of compounds 4e−g were improved 10 624-, 20 507-, and 13 566-fold, respectively. The inhibitory kinetics studies showed that these ultrapotent inhibitors exhibited slow-tight binding characteristics, different from those of classical MOA-type inhibitors, such as azoxystrobin and kresoxim-methyl. X-ray crystal diffraction analysis indicated that, although the binding mode of compound 4e was very similar to that of other MOAtype inhibitors, it involved a unique interaction with residue Tyr278, which constituted a part of the ISP docking crater and was involved in fixing the ISP. It appears that loss of this interaction between Tyr278 and the ISP would induce a more loose state of the ISP extramembrane domain, and it has been established that appropriate ISP mobility is crucial for the catalytic activity of the bc1 complex. Therefore, a possible explanation of the ultrapotencies of compounds 4e−g is that, apart from the formation of C−F···H bonds, they enhanced the mobility of the ISP by interacting with residue Tyr278. In summary, the present promising study shows the newly developed PFVS approach to be a useful tool for the rational design of bc1 inhibitors. We have demonstrated the use of this approach to yield the first picomolar-range Qo site inhibitors of the cytochrome bc1 complex. Furthermore, this highthroughput method is generally applicable to the identification of other types of fragments for drug discovery.
Figure 6. Effect of DBH2 concentration on the inhibition of bc1 complex by compound 4e. The enzyme activity was measured using DBH2 and cyt c as substrates. Each reaction mixture contained 100 mM PBS (pH 6.5), 2 mM EDTA, 750 μM lauryl maltoside, 100 μM oxidized cyt c, 20 nM compound 4e, and various concentrations of DBH2 (1, 20 μM; 2, 40 μM; 3, 60 μM; 4, 80 μM and 5, 120 μM). Each reaction was initiated by adding 0.05 nM SCR, and the time course of the absorbance change at 550 nm was recorded continuously for cyt c reduction. Inset: Secondary plot of kobs against concentration of DBH2.
Four of the 10 contacts were with Tyr278, and of these, three involved the aromatic side chain. This residue is known to undergo conformational changes depending on the position of the iron−sulfur protein extrinsic domain.2,26 It is involved in fixing the iron−sulfur protein in the “b” position or famoxadone-induced position,27 and it may be involved in capturing the iron−sulfur protein from its mobile state. In the presence of MOA inhibitors, Tyr278 formed H-bonds to Ile268 (Figure 7a), partially closing and covering the outward-facing mouth of the Qo pocket.26,27 It seems likely that the interactions of Tyr278 with the trifluoromethyl group of the inhibitor stabilized it in this position, preventing it from being released to capture the iron−sulfur protein and thus accounting for the ultrahigh activities of compounds 4e−g. The structural similarity between the predicted and the X-ray crystal model was found to be 0.65 Å by assessing the values of the root-mean-square deviation (rmsd) of the atomic positions (Figure 7, Supporting Information), which again confirmed the reliability of our computational protocol. Furthermore, the inhibitor binding of the predicted model was very close to that of the crystal, except for an H-bond in the crystal structure; in the predicted structure, the methoxy rather than carbonyl oxygen of the methoxyacrylate formed an H-bond with the backbone N of Glu271. While this could be a difference between the chicken and the porcine heart bc1 complexes, structure−activity relationship studies showed that the methoxy oxygen could be replaced by carbon (giving a ketone instead of ester) with little loss of affinity, whereas the carbonyl oxygen was definitely required for any significant affinity.28 Our previous models may have been unduly influenced by the structure 1SQB used as the starting model; revisiting the modeling results23 showed that the energetic difference was small. As expected from the modeling studies, the N-containing ring of quinoxaline in the inhibitor side chain stacked with the phenyl ring of Phe274 (Figure 7b).
DISCUSSION Although FBDD has been widely used in developing new inhibitors against important protein targets, the low-throughput 11173
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Figure 7. X-ray structure of 4e bound to chicken bc1 complex. Residues are numbered according to the bovine/swine sequence. (a) Overall shape of the inhibitor and quality of the electron density (2Fo−Fc map contoured at 1.5 σ). Multiple van der Walls contacts of the trifluoromethyl group with residues 278 and 294 are shown as brown and H-bonds between the residues as white, dotted lines. (b) Space-filling model of the “bottom” of the binding pocket, viewed from above. The inhibitor is shown as a stick figure with green carbons. The pharmacophore, at right angles to the rest of the molecule, fits into a slot at upper right and contacts Glu271, Phe274, and Ala143. The side-chain quinoxaline ring stacks with Phe274. (c) Stick figure model, detailing interactions of the pharmacophore and trifluoromethyl group with the protein. Distances are described in Table 2, Supporting Information. Stereo views of these figures are available in Figure 6, Supporting Information. (d) Space-filling model of the top of the binding pocket, viewed from below. Tyr278 (magenta, unlabeled) blocks the hole in the “top” through which the ISP accesses the site. The phenyl “bridging” ring of the inhibitor inserts between Pro270 and the cd1 helix at 142−243. The trifluoromethyl group protrudes between Ile146, Phe274, Ala277, and Leu294. Dotted lines show the C−F···H interactions. Both the trifluoromethyl group and the bridging ring make multiple contacts with Tyr278. Stacking of the quinoxaline ring with Phe274 and contacts of the pharmacophore with Glu270, Tyr273, and the cd1 helix can also be seen.
MM/PBSA method31 for the enthalpy and an empirical method for the entropy.32 Fragments were identified by three sequential steps ( Figure 9, Supporting Information): (1) All fragments were preliminarily screened. The energy minimization of each newly produced complex was achieved in four steps by using the Sander module of Amber 8.0. First, the fragment was minimized with the pharmacophore and the protein fixed. Then, the ligand was minimized with the protein fixed. Subsequently, the backbone atoms of the protein were fixed, and other atoms were relaxed. The final minimization was performed with both the ligand and the protein relaxed. In each step, the energy minimization was executed by using the steepest descent method for the first 2000 cycles, and the conjugated gradient method for the subsequent 3000 cycles with a convergence criterion of 0.1 kcal mol−1 Å−1. Then, the ΔH calculation was performed on the minimized complex. To reduce the computational cost, each newly produced ligand was charged by the Gasteiger method, and only the ΔH calculation was considered in the first step. The top ∼10% of hits (170) with the most favorable ΔH were selected. (2) These 170 fragments were further estimated by taking the entropy effect into
EXPERIMENTAL SECTION
Computational Protocol. The previously established homology model of the porcine bc123 and a small library of 1735 fragments (Supporting Information) were used herein. Because all of the fragments were derived from commercial products in practical use, they should possess good druggable properties that are favorable for de novo design. Based on the modification and combination of AutoGrow and the Amber 8.0 program,29,30 the PFVS protocol was designed to automatically perform molecule generation, energy minimization, MD simulation, and binding affinity evaluation. The detailed workflow was as follows: (1) The structure of the pharmacophore-binding bc1 was prepared, and the graft point on the pharmacophore was defined. (2) The fragment was linked to the pharmacophore via a sulfur atom. The orientation of the fragment was minimized to make the minimum steric repulsion with the surrounding residues. (3) The ff99 and gaff parameters for amino acids and ligand were created automatically.31 (4) Energy minimization and MD simulation were performed on the resultant complex to obtain a reasonable binding conformation. (5) ΔG was calculated as previously described by the combination of the 11174
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consideration. According to the calculated ΔG, the top-ranked 17 fragments were identified. (3) These 17 virtual ligands were recharged by the restrained electrostatic potential method,33 then subjected to energy minimization as described in step 1, and additional 20 ps MD simulation. For temperature regulation, the Langevin thermostat was used to maintain a temperature of 300 K.34 The atomic coordinates were saved per ps. Subsequently, the last snapshot of the MD simulation was minimized to a convergence criterion of 0.1 kcal mol−1 Å−1. Finally, the ΔG was calculated, and the top-ranked 10 candidates were selected for synthetic evaluation. Kinetic Assays. The porcine SCR, the mixture of complex II and bc1, was prepared essentially according to the previously reported method.35 The enzyme concentration was estimated using an 540 extinction coefficient of 17.5 mM−1 cm−1 for A552 red −Ared , which was derived from the cyt c1 difference spectra between the reduced and oxidized SCR.36 The three redox reactions are summarized as follows: Assay1: succinate + cyt c
3 + SCR
⎯⎯⎯→ fumarate + cyt c
Article
ASSOCIATED CONTENT
S Supporting Information *
Chemical compound information. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: [email protected] and [email protected] edu.cn Author Contributions ∥
These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS The research was supported in part by the National Basic Research Program of China (no. 2010CB126103) and the NSFC (nos. 20925206, 20932005, and 31070643). We acknowledge Dr. Z. X. Wang for critical discussions and reading of the manuscript. We are also very thankful for the comments and suggestions by anonymous reviewers.
2+
complexII
Assay2: succinate + DCIP ⎯⎯⎯⎯⎯⎯⎯⎯⎯→ fumarate + DCIPH 2 bc1complex
Assay3: DBH 2 + cyt c 3 + ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ DB + cyt c 2 +
The enzymatic activities of SCR, complex II, and the bc1 complex were analyzed in separate reaction mixtures as reported previously.37−39 The reactions were initiated by adding a catalytic amount of enzyme to each reaction mixture. The time course of the absorbance change was recorded continuously at 550 nm for cyt c reduction 600 −1 cm−1) or 600 nm for DCIP reduction (Ared−ox = (A550 red−ox = 18.5 mM 21 mM−1 cm−1). Initial rates were determined from the linear slope of the obtained progress curves, and the experimental data were analyzed using a nonlinear regression analysis program. Crystallization and Structure Determination. Orthorhombic crystals of chicken bc1 in the space group P212121, containing a complete dimer in the asymmetric unit, were prepared by sitting-drop vapor diffusion at 273 K, under optimized initial crystallization conditions with 50 mm cacodylate; 9.4 mM TrisHCl; 30 mM K-MES, pH 6.8; 1.8 mM K-MOPS, pH 7.2; 30 mM NaCl; 31 mM KCl; 10 mM MgCl2; 91 g/L glycerol; 30 g/L PEG 4 kDa; 0.9 mM NaN3; 0.05 mM EDTA; 0.47 g/L undecyl maltoside; and 31 mM octyl glucoside, pH 6.77. Crystals were grown from chicken bc1 treated with a two-fold excess of 4e. Diffraction data were collected at beamline A1 of the Cornell High Energy Synchrotron Source (CHESS) at an X-ray wavelength of 0.9770 Å. Data from one crystal extending to 2.70 Å were used to refine the previously determined structure of the protein (3L71), and an electron density map (2Fo−Fc) was calculated. A model of 4e was placed in the density in the Qo site map, and the structure including inhibitor was subjected to further rounds of manual rebuilding in O40 against 2Fo−Fc maps (CCP4)41 and to automated refinement (atomic positional and individual isotropic ADP) in CNS 1.1.42 Noncrystallographic symmetry was restrained during positional but not ADP refinement, dividing the monomer into 33 NCS groups and releasing NCS restraints for numerous residues that did not seem to conform to the NCS. As reported in Table 3, Supporting Information, the overall Rfree value was 0.289 with 0.404 in the last shell justifying the resolution cutoff. Rms deviation from ideal bond lengths (0.008 Å) and angles (1.3°) was reasonable. A total of 85.0% of the residues were within the most favorable region of the Ramachandran plot as defined in the Procheck program,43 and only 0.3% (nine residues) was in the disallowed region. Four of these (two in each monomer) were known to be “true” outliers from highresolution structures from a number of species,44 and three were in poorly ordered regions of subunit 9. The inhibitor and surrounding protein were relatively well ordered, especially in the first monomer (residue C2001), which had an average isotropic ADP of 42.1, well below the average for the protein. The structure and diffraction data have been deposited in the PDB with ID code 3TGU.
REFERENCES
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-2,987,709,984,438,430,700 | Symptoms of Mild Autism | Autism Expert Advices (2023)
Autism, a developmental disorder that affects one out of every 59 people worldwide, is a lifelong condition. People diagnosed with mild autism experience communication difficulties, developmental delay, repetitive speech style, and social adjustment disorders. They have fewer and milder symptoms than individuals with autism have. For this reason, it can also be called atypical autism. So what are the symptoms of mild/atypical autism and how is it treated if there is any?
We already know that autism is defined as a congenital developmental disorder. If the characteristic features of autism are not observed intensely or are very mild, it is called mild autism. It is also known as pseudo autism, mild autism, transient autism, or semi-autistic with its definition among the people. People with this type of autism disorder do not have as many problems in their lives as other individuals on the autism spectrum. Individuals with mild autism adapt to society more easily than individuals with other types of autism.
The group that responds best to the treatment process and the training they receive is individuals with mild autism. The most important feature that distinguishes children with mild autism from all other children on the autism spectrum is that they can be overcome by early diagnosis, therapy, and correct treatment methods, and they can lead a healthy life like individuals who complete their development normally. It should not be forgotten that the effect of early diagnosis is great in overcoming the problems experienced by an individual with mild autism.
Symptoms of Mild Autism | Autism Expert Advices (1)
Symptoms of Mild Autism
Symptoms may vary from individual to individual in individuals with mild autism. In mild autism, at least one of the following symptoms or milder severity of more than one symptom can be observed. The most known mild autism symptoms can be listed as follows:
• There is a delay or difficulty in language and speech abilities.
• Developmental problems are observed in different neurological abilities such as motor development, visual perception, spatial perception, and cognitive abilities.
• An increase or decrease in the senses of taste, smell, sight, touch, or hearing is observed. They can be overreactive sometimes.
• Stereotypical, that is, repetitive behavior patterns are observed.
• They may be obsessed with specific objects, topics, or things.
• They may exhibit obsessive and repetitive behaviors.
• There is a delay in muscle development.
• They may have difficulties in understanding and perceiving.
• They have social adaptation problems.
• Communication problems are observed.
• They often have anxiety and trust issues.
• Inability or insensitivity is observed in verbal or non-verbal communication.
• They do not feel any sense of danger, fear, or pain.
• They cannot make eye contact or react to the name. (Even if they look into your eyes, this is usually brief or they seem to be looking away from you.)
• They are quite insensitive to heat, cold, or any pain.
• They can be offensive. They tend to harm themselves, others, or property.
• They like to have a routine. Every little change in their routine causes them to experience more stress.
• They can be extremely shy and shy.
• They may overreact to the disruption of the environment in which they live. For example, if the items in the house have been moved, they may cry until the items are put back in their places.
Symptoms of Mild Autism | Autism Expert Advices (2)
(Video) Autism Spectrum Disorder: 10 things you should know
Reasons for Having Mild Autism
One of the most curious subjects is the question of why and how mild autism happens. Genetic factors, environmental factors, hormonal reasons, and some neurodevelopmental differences are among the causes of mild autism. We can list the causes of mild autism as follows:
• The mother’s use of drugs or excessive medication use during pregnancy increases the risk of autism in infants.
• Studies show that the risk of autism in children increases with the age of the parents, and this risk is higher especially for fathers over the age of 35.
• Problems that leave traces in the child’s nervous system, such as premature birth or difficult birth, can cause autism.
• Cesarean delivery can also be listed among the causes of autism. Scientific researches show that in the normal birth of the mother, the child incorporates beneficial bacteria that support the intestinal flora; this shows that there is no such possibility in cesarean delivery. There are some studies that show a relationship between intestinal flora, attention deficit hyperactivity disorder, and autism.
• Some mutations that occur during gene splicing, gene deletion, or some protein synthesis deficiencies that are responsible for gene excess can cause mild autism.
• Heavy metal transmission from mother to child or subsequent accumulation in the child can be listed as a mild autism cause. Heavy metal passing from the mother’s blood to the baby affects the brain tissue of the developing baby.
It is possible to count these reasons among the mild autism causes that may come to the fore at the moment. However, there is no scientifically proven cause of mild autism yet. However, scientific research on this subject is still continuing.
Symptoms of Mild Autism | Autism Expert Advices (3)
Treatments of Mild Autism
Mild autism is a disorder that, although with more basic symptoms, does not go away completely. However, with the support of behavioral therapy, in adulthood, they can reach a level that is indistinguishable from normally developed individuals who do not suffer from these disorders and can lead a healthy life on their own. Autistic symptoms may disappear over time. Therefore, early diagnosis and treatment are of great importance.
There is no known cure for the many types of autism, such as any definite drug or surgery. Treatment is planned according to the needs of the child. In the treatment process, it is aimed to improve the skills of children and strengthen their speech with the help of special pieces of training.
It should be kept in mind that the group that responds best to the treatment process in autism spectrum disorder is the group with mild autism. A child with mild autism can be treated with various therapy support. What kind of support is needed varies over time and according to the child.
(Video) Helping Parents and Therapists Cope with Autism Spectrum Disorder | Susan Sherkow | TEDxYouth@LFNY
Different methods and treatments are used for different delays in development. Play-based activities are used to develop emotional and communication skills. Speech therapy support is provided to improve speaking skills and body language.
In the mild autism treatment process, children improve their social skills by receiving special education and psycho-educational therapies. They begin to express themselves better. Behavioral problems are reduced. Cognitive functions and speaking skills develop. An increase in motor skills is observed. A decrease in obsessions is observed.
Symptoms of Mild Autism | Autism Expert Advices (4)
• Developmental therapies; usually focus on emotional, intellectual, and social skills.
• Occupational therapy; Many gross motor skills such as balance exercises, sports, balance, etc. are carried out with occupational therapy procedures performed in the company of a physiotherapist.
• Nutrition diet practices; Educational studies are carried out on child psychology, music, and art studies.
• Families with children with mild autism also should be informed about treatment studies.
• Along with nutritional treatments, diets are followed depending on the allergy status of the children.
• Individuals with mild autism also have unique characteristics and treatment methods should be planned specifically for each person.
When looking at mild autism recovery signs, it varies according to each individual, as the same symptoms are observed. Especially when these treatments and training are followed from childhood, it is easier and faster for children to get used to social life. There is no definitive treatment for all autism groups as we mentioned before, and together with the necessary rehabilitation, the possibility of recovery, that is, the rate of living more comfortably and alone, is increased. With the support of families, individuals can live independently with predetermined qualitative and specific educational practices.
With mild autism treatment, people are provided with healthier communication, their skills are increased, and their obsessions are reduced. Signs of mild autism recovery may also include being in high spirits and being happy. Because they start to express themselves more easily and comfortably.
The mild autism group is known as an autism group that responds favorably to treatment on the autism spectrum. Since it is a group that responds positively to the treatment, the family, friends, and relatives of the individual should know the situation of the people in this regard and act accordingly.
(Video) 2-Minute Neuroscience: Autism
Symptoms of Mild Autism | Autism Expert Advices (5)
How To Treat A Child With Mild Autism
In fact, children with autism and mild autism should be treated in the same way as any child should be treated. Interest should be shown, warm and understanding behaviors should be displayed and should be approached with love. Remember that what they really need most is the understanding you show them. Try to understand them and make them feel that too. The family of the child who is being treated for mild autism should not despair during the treatment process. Otherwise, the child may be adversely affected psychologically and may refuse treatment. The child with mild autism should always feel support during the treatment process.
Symptoms of Mild Autism in Toddlers
Can a child with mild autism live a healthy life? The short answer to this question is yes. We know that autism is a spectrum disorder. This means that symptoms appear differently in each individual and range from mild to severe. The milder the symptoms, the more likely a child with autism is to live more individually in their daily lives. They have a high ability to overcome many social, communication, and behavioral deficiencies that hinder them.
In children with mild autism, the importance of early intervention is more evident and observable. While not impossible, it becomes increasingly difficult to treat deficiencies and delays as the child with autism grows.
A child with mild autism can eventually lead a productive, free, and independent life compared to other children on the spectrum. With early intervention, they can be successful in communication and social interaction with their peers and learn the necessary skills. They may also work to demonstrate appropriate behavior in school, work, and other social settings. In addition to those, many of them who receive early intervention and guidance during their developmental stages become very indistinguishable from their normally developed peers during adolescence and adulthood.
The best thing that can be done for a child with mild autism is to seek professional support for an intervention soon after diagnosis. ABA is generally considered the best method for this. Starting ABA therapy early will also be very beneficial for parents. This difference will become more visible, especially when the child with mild autism begins to walk. They will learn appropriate life skills and abilities more quickly and parents will be more comfortable about their children’s lives.
(Video) Adult Autism Assessment
Symptoms of Mild Autism | Autism Expert Advices (6)
Amplelife 3D Easter Bunny Pop Fidget Toys – Bubbles Poppers Sensory Toy for Toddlers 1-3 Autistic Children, Pop Rabbit it Ball Fidgets its Pack (3 Packs)
They are fidget toys that can be used multifunctional. They are fun toys that can be squeezed easily. Also, they can be used to reduce stress and increase calmness. They are made of high-quality materials which are soft silicone. Thanks to the material, they are very soft and comfortable. Over time, you will still feel the same softness. They can be used by everyone whether they are on the autism spectrum or not. They are easy to carry and easy to attach to any item. It can be also a great gift alternative. Overall, it is a fun and great item to spend money on.https://www.amazon.com/Easter-Bunny-Pop-Fidget-Toys/dp/B09TK7Y2LQ/ref=sxin_14_pa_sp_search_thematic_sspa?cv_ct_cx=sensory%2Btoys&keywords=sensory%2Btoys&pd_rd_i=B09TK7Y2LQ&pd_rd_r=15fba89d-098a-4159-aa11-3539470146fa&pd_rd_w=DeAl4&pd_rd_wg=dJwQL&pf_rd_p=55f29f81-ec0c-4199-b827-52d2036e3594&pf_rd_r=GAQ5AD1FMFS3596NM2XP&qid=1647776853&sr=1-2-a8004193-6951-43f6-852a-aff7dbba9115-spons&spLa=ZW5jcnlwdGVkUXVhbGlmaWVyPUFOMFgyRUgxU1ZLRlYmZW5jcnlwdGVkSWQ9QTAzNDk1NDkyWEFDMEdITElYU0M5JmVuY3J5cHRlZEFkSWQ9QTA5ODk2OTlZN0NSNlFNTkxIT0kmd2lkZ2V0TmFtZT1zcF9zZWFyY2hfdGhlbWF0aWMmYWN0aW9uPWNsaWNrUmVkaXJlY3QmZG9Ob3RMb2dDbGljaz10cnVl&th=1
Symptoms of Mild Autism | Autism Expert Advices (7)
LESONG Sensory Water Beads Toy for Kids 6 Pack, Shapes Learning Toy for Toddlers, Fidget Stress Toys for Autism/ Anxiety Relief for Adults, Bean Bags Great for Cornhole Tossing Carnival Backyard (Shape)
It is a great multifunctional sensory toy. It helps to reduce stress, reduce anxiety, develop focus and develop concentration while having fun. They are good for individuals with autism, ADHD, high level of anxiety, and even Alzheimer’s. However, fun items for normally developed individuals as well. They are good for sensory and color recognition. There are 6 different colors and 6 different shapes filled with water beads. It can be used as a game to keep toddlers and children busy especially while traveling. It is a great gift alternative for everyone.https://www.amazon.com/Learning-Toddlers-Cornhole-Carnival-Backyard/dp/B0823PVQM9/ref=sr_1_11?keywords=sensory%2Btoys&qid=1647776853&sr=8-11&th=1
Symptoms of Mild Autism | Autism Expert Advices (8)
FAQs
What are the symptoms of very mild autism? ›
What Are Some Possible Signs of Mild Autism?
• Repetitive play or verbal expressiveness (echolalia)
• A fixation on certain activities, ideas, or concepts.
• A reluctance to engage in new experiences or to disrupt routines.
• Aversion to certain forms of interaction, especially hugging or cuddling.
2 Jan 2021
Can a person with mild autism live a normal life? ›
The simple answer to this question is yes, a person with autism spectrum disorder can live independently as an adult. However, not all individuals achieve the same level of independence.
How do you deal with mild autism? ›
Coping strategies for autistic people explained
1. Music. Music is one of the creative mediums that has a range from calm and classic to fast and energetic. ...
2. Going for a walk. ...
3. Exercise. ...
4. Deep breathing. ...
5. Engage in a pleasant and relaxing activity. ...
6. Sensory and fidget toys. ...
7. Prayer and meditation. ...
8. Practice mindfulness.
28 Apr 2022
What are the symptoms of mild to moderate autism? ›
Children with moderate autism may or may not interact with peers. They generally struggle to make eye contact, interpret body language and emotions, and understand figures of speech, and they may simply walk away from conversations that don't involve their favorite topics or interests.
Can mild autism go to normal school? ›
Autism has a wide spectrum and not every individual with autism can find a place in mainstream schools. However, I have had a few success stories where the right support and timely intervention helped. Several students from my schools were able to successfully complete their education from mainstream schools.
Can you correct mild autism? ›
No cure exists for autism spectrum disorder, and there is no one-size-fits-all treatment. The goal of treatment is to maximize your child's ability to function by reducing autism spectrum disorder symptoms and supporting development and learning.
Does mild autism get better with age? ›
Change in severity of autism symptoms and optimal outcome
One key finding was that children's symptom severity can change with age. In fact, children can improve and get better. "We found that nearly 30% of young children have less severe autism symptoms at age 6 than they did at age 3.
Can mild autism get worse? ›
Untreated autism spectrum disorder symptoms worsen over time
That said, as with any symptom, untreated autism spectrum disorder symptoms will get worse over time.
What is the mildest type of autism? ›
Asperger's Syndrome is the mildest form of autism and is closely associated with level one of ASD.
What therapy is best for mild autism? ›
The most common developmental therapy for people with ASD is Speech and Language Therapy. Speech and Language Therapy helps to improve the person's understanding and use of speech and language. Some people with ASD communicate verbally.
What causes mild autistic? ›
Autism spectrum disorder (ASD) is a developmental disability caused by differences in the brain. Some people with ASD have a known difference, such as a genetic condition. Other causes are not yet known.
What causes mild autism? ›
Both genetics and environment may play a role. Genetics. Several different genes appear to be involved in autism spectrum disorder. For some children, autism spectrum disorder can be associated with a genetic disorder, such as Rett syndrome or fragile X syndrome.
What happens if mild autism is not treated? ›
If the autism spectrum disorder left untreated it will have a detrimental effect on that person's life make him dependent on others. Additionally there are higher chances for the appearance of new symptoms which were absent before that eventually worsen the situation.
What is borderline autism? ›
“This category should be used when there is severe and pervasive impairment in the development of reciprocal social interaction associated with impairment in either verbal or nonverbal communication skills or with the presence of stereotyped behavior, interests, and activities, but the criteria are not met for a ...
How do you raise a child with mild autism? ›
Helping your child with autism thrive tip 1: Provide structure and safety
1. Be consistent. ...
2. Stick to a schedule. ...
3. Reward good behavior. ...
4. Create a home safety zone. ...
5. Look for nonverbal cues. ...
6. Figure out the motivation behind the tantrum. ...
7. Make time for fun. ...
8. Pay attention to your child's sensory sensitivities.
Is mild autism a learning disability? ›
Is Autism a Learning Disability? Autism spectrum disorder (ASD) is not a learning disability, but it can affect learning — in part because autism can affect language skills, both when listening and speaking.
How do you get an autistic child to listen? ›
Keep your turns short at first, so your son needs to listen for only a short time before you praise or reward him. As he gets better at listening and waiting his turn, try gradually lengthening your answers (or those of another partner). We like combining this game with the talking stick or listen/talk signs.
Does mild autism need therapy? ›
Treatments for Children
They may also benefit from social-skills training, mental health counseling, a special diet, and help to build motor skills. As with any type of autism, the most helpful treatments for mild autism often involve a variety of therapies.
At what age does autism peak? ›
A recent study by UC Davis MIND Institute researchers found that the severity of a child's autism symptoms can change significantly between the ages of 3 and 11.
Does autism affect sleep? ›
Autistic people can often have trouble sleeping. There are a range of reasons for this including difficulties with relaxing or winding down and irregular melatonin levels. Problems with sleep can be an issue for both autistic adults and children.
What is the prognosis of mild autism? ›
The prognosis in patients with ASD is highly correlated with their IQ. Low-functioning patients may never live independently; they typically need home or residential care for the rest of their lives. High-functioning patients may live independently, hold jobs successfully, and even marry and have children.
Is mild autism permanent? ›
It's a lifelong condition. People with ASD benefit from therapies that can teach new skills.
What does mildly autistic mean? ›
However, a person can be mildly autistic. Mildly autistic people are unable to understand the body language or emotions (sarcasm, pain and anger) of the people around them. However, they have normal intelligence and can carry their day-to-day activities.
What is the difference between autism and mild autism? ›
The principal difference between autism and what was once diagnosed as Asperger's is that the latter features milder symptoms and an absence of language delays. Most children who were previously diagnosed with Asperger's have good language skills but may have difficulty “fitting in” with their peers.
Is mild autism a thing? ›
Autism is a significant developmental disorder that is usually diagnosed in very young children. 1 While it is possible to be mildly autistic, it takes more than a few quirks to earn the diagnosis.
Which foods are good for autistic child? ›
The best food for children with autism are fatty fish, eggs, grass-fed beef, sustainably raised animal proteins, shellfish, beans, nuts, and seeds. Research has found that fatty fish such as salmon and free-range eggs share the healthy omega 3 acid. Foods that contain omega 3s help fight inflammation in the body.
Can autism get worse as you get older? ›
Autism does not change or worsen as someone gets older, and there's no cure.
What other disorders are like autism? ›
Avoidant personality disorder. Obsessive compulsive disorder (OCD) Reactive attachment disorder. Social (pragmatic) communication disorder.
Can autism be sociable? ›
Some people on the autism spectrum may seek social opportunities and may initiate social interactions themselves, others may enjoy social situations and interactions when they are initiated effectively by others.
Is there such a thing as slightly autistic? ›
No, there is no such thing as being a little autistic. Many people may show some characteristics of autism from time to time. This may include avoiding bright lights and noises, preferring to be alone and being rigid about rules. This does not make them autistic.
At what age is mild autism diagnosed? ›
ASD can sometimes be detected at 18 months of age or younger. By age 2, a diagnosis by an experienced professional can be considered reliable. However, many children do not receive a final diagnosis until much older. Some people are not diagnosed until they are adolescents or adults.
What is an example of mild autism? ›
For example, someone with mild autism may: Be able to speak but has trouble with back-and-forth conversation. Tries to make friends but are not successful because they appear "odd" to others. Does age-appropriate schoolwork or tasks, but has a hard time changing activities or trying new ways of doing something.
Can you have autistic traits and not be autistic? ›
Two large studies published in the past two months have found that traits linked to autism are widely distributed in the general population. Although about 1 in 100 children is diagnosed with autism, up to 30 percent of people may have at least one of the traits associated with the disorder.
Is it hard to diagnose mild autism? ›
Diagnosing autism spectrum disorder (ASD) can be difficult since there are no medical tests to diagnose it, and it's exhibited as a spectrum of closely related symptoms.
Videos
1. What it’s like to live as an adult with autism | Your Morning
(CTV Your Morning)
2. Treatment for Mild Autism Spectrum Disorder | No. 3024
(Neurogen Brain and Spine Institute)
3. Autism Diagnosis at 21 Years Old
(ABC News)
4. Once a non-verbal child with autism, Ava hopes her story will help other kids with special needs
(11Alive)
5. A Life-Changing Therapy For Children With Autism At The Child Study Center
(Yale Medicine)
6. Worried about AUTISM: The early signs, how doctors screen for autism PLUS tips | Dr. Kristine Kiat
(Dr. Kristine Alba Kiat - Pediatrician)
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Introduction: My name is Chrissy Homenick, I am a tender, funny, determined, tender, glorious, fancy, enthusiastic person who loves writing and wants to share my knowledge and understanding with you. | {
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Read more about the study here. For a summary of this and other studies related to exercise, cancer, and the immune system, see this article in the New York Times. | {
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-6,997,730,864,854,109,000 | 468
I was asked to take a look at a 50-page report on a wound center’s post-payment review of hyperbaric oxygen therapy (HBOT) services. Nearly all the wounds that were treated were truly limb-threatening, and most of the patients got better. Unfortunately, their post-payment review has not gone well, and sadly, most of the reasons are avoidable.
I reviewed many (but not all) of the patient records. The issues that I noted largely fall into the categories of:
1. Not coding correctly for HBOT to be covered
2. Not documenting off-loading of DFU’s at each visit
3. Not documenting arterial assessment
4. Not documenting conservative treatments for 30 days before HBOT
5. Not documenting studies that would support the diagnosis (e.g. angiograms, MRIs, X-rays, etc.).
Here is some more detail around these issues (see the items in red and my WARNING, below):
• Wagner 3 DFU not documented: In many cases, the ulcers were clearly a Wagner 3 or 4, but were coded as arterial ulcerations even though the patient had diabetes and my read of the photographs is that the ulcers would better have been coded as DFU’s
• Needs more clinical evidence to support the diagnosis (e.g. arterial insufficiency)
• The review specifically states that documenting a diagnosis code alone is not enough – there has to be supporting information to prove osteomyelitis, arterial disease, etc.
• No documentation of wound measurements: This one worries me a lot, because I reviewed the clinical records and measurements are clearly THERE. However, I don’t know what was sent to the payer in response to the review. I worry that it might have only been documentation of today’s hyperbaric treatment and not the separate wound documentation.
• No proof of 30 days failed care before HBOT: See concern above in terms of what was sent to the payer.
• No proof of offloading: Off-loading was not documented despite a clinical practice suggestion inside the EHR suggesting that it be documented. In other words, the physicians ignored the tools trying to help them.
• No documentation of arterial evaluation: Every patient should get an arterial screen in the wound center. Pick a modality (ABI, TCOM, SPP, PVR)
• HBOT records did not include ascent time, descent time, total compression time, dose, pressure, attendance by doctor: ???
• No signed order for HBOT on the date of service
• Record not signed on day of debridement
• Debridement (billed for) was not documented
• Documentation of arterial occlusion but no plan to correct it
• No notes from referring doctor to substantiate neoplasm and prior XRT for late effects of radiation
• No date of skin graft for failing grafts
• HBOT for failing graft was started >30 days after graft
• Too many treatments given for HBOT for failing graft (“not expected to exceed 20” but 30 treatments were ordered and 41 provided)
I highlighted in red some things that have big implications with regard to providing HBOT for a failing graft. The payer is requiring the exact date on which a skin graft was performed, refusing payment if HBOT was started more than 30 days after that date, and refusing payment in excess of 20 treatments.
The payer is requiring that a specific patient with late effects of radiation had notes from the referring doctor to substantiate the diagnosis. That’s big.
A lot of payments are in jeopardy because charts weren’t signed, diagnoses were not coded correctly, or the documentation that was done was NOT SENT in response to the request for records! We can’t survive unless we can do a better job of the basics.
However, a lot of payments are in jeopardy because off-loading was not consistently documented and arterial screening was not done or documented. We have quality measures for those, but no one seems interested in using quality reporting as a way to preserve their payments.
As the Chief Medical Officer of an electronic medical records company with a product specific to wound care, I get asked by a lot of doctors “how long does it take to use your EHR to document a new patient?” They tell me that they are super busy and have a LOT of patients to see and that the EHR will just slow them down. I am sure they are busy. When I am seeing patients I am busy, too. My answer is, “Are you asking me how long it takes to document what you need in order to get paid, or how long it takes to document the way you do it NOW?” Because they are not the same.
Here’s a graphic to help understand the difference between Prior Authorization, Pre-payment review and Post-payment review: | {
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7,383,243,743,127,205,000 | How to Tell if You are Depressed or Burned out
stress
Have you ever woken up in the morning, stumbled to the coffee machine, and wondered if you were depressed, burnt out, or just really, really tired? In today’s fast-paced world, it’s all too easy to get caught up in the endless cycle of work, stress, and exhaustion. Feeling down or overwhelmed at times is a normal part of life, but when these feelings persist, they can be a sign of a more serious condition such as depression or burnout.
But how do you tell if you are dealing with depression or burnout, or both? While these two conditions can share similar symptoms, they are different and require different types of treatment. In this article, we will discuss the key differences between depression and burnout and how to tell which one you may be experiencing.
What is depression or burnout?
Depression is recognized as a significant mental health issue by the World Health Organization. According to the WHO, depression is a common mental disorder that can have a significant impact on an individual’s ability to carry out everyday activities. Depression can be like wearing glasses with the wrong prescription. Everything around you looks a little bit blurry, and no matter how hard you try to focus, you can’t seem to see things clearly. It’s like you’re moving through life in slow motion, and nothing seems to bring you joy.
On the other hand, WHO defines burnout as a syndrome that results from chronic workplace stress that has not been successfully managed. The organization identifies three dimensions of burnout: feelings of energy depletion or exhaustion, increased mental distance from one’s job or feelings of cynicism or negativity related to one’s job and reduced professional efficacy. Burnout, on the other hand, can feel like being in a video game where you’re stuck on the same level, doing the same thing over and over again, and you can’t seem to move on to the next challenge. Recognizing emotional exhaustion, one of the key symptoms of burnout, is an essential mental health check.
See also Excellent Flu Prevention Suggestion
Depression vs burnout: What are the key differences?
How do you tell if you are depressed or burned out? Here are some key differences that can help you identify whether you are experiencing depression or burnout:
Symptoms of Depression:
• Persistent sadness or feeling down
• Loss of interest or pleasure in activities you once enjoyed
• Changes in appetite or weight
• Insomnia or sleeping too much
• Fatigue or lack of energy
• Difficulty concentrating, remembering, or making decisions
• Feelings of worthlessness or guilt
• Thoughts of death or suicide
Symptoms of Burnout:
• Exhaustion, both physical and emotional
• Feeling cynical or detached from work or relationships
• Reduced productivity or effectiveness
• Increased negativity or irritability
• Loss of enjoyment or satisfaction in work or other activities
• Feeling overwhelmed, frustrated, or trapped
• Decreased motivation or initiative
What to do if you are depressed or burned out?
Whether you’re experiencing depression or burnout, there are steps you can take to improve your well-being.
For depression, firstly, seek professional help from a healthcare professional such as a doctor or therapist. They can provide an accurate diagnosis and recommend appropriate treatment options, which may include therapy, medication, or a combination of both.
It’s also important to take care of yourself by prioritizing self-care. This can include getting regular exercise, eating a healthy diet, and getting enough sleep. Self-care activities like taking a warm bath, reading a book, or spending time with friends can also help you feel better.
Staying connected with friends and loved ones is also crucial. Depression can make you feel isolated and alone, but it’s important to stay connected with others who can provide emotional support and help you through tough times.
See also 7 Ways to Observe National Wellness Month
In some cases, medication may be necessary to help manage depression. It’s important to talk to your doctor about the risks and benefits of medication and whether it’s right for you.
For burnout, it is important to prioritize self-care, seek support, address the underlying causes, and develop strategies to manage stressors and improve your overall well-being.
Angela Neal-Barnett, a psychology professor, highlights the impact of burnout on individuals, particularly Black women, and emphasizes the need for self-care, social support, and addressing workplace culture and policies to promote employee well-being.
Research has also shown that:
• Taking breaks can improve productivity and job satisfaction.
• Self-care activities like exercise and meditation can reduce burnout and improve well-being.
• Setting boundaries can improve job satisfaction and reduce work-family conflict.
• Prioritizing tasks can lead to reduced stress and increased productivity.
• Social support is associated with reduced burnout.
Remember, it’s important to prioritize your mental health and take the necessary steps to recover. With the right support and resources, you can regain your sense of motivation, purpose, and fulfillment. Don’t hesitate to reach out for help, and remember that recovery is possible.
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-2,338,389,427,479,041,000 | Menu
heel Pain GoutThe word gout comes from the Greek word podagra, which literally translates to “foot grabber.”
Gout is a type of arthritis caused by a buildup of uric acid and characterized by foot pain, swelling, redness, and difficulty walking is typically localized in the big toe. However, some types of gout may be localized in the heel, making it difficult to distinguish from plantar fasciitis.
Let’s explore the connection between gout and heel pain, as well as symptoms that can help you tell the difference between plantar fasciitis and gout
The Connection Between Heel Pain and Gout
While it’s fairly rare for gout pain to appear in the heel (instead of near the big toe), it does happen!
Gout that leads to foot pain develops when there are high levels of uric acid in the body. And high levels of uric acid are most likely to develop under the following conditions:
• Diet: A diet that is heavily focused on red meat, sugar (particularly fructose), and alcohol (beer, in particular) can increase levels of uric acid and gout.
• Increase in body fat: As your body increases its stores of body fat, uric acid levels rise, and your kidneys may struggle to eliminate the excess.
• Medications: Some medications, including hypertension, may increase uric acid in the body. Studies show that Thiazide diuretics (which treat hypertension) are key culprits.
• Untreated medical conditions: High blood pressure, metabolic syndrome, diabetes, and kidney disease can all contribute to higher than usual levels of uric acid in the body, and gout.
• Genetics and gender: There is a genetic link to gout. If you have a family history of gout, you may be especially susceptible. Younger men are more likely to get gout than women; however, postmenopausal women have an increased risk as well.
How Can High Uric Acid Cause Heel Pain?
So, why does gout show up in the feet (as opposed to other body parts)? Uric acid is very sensitive to cooler temperatures. As it circulates throughout the body and reaches the feet (furthest from the heart and typically the coolest), the liquid uric acid crystalizes, leading to pain in the joints of the big toe or joint of the heel (where the heel bone meets the ankle bone).
Uric acid levels rise when your body breaks down “purines.” Purines are found in foods like red meat and alcohol, as well as in certain medications and naturally in the human body (especially as fat stores increase).
Most of the time, your body is able to manage uric acid levels effectively, simply dumping the uric acid into your kidneys where it is excreted as urine. However, when uric acid levels get high enough, your kidneys may struggle to keep up, and uric acid may stay in your bloodstream where it causes inflammation, pain, and swelling as it crystallizes in the joints of the foot.
Is My Heel Pain Gout or Plantar Fasciitis?
Heel pain can be confusing at times. While the most common cause of heel pain is plantar fasciitis, other less common ailments like gout can mimic similar symptoms! Use this helpful symptom guide to determine whether you’re dealing with plantar fasciitis or gout:
Symptoms of Heel Pain from Plantar Fasciitis
The hallmark symptoms of plantar fasciitis include the following:
• Heel pain that’s most intense first thing in the morning (when the plantar fascia hasn’t “warmed up” yet through movement).
• Pain that improves somewhat with stretching and low-impact physical activity
• Sharp or dull pain, accompanied by redness or swelling
• Pain that coincides with weight gain
• Difficulty walking or standing on the affected foot (plantar fasciitis can happen in both feet, though more rarely!)
• Pain that improves through the use of orthotics that help properly realign and cushion the plantar fascia
Symptoms of Heel Pain Due to Uric Acid
Anyone can get gout, although it’s most common in individuals with the risk factors we covered earlier (like heavy alcohol use, or a diet that includes a lot of red meat.) The symptoms of gout in the heel are subtly different from those of plantar fasciitis in the heel:
• Redness, swelling and tenderness that is most pronounced where the heel meets the ankle. You are also likely to notice symptoms at the base of the big toe.
• Often, gout symptoms will flare-up in the middle of the night (when that uric acid settles and cools during this period of low activity)
• During a flare-up, your heel will feel so hot and painful to the touch that even wearing socks is excruciating
• Pain that is less intense but lingers after a “gout attack” flare-up of pain
• Increasing difficulty moving the joint
As a general rule of thumb, pain from plantar fasciitis will improve with rest, while pain from gout will flare up during long periods of inactivity and rest.
Treating Heel Pain from Gout
Thankfully, most cases of heel pain from gout can be successfully resolved with minimal medical intervention and changes to diet and lifestyle.
Medications
NSAIDs (non-steroidal anti-inflammatory drugs) like Tylenol and Ibuprofen can help relieve pain from a gout attack, as well as reduce pain and swelling in the heel.
Colchicine is another common medication prescribed to treat pain from gout, however, it can cause severe side effects like nausea and diarrhea. Your doctor will likely recommend the minimal dose needed.
Corticosteroids are used in rare cases when NSAIDs or Colchicine can’t be taken since these drugs have serious side effects including high blood pressure and high blood sugar.
If you have ongoing gout attacks, or severe ongoing gout symptoms your doctor may also consider prescribing medication that limits the amount of uric acid your body produces.
Lifestyle Changes
Limit foods that increase uric acid production: These foods include alcohol, red meat, seafood, organ meats, fructose sugars, and other foods high in purines.
Exercise and manage weight when possible: As possible, maintain a healthy weight to keep the body’s own production of uric acid down.
Drink coffee: While scientists don’t understand the link completely, some studies have shown that drinking coffee can help lower your levels of uric acid!
Add more vitamin C to your diet: Taking at least 500 mg of vitamin C each day (and eating foods rich in vitamin C) has been shown to make a measurable, positive impact on uric acid levels in the body!
Have you suffered from heel pain that turned out to be gout? Tell us about your experience in the comments below! | {
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658,445,385,757,217,500 | 5 Major Diseases Caused by Smoking
There are so many diseases caused by smoking. And there’s no doubt about this. Tobacco contains thousands of chemicals that destroy cells and weaken your immune system, making your body vulnerable to illness. Today, let’s tackle some of the major, life-threatening diseases that are caused by smoking.
Does Smoking Calm The Nerves?
Smoking is a disease creating habit. More and more diseases caused by smoking are piled on everyday. The latest are anxiety disorders. There is the common assumption mostly by smokers that the act of smoking relieves anxiety. When actually the opposite is true, smoking is a risk factor for severe anxiety. Believe it or not […]
Case of the Day
A 35-year-old woman visits the clinic with complaint of difficulty swallowing liquids and solids. There is also a mild chest pain on swallowing foods. She sometimes wakes up in the morning with coughing and brings up undigested food on the pillow. Her symptoms began about 3 months ago and have slowly progressed over time. She […] | {
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1,037,716,556,304,027,900 | heparin
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 76
I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.
89. How does mast cell disease affect platelet counts?
Before I continue, I want to explain one basic fact. Even though they are often included in the term “blood cells”, platelets are not actually cells. They are actually pieces of an original large cell called a megakaryocyte that lives in the bone marrow. Even though platelets are not really cells, they more or less act like they are.
An unusual thing about platelets is that sometimes a specific trigger can cause platelets to become lower or higher.
There are several ways in which mast cell disease can make platelet counts lower.
• Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells and platelets, causing lower platelet counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells and platelets is much more pronounced. This may further lower platelet counts. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
• Medications. Some medications that are used to manage mast cell disease can cause low red blood cell count. Chemotherapies, including targeted chemotherapies like tyrosine kinase inhibitors, can cause low platelet counts. Non steroidal anti-inflammatory drugs (NSAIDs) are used by some mast cell patients to decrease production of prostaglandins. They can interfere with platelet production in the bone marrow. Proton pump inhibitors, often used by mast cell patients to help with GI symptoms like heart burn, can decrease platelet coun Some H2 antihistamines can also lower platelet production. However, none of these H2 antihistamines are currently used in medicine.
• Heparin induced thrombocytopenia. Mast cells make and release large amounts of heparin, a powerful blood thinner. When there is an excessive amount of heparin circulating, it can cause your body to incorrectly produce antibodies that cause an immune response to heparin. A side effect of this situation is that platelets are activated incorrectly, which can lead to the formation of blood clots and low platelet counts. Heparin induced thrombocytopenia has only been definitively described in patients who receive medicinal heparin as a blood thinner. However, it is reasonable to assume that this situation can also affect mast cell patients who have higher than normal levels of platelets circulating in the blood.
• Liver damage. Liver damage is associated with malignant forms of systemic mastocytosis such as aggressive systemic mastocytosis and mast cell leukemia. Liver damage can also occur as the result of IV nutrition, which is sometimes needed by patients with mastocytosis or mast cell activation syndrome. When the liver is damaged enough, it may not make enough of the molecules that tell the bone marrow to make platelets.
• Excessive production of blood cells. In very aggressive forms of systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia, the bone marrow is making huge amounts of mast cells. As a result, the bone marrow makes fewer platelets and cells of other types.
• Vitamin and mineral deficiencies. Chronic inflammation can affect the way your body absorbs vitamins and minerals through the GI tract, and the way it uses vitamins and minerals that it does absorb. Deficiency of vitamin B12 or folate can decrease platelet production.
• Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few platelets, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few platelets if they do a blood test. This can also happen if a patient receives a lot of IV fluids.
There are also reasons why mast cell disease can cause the body to make too many platelets.
• Anemia of chronic inflammation. This is when chronic inflammation in the body affects the way the body absorbs and uses iron. It can result in iron deficiency. Iron deficiency can increase platelet counts.
• Hemolytic anemia. In hemolytic anemia, the body destroys red blood cells. This can happen for several reasons that may be present in mast cell patients. Hemolytic anemia can increase platelet counts.
• Iron deficiency. Iron deficiency for any reason can elevate platelet counts.
• Excessive bleeding. Mast cell disease can cause excessive bleeding in several ways. Mast cells release lots of heparin, a very potent blood thinner that decreases clotting. This makes it easier for the body to bleed. It is not unusual for mast cell patients to have unusual bruising. Bleeding in the GI tract can also occur. Mast cell disease can cause ulceration, fissures, and hemorrhoids, among other things. Mast cell disease can contribute to dysregulation of the menstrual cycle, causing excessive bleeding in this way. It is not unusual for mast cell patients to have GI bleeding, as well as ulceration, fissures, and hemorrhoids.
• Sustained GI inflammation. Sustained GI inflammatory disease can cause elevated levels of platelets. Given what we know about mast cell driven GI inflammation, it is reasonable to infer that mast cell GI effects and damage may also elevate platelet levels.
• Clot formation. If a large clot forms, it can affect the amount of platelets circulating in the blood. Some mast cell patients require central lines for regular use of IV therapies or to preserve IV access in the event of an emergency. Blood clots can form on the outside surface of the line, inside the line, or between the line and the wall of the blood vessel it is in.
• General inflammation. Platelets are activated by a variety of molecules released when the body is inflamed for any reason. This can translate to increased levels of platelet production.
• Allergic reactions. Platelets can be directly activated by mast cell degranulation through molecules like platelet activating factor (PAF).
• Heparin. Heparin can cause platelet levels to increase. As I mentioned above, it can also cause platelet levels to decrease.
• Removal of the spleen. The spleen can become very stressed and work too hard, a condition called This situation is remedied by removing the spleen. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
• Glucocorticoids. In particular, prednisone is known to increase platelet counts. Prednisone and other glucocorticoids can be used for several reasons in mast cell patients.
• Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many red blood cells, it just looks like that on a blood test.
For additional reading, please visit the following posts:
Anemia of chronic inflammation
Effect of anemia on mast cells
Mast cell disease and the spleen
MCAS: Anemia and deficiencies
Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system
MCAS: Blood, bone marrow and clotting
Third spacing
Gastrointestinal manifestations of SM: Part 1
Gastrointestinal manifestations of SM: Part 2
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 74
I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.
1. How does mast cell disease affect red blood cell counts?
There are several ways in which mast cell disease can make red blood cell count lower.
• Anemia of chronic inflammation. This is when chronic inflammation in the body affects the way the body absorbs and uses iron. It can result in iron deficiency. Iron is used to make hemoglobin, the molecule used by red blood cells to carry around oxygen to all the places in the body that need it. If there’s not enough iron to make hemoglobin, the body will not make a normal amount of red blood cells.
• Vitamin and mineral deficiencies. Like I mentioned above, chronic inflammation can affect the way your body absorbs vitamins and minerals through the GI tract, and the way it uses vitamins and minerals that it does absorb. While iron deficiency is the most obvious example of this, deficiency of vitamin B12 or folate can also slow red cell production.
• Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells, including red blood cells, causing lower red blood cell counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells is much more pronounced. This may further lower the red blood cell count. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
• Medications. Some medications that are used to manage mast cell disease can cause low red blood cell count. Chemotherapies, including targeted chemotherapies like tyrosine kinase inhibitors, can cause low red blood cell count. Medications that specifically interfere with the immune system can do the same thing, including medications for autoimmune diseases like mycophenolate. Non steroidal anti-inflammatory drugs (NSAIDs) are used by some mast cell patients to decrease production of prostaglandins. They can interfere with red blood cell production in the bone marrow and also cause hemolytic anemia, when the immune system attacks red blood cells after they are made and damages them.
• Excessive bleeding. Mast cell disease can cause excessive bleeding in several ways. Mast cells release lots of heparin, a very potent blood thinner that decreases clotting. This makes it easier for the body to bleed. It is not unusual for mast cell patients to have unusual bruising. Bleeding in the GI tract can also occur. Mast cell disease can cause ulceration, fissures, and hemorrhoids, among other things. Mast cell disease can contribute to dysregulation of the menstrual cycle, causing excessive bleeding in this way.
• Excessive production of other types of blood cells. In very aggressive forms of systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia, the bone marrow is making huge amounts of mast cells. As a result, the bone marrow makes fewer cells of other types, including red blood cells. Some medications can also increase production of other blood types, causing less production of red cells. Corticosteroids can do this.
• Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few red blood cells, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few red cells if they do a blood test. This can also happen if a patient receives a lot of IV fluids.
There are also a couple of scenarios where mast cell disease can make the red blood cell count higher. This is much less common.
• Chronically low oxygen. If a person is not getting enough oxygen for a long period of time, the body will make more red blood cells in an effort to compensate for the low oxygen. This could happen in mast cell patients with poor oxygenation.
• Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many red blood cells, it just looks like that on a blood test.
For additional reading, please visit the following posts:
Anemia of chronic inflammation
Effect of anemia on mast cells
Effects of estrogen and progesterone and the role of mast cells in pregnancy
Explain the tests: Complete blood cell count (CBC) – Low red cell count
Explain the tests: Complete blood cell count (CBC) – High red cell count
Explain the tests: Complete blood cell count (CBC) – Red cell indices
Gastrointestinal manifestations of SM: Part 1
Gastrointestinal manifestations of SM: Part 2
Mast cell disease and the spleen
Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system
MCAS: Anemia and deficiencies
MCAS: Blood, bone marrow and clotting
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 3
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 12
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 20
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 45
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73
Third spacing
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 45
54. How does mast cell disease affect clotting?
Heparin is a very potent blood thinner and inhibits the body’s ability to form clots. Mast cells are full of heparin. Mast cells stores chemicals like heparin in little pouches inside them called granules. In the granules, histamine is stuck to heparin. This means that when mast cells open their granules and release histamine, heparin comes out with it. This can contribute to things like bruising or bleeding more than expected.
Mast cells release other chemicals that can affect clotting. Platelet activation factor and thromboxane A2 both encourage the body to make clots. Some chemicals that help to regulate when to make a clot can activate mast cells, like complement C3a and C5a.
55. How many people have mast cell disease?
It is hard to know exactly how many people have a rare disease because they are not reported if they are recognized and correctly diagnosed. As recognition and diagnosis improves, rare diseases are often found to be more prevalent than previously thought. The numbers below are current estimates.
Systemic mastocytosis is thought to affect around 0.3-13/100000 people. In one large study, indolent systemic mastocytosis (ISM) makes up 47% of cases. Aggressive systemic mastocytosis (ASM) has been described in various places as comprising 3-10%. Systemic mastocytosis with associated hematologic disease could count for as many of 40% of cases of SM. Mast cell leukemia is extremely rare and accounts for less than 1% of SM cases.
Systemic mastocytosis accounts for about 10% of total mastocytosis cases. This means that total mastocytosis cases come in at around 3-130/100000 people. The remaining 90% of mastocytosis cases are cutaneous with incidence roughly around 2.7-117/100000 people.
We do not have yet have a great grasp upon how many people have mast cell activation syndrome (MCAS) but from where I am sitting, it’s a lot and that number is likely to grow. We know that genetic studies have found mutations that might be linked to MCAS in up to 9% of the people in some groups. However, having a mutation is not the same thing as having a disease. As we learn more about MCAS, we will gain some clarity around how many people have it.
For more detailed reading, please visit the following posts:
Progression of mast cell diseases: Part 2
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)
The Provider Primer Series: Natural history of SM-AHD, MCL and MCS
The Provider Primer Series: Cutaneous mastocytosis/Mastocytosis in the skin
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 6
I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.
12. What do these blood and urine tests look for?
• There are a lot of tests ordered for mast cell disease. How they are interpreted can depend upon a lot of factors. Some of the tests are unreliable, a fact that will be addressed in detail later in this series. (And has been addressed in detail elsewhere on this blog). Please keep in mind when reading this post that I am being VERY general and assumed the test was performed correctly on a correctly stored sample.
• The most common test ordered for mast cell disease is serum tryptase. Tryptase is a molecule that mast cells release. While it has lots of functions in the body, and is especially important in healing wounds and tissue growth, the amount present in your body at a given moment should be low.
• Tryptase is special because mast cells release it in two ways. Firstly, they make and release a little bit steadily. This is not related to activation. Mast cells just normally release a little tryptase as they go about their work. So the idea is that if you have more mast cells than you should, and each of those mast cells releases a little tryptase all the time, that you will have a higher than normal serum tryptase.
• Patients with a clonal mast cell disease, in which they have too many broken mast cells, usually have elevated baseline tryptase. This means tryptase that is elevated at least two times when you are NOT having a big reaction or anaphylaxis.
• Mast cells also store lots of tryptase in their pockets. When the mast cell is activated and it empties out its pockets, lots of tryptase comes out at once. This is why tryptase can be higher after a reaction or anaphylaxis, because mast cells release a bunch at once.
• Patients with mast cell activation syndrome or cutaneous mastocytosis do not always have elevated tryptase even with a big reaction or anaphylaxis.
• Mast cells have huge amounts of histamine stored in their pockets inside their cells. Histamine has lots of functions inside the body and is required for normal body functions. In particular, it is important to our nervous system. Smaller amounts are released as a normal function of the body.
• A lot of histamine is released when mast cells are activated. The idea is that if your mast cells are more activated than they should be that your histamine level will be higher. However, the test recommended for us to consider the histamine level in mast cell patients is not for histamine. It is for n-methylhistamine. This is a molecule that is formed when the body breaks down histamine, which happens very quickly (within minutes of release). n-methylhistamine is more stable, which is why we look at it.
• The test for n-methylhistamine is most reliable when performed in a 24 hour urine sample. This is because the level in urine can fluctuate throughout the day.
• Mast cells make a lot of prostaglandin D2 (abbreviated PGD2). PGD2 is very important for cell communicating. It can carry a message from one cell to another, allowing cells to work together. Unlike histamine and tryptase, mast cells do not keep PGD2 stored in their pockets. They make it only when they need it and then release it.
• PGD2 is released in large amounts when mast cells are activated. However, because it is not stored in the pockets, it is not always elevated right away when you have a big activation event or anaphylaxis. Prostaglandin D2 is broken down quickly. While we do test directly for PGD2 for mast cell disease, we also test for 9a,11-PGF2, a molecule formed when PGD2 breaks down.
• The tests for PGD2 and 9a,11b-PGF2 are most reliable when performed in 24 hour urine samples. This is because the levels in urine can fluctuate throughout the day.
• Heparin is a blood thinning molecule that is stored in pockets inside mast cells. Mast cells are the only cells that release significant amounts of histamine. When the mast cell is activated and it releases histamine, the histamine comes out stuck to heparin. Heparin is broken down very quickly so it is hard to measure accurately.
• The test to assess heparin level actually looks for a molecule called anti-factor Xa that can interact with heparin. This test is performed in serum.
• Chromogranin A is released by mast cells. It is also released by a lot of other cells. The level of this molecule can be affected by many things, including common medications. It is sometimes tested for and considered a sign of mast cell disease if elevated when all other possible reasons can be excluded.
• Chromogranin A levels are most reliable in serum.
For more detailed reading, please visit these posts:
The Provider Primer Series: Management of mast cell mediator symptoms and release
The Provider Primer Series: Mast cell activation syndrome (MCAS)
The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)
The Provider Primer Series: Mediator testing
Evidence of mediator release
• Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[i].
• Objective evidence of mast cell mediator release is required for diagnosis of MCAS (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
• Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in MCAS testing recommendations (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
• It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[v]; plasma heparin[ix]; serum chromogranin A[ix]; and leukotriene E4[ix].
Tryptase
• Tryptase is extremely specific for mast cell activation in the absence of hematologic malignancy or advanced kidney disease. Of note, rheumatoid factor can cause false elevation of tryptase[ix].
• Serum tryptase levels peak 15-120 minutes after release with an estimated half-life of two hours[vi].
• Per key opinion leaders, tryptase levels should be drawn 15 minutes to 4 hours after onset of anaphylaxis or activation event (Castells 2013[ii]), (Akin 2010[iii]), (Valent 2012)[iv]). Phadia, the manufacturer of the ImmunoCap® test to quantify tryptase, recommends that blood be drawn 15 minutes to 3 hours after event onset[vii].
• Serum tryptase >11.4 ng/mL is elevated[i]. In addition to measuring tryptase level during the event, another sample should be drawn 24-48 hours after the event, and a third sample drawn two weeks later. This allows comparison of event tryptase level to baseline[vi].
• An increase in serum tryptase level during an event by 20% + 2 ng/mL above patient baseline is often accepted as evidence of mast cell activation[v],[i].
• Absent elevation of tryptase level from baseline during an event does not exclude mast cell activation[viii].
• Sensitivity for serum tryptase assay in MCAS patients was assessed as 10% in a 2014 paper[ix].
• A recent retrospective study of almost 200 patients found serum was elevated in 8.8% of MCAS patients[x].
• Baseline tryptase >20.0 ng/mL is a minor criterion for diagnosis of systemic mastocytosis. 77-85% of SM patients have baseline tryptase >20.0 ng/mL[ix].
Histamine and degradation product n-methylhistamine
• N-methylhistamine is the breakdown product of histamine.
• Histamine is degraded quickly. Samples should be drawn within 15 minutes of episode onset[vii].
• Serum histamine levels peak 5 minutes after release and return to baseline in 15-30 minutes[vii].
• Sample (urine or serum) must be kept chilled[xi].
• In addition to mast cells, histamine is also released by basophils. Consumption of foods or liquids that contain histamine can also inflate the level when tested[ix].
• A recent retrospective study of almost 200 patients found that n-methylhistamine was elevated in 7.4% of MCAS patients in random spot urine and 5.4% in 24-hour urine[xi].
• Sensitivity of 24-hour n-methylhistamine for MCAS was assessed as 22% in 24-hour urine[ix].
• Plasma histamine was elevated in 29.3% of MCAS patients[xi].
• 50-81% of systemic mastocytosis patients demonstrate elevated n-methylhistamine in 24-hour urine[ix].
Prostaglandin D2 and degradation product prostaglandin 9a,11b-F2
• 9a,11b-prostaglandin F2 is the breakdown product of prostaglandin D2.
• Prostaglandin D2 is only produced in large quantities by mast cells. Basophils, eosinophils and other cells produce minute amounts[ix].
• A recent retrospective study of almost 200 patients found that PGD2 was elevated in 9.8% of MCAS patients in random spot urines and 38.3% in 24-hour urine[xi].
• PGD2 was elevated in 13.2% of MCAS patients in plasma[xi].
• 9a,11b-PGF2 was elevated in 36.8% in 24-hour urine[xi].
• 62-100% of systemic mastocytosis patients demonstrate elevated prostaglandin D2 or 9a,11b-PGF2 in urine[ix].
• Prostaglandins are thermolabile and begin to break down in a minutes. This can contribute to false negative results[xi].
• Medications that inhibit COX-1 and COX-2, such as NSAIDs, decrease prostaglandin production[xi].
Leukotriene E4
• Leukotriene E4 is produced by mast cells and several other cell types[ix] including eosinophils, basophils and macrophages.
• A recent retrospective study of almost 200 patients found that LTE4 was elevated in 4.4 % of MCAS patients in random spot urines and 8.3% in 24-hour urine[xi].
• 44-50% of systemic mastocytosis patients demonstrate elevated leukotriene E4 in urine[ix].
• Medications that inhibit 5-LO, such as lipoxygenase inhibitors, decrease leukotriene production[xii].
Chromogranin A
• Chromogranin A is produced by mast cells and several other cell types including chromaffin cells and beta cells.
• Proton pump inhibitors can cause increased values during testing[xi].
• A 2014 paper reported chromogranin A was elevated in 12% of MCAS patients and 63% of systemic mastocytosis patients tested[ix].
Heparin
• Heparin is a very specific mediator for mast cell activation[ix].
• Heparin is extremely heat sensitive. The sample must be kept on ice or refrigerated at all times[ix].
• Venous occlusion of upper arm for ten minutes has been successful in provoking mast cell activation leading to heparin release[ix].
• A 2014 paper reported plasma heparin was elevated in 59% of MCAS patients and 47% of systemic mastocytosis patients tested[ix].
• A recent retrospective study of almost 200 patients found that plasma heparin was elevated in 28.9% tested[ix].
References
[i] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.
[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.
[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4
[iv] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.
[v] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.
[vi] Payne V, Kam PCA. (2004). Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia, 59(7), 695-703.
[vii] Phadia AB. ImmunoCAP® Tryptase in anaphylaxis. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_anafylaxi.pdf
[viii] Sprung J, et al. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122(3), 713-717.
[ix] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912
[x] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).
[xi] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.” Mast Cells, edited by David B. Murray, Nova Science Publishers, Inc., 2013, 155-231.
[xii] Hui KP, et al. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax, 46, 184-189.
Symptoms, mediators and mechanisms: A general review (Part 2 of 2)
Gynecologic symptoms
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction
Increased estrogen
Neurologic symptoms
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters
Low serotonin
Decreased blood flow to brain
Depression Serotonin (low), TNF, histamine (H1) Low serotonin
Disordered release of dopamine
Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines
Miscellaneous symptoms
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways
Symptoms, mediators and mechanisms: A general review (Part 1 of 2)
Skin symptoms
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels
Blood is closer to the skin and redness is seen
Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels
Fluid is trapped inappropriately between layers of skin
Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels
Fluid is trapped inappropriately between layers of tissue
Respiratory symptoms
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production
Smooth muscle constriction
Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production
Smooth muscle constriction
Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production
Smooth muscle constriction
Cardiovascular symptoms
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF, PGD2, bradykinin Decreased force of heart contraction
Increased vasodilation and permeability of blood vessels
Impact on norepinephrine signaling
Change in heart rate
Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels
Decrease in blood pressure
Dysfunctional release of neurotransmitters
High blood pressure Chymase, 9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway
Impact on norepinephrine signaling
Tightening and decreased permeability of blood vessels
Tachycardia Histamine (H2), PGD2 Increasing heart rate
Increasing force of heart contraction
Impact on norepinephrine signaling
Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway
Impact on norepinephrine signaling
Gastrointestinal symptoms
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction
Increased gastric acid secretion
Dysfunctional release of neurotransmitters
Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction
Increased gastric acid secretion
Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction
Increased gastric acid secretion
Dysfunctional release of neurotransmitters
Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters
Master table of stored mast cell mediators
Mediator Symptoms Pathophysiology
Angiogenin Tissue damage Formation of new blood vessels, degradation of basement membrane and local matrix
Arylsulfatases Breaks down molecules to produce building blocks for nerve and muscle cells
Bradykinin Angioedema, swelling of airway, swelling of GI tract, inflammation, pain, hypotension Vasodilation, induces release of nitric oxide and prostacyclin
Carboxypeptidase A Muscle damage Tissue remodeling
Cathepsin G Pain, muscle damage Converts angiotensin I to II, activates TGF-b, muscle damage, pain, fibrosis, activates platelets, vasodilation
Chondroitin sulfate Cartilage synthesis
Chymase Cardiac arrhythmia, hypertension, myocardial infarction Tissue remodeling, conversion of angiotensin I to II, cleaves lipoproteins, activates TGF-b, tissue damage, pain, fibrosis
Corticotropin-releasing hormone Dysregulation has wide reaching and severe effects Stimulates secretion of ACTH to form cortisol and steroids
Endorphins Numbness Pain relief
Endothelin Hypertension, cardiac hypertrophy, type II diabetes, Hirschsprung disease Vasoconstriction
Eotaxin (CCL11) Cognitive deficits Attracts eosinophils, decreases nerve growth
Heparin Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers Cofactor for nerve growth factor, anticoagulant, prevents platelet aggregation, angiogenesis
Histamine Headache, hypotension, pruritis, urticaria, angioedema, diarrhea, anaphylaxis Vasodilation of vessels, vasoconstriction of atherosclerotic coronary arteries, action of endothelium, formation of new blood vessels cell proliferation, pain
Hyaluronic acid Degradation contributes to skin damage Tissue repair, cartilage synthesis, activation of white blood cells
IL-8 (CXCL8) Mast cell degranulation Attracts white blood cells (mostly neutrophils) to site of infection, activates mast cells, promotes degranulation
Kininogenases Angioedema, pain, low blood pressure Synthesis of bradykinin
Leptin Obesity Regulates food intake
Matrix metalloproteinases Irregular menses (MMP-2) Tissue damage, modification of cytokines and chemokines (modifies molecules to make them useful)
MCP-1 (CCL2) Nerve pain Attracts white blood cells to site of injury or infection, neuroinflammation, infiltration of monocytes (seen in some autoimmune diseases)
MCP-3 (CCL7) Increases activity of white blood cells in inflamed spaces
MCP-4 (CCL13) Shortness of breath, tightness of airway, cough Attracts white blood cells to inflamed spaces, induces mast cell release of TNFa and IL-1, asthma symptoms
Phospholipase A2 Vascular inflammation, acute coronary syndrome Generates precursor molecule for prostaglandins and leukotrienes
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
Renin Cardiac arrhythmias, myocardial infarction, blood pressure abnormalities Angiotensin synthesis, controls volume of blood plasma,lymph and interstitial fluid, regulates blood pressure
Serotonin/5-HT Nausea, vomiting, diarrhea, headache, GI pain Vasoconstriction, pain
Somatostatin Low stomach acid symptoms, low blood sugar Regulates endocrine system, cell growth and nerve signals, inhibits release of glucagon and insulin, decreases release of gastrin, secretin and histamine
Substance P Neurologic pain, inflammation, nausea, vomiting, mood disorders, anxiety Transmits sensory nerve signals, including pain, mood disorders, stress perception, nerve growth and respiration
Tissue plasminogen activator Blood clots Activates plasminogen, clotting
Tryptase Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers; inflammation Activation of endothelium, triggers smooth muscle proliferation, activates degradation of fibrinogen, activates MMP molecules,tissue damage, activation of PAR, inflammation, pain
Urocortin Increased appetite when stressed, inflammation, low blood pressure Vasodilation, increases coronary blood flow
Vasoactive intestinal peptide Decreased absorption, low blood pressure, low stomach acid symptoms Vasodilation, mast cell activation, lowers blood pressure, relaxes muscles of trachea, stomach and gall bladder, inhibits gastric acid secretion, inhibits absorption
VEGF Diseases of blood vessels Formation of new blood vessels, vasodilation and permeability of smaller vessels
Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system
The kinin-kallikrein system is a hormonal system with effects on inflammation, blood pressure, coagulation and pain perception. This system is known to have a significant role on the cardiovascular system, including cardiac failure, ischemia and left ventricular hypertrophy. Despite significant research, it is not entirely understood.
Kininogens are proteins that have extra pieces on them. Kininogenases cut off those extra pieces. Active kinins that can act on the body are the result of this action. So kininogenases change kininogens to form kinins.
There are two types of kininogens: low molecular weight (smaller) and high molecular weight (larger.) We are going to focus on HMW, which circulates in the blood.
Also circulating in the blood are two other components called prekallikrein (sometimes called Fletcher factor) and Hageman factor (Factor XII.) When Hageman factor lands on a negatively charged surface, it changes shape and becomes Factor XIIa. Factor XIIa changes the prekallikrein to kallikrein. Kallikrein is a kininogenase.
When kallikrein finds a kininogen, it cuts off the extra piece to release bradykinin. Bradykinin is a kinin and is ready to act on the body.
Bradykinin has several functions in the body. It contributes to contractility of duodenum, ileum and cecum. In the lungs, it can cause chloride secretion and bronchoconstriction. It can cause smooth muscle contraction in the uterus, bladder and vas deferens. It contributes to rheumatoid arthritis, inflammation, pain sensation and hyperalgesia. It also induces cell proliferation, collagen synthesis, and release of nitric oxide, prostacyclin, TNF-a and interleukins. It can also cause release of glutamate by nerve cells. Glutamate has a variety of actions in the body and excessive release can cause epileptic seizures, ALS, lathyrism, autism and stroke.
Bradykinin acts on the endothelium, the cells that line the inner surface of blood and lymphatic vessels, to cause the blood vessels to dilate. This decreases blood pressure. It also regulates sodium excretion from the kidneys, which can further decrease blood pressure. Kininogen levels are reduced in hypertensive patients. Kinins, including bradykinin, oppose the action of angiotensin II, a hypertensive agent.
So how are mast cells related to this system? A couple of ways. The first way is that they release kininogenases and bradykinin. Tryptase can actually behave as a kininogenase. The second way is by being the exclusive producers of heparin.
As I mentioned above, Factor XII needs to change to Factor XIIa to initiate the formation of bradykinin. It does this when it contacts a negatively charged surface. In the lab, you can use a surface like glass for this. But in the body, it often happens on the surfaces of large, negatively charged proteins like heparin. (Side note: Factor XII is part of the clotting cascade. It can be activated by medical devices like PICC lines and that is why they carry a risk of clot formation.) So by releasing heparin, mast cells cause the formation of bradykinin. When the mast cells release heparin in inappropriate amounts, too much bradykinin is formed.
Overproduction of bradykinin is one of the principal causes of angioedema. In hereditary angioedema, the body is deficient in a component that regulates bradykinin. One of the reasons that physical trauma can cause mast cell degranulation is because it causes formation of bradykinin. Bradykinin in turn causes mast cell degranulation with release of histamine and serotonin, among other contents.
Bradykinin antagonists are being researched as possible therapies for hereditary angioedema. Icatibant is one such medication. Bromelain, found in the stems and leaves of pineapples, are known to suppress swelling caused by bradykinin. Aloe and polyphenols, like those in green tea, are also known to suppress bradykinin activity.
References:
Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol. 2010 Aug; 47(13):2161-9
Oschatz C, et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011 Feb 25; 34(2):258-68.
Brunnée T, et al. Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy. 1997 Jun;27(6):653-63.
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2,208,407,307,062,901,500 | Show simple item record
dc.contributor.authorGordon, Lynne
dc.date.accessioned2023-06-05T10:18:42Z
dc.date.available2023-06-05T10:18:42Z
dc.date.issued2023-03-03
dc.identifier.urihttp://hdl.handle.net/2299/26387
dc.description.abstractApproximately 52,000 men are diagnosed with prostate cancer each year in the UK with around 60% (~31,000) diagnosed at an early stage (locally advanced or localised disease). Around a third of men diagnosed with these locally advanced or localised prostate cancers will receive radical radiotherapy. Men will receive information and have discussions with health care professionals (HCPs) before, during and after radiotherapy related to decision making and management options, treatment procedures and the likely long term sequalae of their cancer management. Whilst previous studies have explored information across the course of a patient’s prostate cancer diagnosis, none has previously focused specifically on the information related to radiotherapy for men with prostate cancer. This study aims to explore the experiences of men with early-staged prostate cancer regarding information related to radiotherapy in the UK A qualitative study situated within a social constructivist paradigm was devised, utilising patient and public involvement as an integral component of the early stages of development of the research design. Semi-structured interviews were undertaken with 20 men with prostate cancer who had received radiotherapy and 13 of their wives, to gain their perspectives regarding information exchanged before, during and after radiotherapy. Three focus-group interviews comprising 14 therapeutic radiographers across bands 5-8 recruited from one NHS Trust were carried out in order to provide context to the experiences reported by the men and their wives. Data were analysed using a thematic analysis approach. Three distinct periods arose as being important regarding information related to radiotherapy: the pre-radiotherapy period from point of diagnosis through to just before the radiotherapy planning appointment, the peri-radiotherapy period covering radiotherapy planning and treatment, and the post-radiotherapy period from end of treatment to the time the patient was interviewed (from 3 to 18 months after the end of treatment). Across these three periods, 12 semantic themes were identified. In the pre-radiotherapy period these were a) information and being diagnosed and b) information and decision making. In the Peri-radiotherapy period themes were c) being prepared for planning and treatment, d) information related to external beam radiotherapy procedures, e) retention of and compliance with information, f) information about practicalities, g) peer support and the “waiting room club” and h) therapeutic radiographers and information. In the post-radiotherapy period, the themes were i) the end of radiotherapy – information about what happens next and follow up, j) information on treatment-related outcomes, k) information and decision regret and l) information about sexual dysfunction. In addition, two latent themes of time and communication were identified as arising across all periods and underpinning the semantic themes. To demonstrate the interconnectedness of the themes within the chronology of the three identified periods, two contrasting cases are described to illustrate the impact and place of information in the experiences of two men. The issues related to information reported by the participants had multiple mediating factors that differed across the three periods and so were considered with respect to Bronfenbrenner’s ecological systems theory. As a result, a new model of ecology of information in radiotherapy has been proposed to describe their experiences. Patients’ experiences related to information and communication during their radiotherapy must be contextualised within the whole cancer journey, their personal ecological systems and changing needs over time. Information needs related to decision making during the pre-radiotherapy period can profoundly impact on longer term outcomes, particularly, with respect to sexual functioning. However, this could be mediated by improved opportunities for communication during the pre-radiotherapy period and further opportunities for specialist information and support in the post-radiotherapy period. This study has demonstrated that information before and after, as well as during radiotherapy is a crucial factor in determining the long-term quality of life outcomes for men with prostate cancer.en_US
dc.language.isoenen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subjectProstate canceren_US
dc.subjectpatient experienceen_US
dc.subjectinformationen_US
dc.subjectradiotherapyen_US
dc.titleExperiences of Men with Prostate Cancer Regarding Information Related to Radiotherapy in the UKen_US
dc.typeinfo:eu-repo/semantics/doctoralThesisen_US
dc.identifier.doidoi:10.18745/th.26387*
dc.identifier.doi10.18745/th.26387
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnameDHResen_US
dcterms.dateAccepted2023-03-03
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US
rioxxterms.versionNAen_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/en_US
rioxxterms.licenseref.startdate2023-06-05
herts.preservation.rarelyaccessedtrue
rioxxterms.funder.projectba3b3abd-b137-4d1d-949a-23012ce7d7b9en_US
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2,061,581,954,664,614,700 | Monitor the health of your community here
Diet & the Stomach Lining
Your stomach's lining is like a home security system; it provides protection only when it functions well. Cells in your stomach lining produce acid and enzymes, which help break down food and mucus -- a slippery substance the protects the lining from acid. When your stomach lining becomes inflamed, it releases less acid, enzymes and mucus, making way for pain and discomfort. Dietary changes can help minimize symptoms of gastritis, which is the medical term for an inflamed stomach lining. For best results, seek guidance from your doctor.
Function
Dietary changes suited for a healthy stomach lining serve multiple purposes. If you have gastritis, certain foods and eating habits can help manage pain and other potential symptoms, such as indigestion, heartburn, appetite loss, nausea and vomiting. Dietary changes can also prevent or reduce symptoms related to stomach ulcers, or open sores in your stomach lining, and strengthen your body's ability to resist and heal form other stomach-related conditions.
Helpful Foods
How Does Caffeine Affect the Bowels of a Person Who Has Acute Chronic Gastritis & Diverticulitis?
Learn More
Fiber is an indigestible carbohydrate that promotes digestive function and increases stool bulk and smoothness. A fiber-rich diet, limited in fatty foods, can help reduce stomach irritation associated with gastritis, according to the University of Maryland Medical Center. Particularly fiber-rich foods include beans, lentils, peas, raspberries, artichokes, oatmeal and popcorn. Other helpful foods include antioxidant-rich foods, such as berries, tomatoes, squash and bell peppers, and foods containing flavonoids, such as apples, celery and tea. Flavonoids can help inhibit H. pylori bacteria, which causes most ulcers. Probiotics, which are found in kefir and yogurt with live active cultures, promote bacterial balance in your digestive tract and may help reduce stomach inflammation and ulcer symptoms.
Foods to Avoid
Avoiding foods and beverages that increase stomach acid can minimize irritation in your stomach lining and guard against heartburn. Although people's specific heartburn triggers vary, common triggers that may worsen gastritis symptoms include fried and fatty foods, such as high-fat dairy products and red meat, chocolate, onions, garlic, caffeine, alcohol and mint. Acidic beverages, such as orange juice and coffee, with or without caffeine, can have similar effects. To leave plentiful room in your diet for high-fiber foods, limit refined foods, such as white bread, instant rice, candy and low-fiber cereals. Stay well-hydrated by drinking water throughout each day, particularly if you experience fluid loss as a result of vomiting.
Dining Behaviors
Foods Safe to Eat with Stomach Ulcers
Learn More
Preparing your own meals allows you control over the ingredients contained and guards against overeating associated with large restaurant-size portions. The University of Maryland Medical Center recommends cooking dishes with healthy oils, such as olive or vegetable oil, and avoiding trans-fatty acids, which are prevalent in stick margarine. When you do dine out, stick to low-fat dishes, such as steamed vegetables, skinless, baked poultry, grilled fish and plain baked potatoes. Eat in a calm, pleasurable atmosphere and avoid lying down after meals, which can trigger heartburn.
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6,876,110,376,760,040,000 | Sign in →
Test ID SCOFR Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA, Influenza Virus Type A and Type B RNA, and Respiratory Syncytial Virus (RSV) RNA Detection by PCR, Varies
Ordering Guidance
Due to the non-specific clinical presentation of COVID-19, influenza and respiratory syncytial virus during the early stages of flu-like illness, concurrent testing for these 4 respiratory tract viral pathogens may be warranted.
For the most up-to-date information and testing recommendations, visit:
www.cdc.gov/coronavirus/2019-ncov/index.html
www.cdc.gov/flu/professionals/diagnosis/index.htm
www.cdc.gov/rsv/clinical/index.html#lab
Shipping Instructions
Ship specimens refrigerated (if less than 72 hours from collection to arrive at MCL) or frozen (if greater or equal to 72 hours from collection to arrive at MCL).
Specimen Required
Specimen Type: Nasopharyngeal (NP), oropharyngeal (OP ie, throat), nasal mid-turbinate, or nares/nasal swab
Supplies:
-Swab, Sterile Polyester, 10 per package (T507)
-Dacron-tipped swab with plastic shaft is acceptable
Container/Tube: Universal transport media, viral transport media, or equivalent (eg, Copan UTM-RT, BD VTM, MicroTest M4, M4-RT, M5)
Media should not contain guanidine thiocyanate (GTC).
For more information on acceptable transport media, see www.fda.gov/medical-devices/emergency-situations-medical-devices/faqs-diagnostic-testing-sars-cov-2
Specimen Volume: Entire specimen with a minimum of 1.5 mL (maximum 3 mL) of transport media.
Collection Instructions:
1. Collect specimen by swabbing back and forth over nasal or pharyngeal mucosa surface to maximize recovery of cells. For more information on OP swab specimen collection, see COVID-19 Oropharyngeal Collection Instructions
2. NP and OP swab specimens may be combined at collection into a single vial of transport media but only one swab is required for analysis.
3. Swab must be placed into transport medium. Swab shaft should be broken or cut so that there is no obstruction to the sample or pressure on the media container cap.
4. Do not send in glass tubes, vacutainer tubes, or tubes with push caps.
5. Do not overfill with more than 3 mL total volume of media.
Specimen Type: Nasopharyngeal aspirate or nasal washings
Container/Tube: Sterile container
Specimen Volume: Minimum of 1.5 mL
Additional Information: Do not aliquot into viral transport media, glass tubes, vacutainer tubes, or tubes with push caps.
Useful For
Simultaneous detection and differentiation of COVID-19 (due to SARS-CoV-2), influenza A, influenza B, and respiratory syncytial viral infection in a single upper respiratory tract specimen from an individual with flu-like illness
See following websites on indications and recommendations for testing:
www.cdc.gov/coronavirus/2019-ncov/index.html
www.cdc.gov/flu/professionals/diagnosis/index.htm
www.cdc.gov/rsv/clinical/index.html#lab
Profile Information
Test ID Reporting Name Available Separately Always Performed
COFLU SARS-CoV-2 and Influenza A+B PCR, V Yes Yes
Additional Tests
Test ID Reporting Name Available Separately Always Performed
RSVQL RSV RNA PCR Detect, V Yes Yes
Method Name
Real-Time Reverse Transcription Polymerase Chain Reaction (RT-PCR)
Reporting Name
SARS-CoV-2, Flu A+B, and RSV PCR, V
Specimen Type
Varies
Specimen Minimum Volume
See Specimen Required
Specimen Stability Information
Specimen Type Temperature Time Special Container
Varies Frozen (preferred) 14 days
Refrigerated 72 hours
Clinical Information
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single-stranded RNA virus that causes COVID-19. Like other coronaviruses that infect humans, SARS-CoV-2 can cause both upper and lower respiratory tract infection. Symptoms can range from mild (ie, the common cold) to severe (ie, pneumonia) in both healthy and immunocompromised patients. SARS-CoV-2 transmission occurs primarily via respiratory droplets. During the early stages of COVID-19, symptoms maybe nonspecific and resemble other common respiratory tract infections, such as influenza. If testing for other respiratory tract pathogens is negative, specific testing for SARS-CoV-2 may be warranted.
SARS-CoV-2 is likely to be at the highest concentrations in the nasopharynx during the first 3 to 5 days of symptomatic illness. As the disease progresses, the viral load tends to decrease in the upper respiratory tract, at which point lower respiratory tract specimens (eg, sputum, tracheal aspirate, bronchoalveolar fluid) would be more likely to have detectable SARS-CoV-2.
Influenza, also known as the "flu," is an acute, contagious respiratory illness caused by influenza A, B, and C viruses. Of these, only influenza A and B are thought to cause significant disease, with infections due to influenza B usually being milder than infections with influenza A. Influenza A viruses are further categorized into subtypes based on the 2 major surface protein antigens: hemagglutinin (H) and neuraminidase (N).
Common symptoms of influenza infection include fever, chills, sore throat, muscle pains, severe headache, weakness, fatigue, and a nonproductive cough. Certain patients, including infants, the elderly, the immunocompromised, and those with impaired lung function, are at risk for serious complications. In the northern hemisphere, annual epidemics of influenza typically occur during the fall or winter months. However, the peak of influenza activity can occur as late as April or May, and the timing and duration of flu seasons vary.
Influenza infection may be treated with supportive therapy, as well as antiviral drugs such as the neuraminidase inhibitors: oseltamivir (Tamiflu) and zanamivir (Relenza). These drugs are most effective when given within the first 48 hours of infection, so prompt diagnosis and treatment are essential for proper management.
Respiratory syncytial virus (RSV) is an infectious pathogen that infects the human respiratory tract causing an influenza-like illness. Most healthy people spontaneously recover from RSV infection in 1 to 2 weeks, but infection can be severe in infants, young children, and older adults. The virus is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia in children under 1 year of age in the United States, and it is recognized increasingly as a frequent cause of respiratory illnesses in older adults.
RSV can be detected by polymerase chain reaction in the human upper and lower respiratory tract specimens. Nasopharyngeal swabs or aspirates are the preferred specimen types for detection of RSV RNA. Nasal swabs may not yield as high detection rate as those of nasopharyngeal specimens for molecular detection of RSV RNA.
Reference Values
Undetected
Interpretation
A "Detected" result indicates that the specific virus is present and suggests infection with the virus. Test results should always be considered in the context of patient's clinical history, physical examination, and epidemiologic exposures when making the final diagnosis.
An "Undetected" result indicates that the specific virus is not present in the patient's specimen. However, this result may be influenced by the stage of the infection, quality, and type of the specimen collected for testing. Result should be correlated with patient's history and clinical presentation.
An "Indeterminate" result of SARS CoV-2 RNA polymerase chain reaction (PCR) suggests that the patient may be infected with a variant SARS-CoV-2 or SARS-related coronavirus. Additional testing with an alternative molecular method is recommended on a newly collection specimen may be considered if the patient does not have signs and/or symptoms of COVID-19.
An "Inconclusive" result indicates that the presence or absence of the specific virus in the specimen could not be determined with certainty after repeat testing in the laboratory, possibly due to reverse transcription-polymerase chain reaction inhibition. Submission of a new specimen for testing is recommended.
Clinical Reference
1. Centers for Disease Control and Prevention (CDC). Overview of testing for SARS-CoV-2. CDC; Updated August 25, 2022. Accessed September 8, 2022. Available at www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html
2. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases (NCIRD). Information for clinicians on influenza virus testing. Updated August 29, 2022. Accessed September 8, 2022. Available at www.cdc.gov/flu/professionals/diagnosis/index.htm
3. US Food and Drug Administration. FAQs on testing for SARS-CoV-2. Updated January 22, 2022. Accessed September 8, 2022. Available at www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/faqs-testing-sars-cov-2
4. National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases, Centers for Disease Control and Prevention (CDC). Respiratory syncytial virus infection (RSV). Updated December 18, 2020. Accessed September 8, 2022. Available at www.cdc.gov/rsv/clinical/index.html
Day(s) Performed
Monday through Sunday
Report Available
2 to 3 days
Test Classification
See Individual Test IDs
CPT Code Information
87636-COFLU
87634-RSVQL
LOINC Code Information
Test ID Test Order Name Order LOINC Value
SCOFR SARS-CoV-2, Flu A+B, and RSV PCR, V 95941-1
Result ID Test Result Name Result LOINC Value
610295 Influenza A RNA PCR 92142-9
610296 Influenza B RNA PCR 92141-1
610294 SARS CoV-2 RNA PCR 94500-6
CFLUS SARS-CoV-2 & Flu A/B Specimen Source 31208-2
CFRAC Patient Race 72826-1
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8,427,115,748,054,219,000 | HomeHerbal ArticlesTreating Your Prostate With Herbs Sunday, July 24, 2016
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Treating Your Prostate With Herbs
Doctors in Europe are on the cutting edge of herbal medicine. Twenty years ago they discovered the power of this mysterious tree bark for treating prostate problems. And they've been using it ever since.
The United States is finally beginning to catch on. But now it may be too late. In fact, this proven remedy is so scarce that most prostate formulas in the U.S. don't include it. Even though it may be the most powerful natural prostate remedy in the world!
Your prostate supplement probably works... to a degree. But without this difficult-to-get ingredient you'll never get complete relief from your embarrassing and dangerous prostate symptoms. Without it, your formula only does half the job - at best!
Pygeum africanum grows in the mountains of southern Africa. The bark of this tree has been used for centuries as a traditional remedy for urinary disorders. Natives of southern Africa still brew pygeum tea to relieve symptoms associated with prostate enlargement.
The demand for it in Europe and throughout the world has been so great that pygeum tree bark has become very valuable. So valuable that it's been over-harvested.
In fact, pygeum is now listed on Appendix II of the Convention on International Trade in Endangered Species. In many areas it's been harvested nearly into extinction.
Because pygeum is endangered, many countries in Africa have banned harvesting it. The short supply has caused prices to rise. So much so, that many prostate supplement makers have stopped using it.
Or, worse, they use trace amounts. Just enough to list it on their label so you think your formula offers complete protection. But it's not enough to do you any good. It's just there for show. (You'd be surprised how common that is.)
Are you secretly settling for incomplete relief?
To get real relief from your symptoms you need the right combination of remedies. At the right dosages.
Many herbal extracts, vitamins and minerals are proven to relieve prostate symptoms. For example, you've probably heard about saw palmetto. In fact, you may already take it on a daily basis. But saw palmetto can't do the job by itself!
If your prostate formula doesn't have pygeum - or doesn't combine the right remedies at the right doses - you aren't getting the most relief possible from your embarrassing and uncomfortable symptoms.
Worse, if you still have symptoms you could be at greater risk. In fact, just not being able to empty your bladder completely could lead to bladder infections , to kidney stones, even kidney failure and death. Fortunately, you can avoid these gruesome outcomes if your supplement has the right ingredients.
26 separate studies prove the power of pygeum
Pygeum was shown to relieve common prostate symptoms in 26 different scientific studies. Remember, it works so well that there isn't enough pygeum left in the world to meet demand.
A study of 263 patients in Germany, France and Austria tested the effects of 100 mg of pygeum a day against a placebo. The results showed a full 66% improvement in urination for the group taking the pygeum - more than double that of the placebo group.
But how well it works by itself is only part of the magic. Another reason it's so valuable is because it makes other herbal remedies work better. That's right. Pygeum actually makes other ingredients, like saw palmetto and stinging nettle, more effective.
In a Swiss study, researchers showed that a combination of pygeum and stinging nettle partially blocked two enzymes that cause your body to produce dihydrotestosterone or DHT, which is considered a key factor in causing painful prostate problems.
This study showed that a combination of pygeum and nettle worked a lot better than either one by itself. And, the study supports using combinations of both ingredients for the treatment of prostate symptoms. Decrease overnight trips to the bathroom and get a good night's sleep - at last!
One study in Europe showed that patients taking pygeum reported a 32% decrease in urination during the night hours. Imagine, finally being able to get a good night's sleep and not having to run to the bathroom every 10 minutes - especially for those false alarms.
26 studies can't be wrong! This stuff works! And you'll get other benefits too. An Italian study done in 1991 showed that pygeum not only reduced prostate symptoms and urinary problems but it can also increase libido. How's that for a side benefit!?
Pygeum is also a powerful anti-inflammatory that works to reduce swollen prostate tissue. Urology Times magazine stated "Pygeum helps decrease prostate swelling and painful urination."
Plus it lowers blood cholesterol. That's important because scientists believe cholesterol increases the binding sites for DHT in the prostate. Reducing cholesterol levels reduces DHT binding sites. Fewer binding sites means less prostate tissue growth.
But how can we include pygeum when it's so hard to get?
After seeing the studies and talking with numerous doctors and nutritionists, we knew we had to offer ample amounts of pygeum in order to help you protect your prostate. But we didn't want to contribute to the harvesting problem - or, obviously, do anything underhanded. So we entered into a special arrangement with Euromed in Spain. They're one of the leading suppliers of herbal ingredients in Europe, maybe even the world. They harvest the pygeum tree bark in a sustainable way, which is certified by European authorities. So you can rest assured that Ultimate Prostate Support will always contain the highest quality pygeum at the right dosage so you get the most out of it.
Used with pygeum, saw palmetto becomes even more powerful
Native Americans have used saw palmetto for centuries. During the early parts of the last century, tea made from saw palmetto was used to treat prostate problems. In fact, the U.S. Pharmacopoeia has listed it as a remedy for prostate problems since 1905.
Now there's proof that saw palmetto relieves prostate symptoms as well as some prescription drugs, but without the dangerous and embarrassing side effects!
The Journal of the American Medical Association published a study of nearly 3,000 men treated with saw palmetto versus a popular prescription drug. Their conclusion: "Saw palmetto extract produces similar improvements in urinary tract symptoms and urinary flow and was associated with fewer adverse treatment events."
Saw palmetto is a great natural solution, but it can't do the job alone. But, once you combine it with other remedies like pygeum, you can get the relief you've been looking for.
Not only does pygeum magnify the power of saw palmetto, it boosts the power of stinging nettle, too. One study found that patients who took both saw palmetto and stinging nettle experienced changes in urine flow and in residual urine. Study organizers declared the combination safe and effective.
Another study followed 2,080 BPH (Benign Prostatic Hyperplasia) patients for 12 weeks. Men in the study were treated with a combination of saw palmetto and nettle root. The results were amazing.
• 26% increase in maximum urinary flow
• 44.7% reduction in residual urine
• 62.5% reduction in painful urination
• 53.6% reduction in post urination dribbling
• 50% reduction in nighttime urination
Stinging nettle delivers 82% improvement in 8 weeks!
A French study found that a combination of stinging nettle and pygeum led to dramatic improvements in BPH in only one month.
Another study showed that eight weeks of treatment with stinging nettle led to an 82% improvement in symptoms. A different study showed an 86% improvement in symptoms after three months treatment. Either way, that's a huge improvement in just 2 or 3 months. Imagine if you could cut your painful symptoms and trips to the bathroom by over 80%!
Stinging nettle is just one more part of the total package. It works in concert with both pygeum and saw palmetto to deliver powerful relief from your symptoms.
Lycopene may be man's new best friend
Lycopene comes from tomatoes. It's the stuff that makes them red. And, it's now thought to be the world's most powerful antioxidant. And a powerful defense against prostate cancer .
The proof is just too strong to ignore. A six-year study of 48,000 men at Harvard Medical School found that men who ate tomato products twice a week had a 21% to 34% reduced risk of prostate cancer.
Some research even suggests that lycopene can help treat existing cancer.
Dr. Omer Kacuk, professor of medicine and oncology at the Karmanos Cancer Institute in Detroit, Michigan, studied the effect of lycopene on prostate cancer patients. The study followed 30 men who were going to have their prostates surgically removed. Half were given lycopene. The other half were given a placebo.
Patients taking lycopene had smaller tumors. And, their tumors showed signs of regression and decreased malignancy. Dr Kacuk states "Our findings suggest that lycopene as tomato extract may not only help prevent prostate cancer, but may also be useful in treating prostate cancer".
Vitamins and minerals protect your prostate at the cellular level
All natural vitamin E is another powerful antioxidant. And a powerful ally in your fight against prostate disease. Now there's evidence that it may help fight prostate cancer.
A University of Helsinki study in Finland gave 29,133 men, ages 50 to 69, vitamin E, beta-carotene, both supplements together, or a placebo. The treatments continued for five to eight years.
Compared with the placebo group, the men taking vitamin E were 36% less likely to develop prostate cancer. The results of the study also suggested that vitamin E may help prevent prostate cancer from moving from the latent to the progressive stages.
Selenium works with vitamin E to protect the whole cell. While selenium protects the inside of the cell, vitamin E protects the cell membrane. Alone, they each have their benefits, but together they're a powerful defense against cell damage that can lead to cancer.
Zinc is another important mineral for your prostate health. It's been shown to improve urinary symptoms and reduce the size of the prostate in men with BPH.
Zinc also helps control the enzyme that converts testosterone into DHT. Since DHT makes your prostate grow, less DHT is better. And, since zinc is required for normal testosterone and sperm production, it's thought that a zinc deficiency can lead to impotence.
Now you have the whole list. A scientifically formulated combination of these ingredients is the best way to relieve your symptoms. Take any less and you're selling yourself short!
You'll benefit most from the right combination
Taken alone, each of these natural remedies can improve your prostate health.
Each can give you some relief from your embarrassing and dangerous symptoms. But, only when you take the right combination, at the right doses, can you get total relief.
The power comes from the complete combination of ingredients that is built around pygeum. Many prostate formulas on the market today have some of these ingredients. And they probably work...to some degree.
But if you want the ultimate in prostate support...if you want the most powerful weapon available...if you want total relief from your symptoms and the worry that goes with them...then you need to take a complete formulation. And it must include at least 100 mg of pygeum every day.
Everything you need - in one GUARANTEED formulation
You could buy each of these ingredients at the health food store. But, it'd probably cost you at least $75 a month. That's if you can even find a quality source of the most important one of all - pygeum!
Even if you can find each part of this powerful combination you'd have a hard time getting the right dosage or the best quality. Plus you'd have to take six or seven different pills a few times a day to get the maximum benefit.
Ultimate Prostate Support is a scientifically formulated mixture of all these proven ingredients. The nutritional team working for NorthStar Nutritionals has combined these prostate protecting botanicals, vitamins and minerals into a powerful formula.
Pygeum, combined with saw palmetto, stinging nettle and zinc, works to reduce the size of your prostate. And it's only then that your symptoms can start to disappear.
Lycopene, vitamin E and selenium work together to promote optimum prostate health and studies show they may even protect you from prostate cancer.
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-5,353,878,118,018,813,000 | Hello and Welcome to Implant Center!
Achieving a perfect bite goes beyond just aesthetics; it’s about ensuring the proper alignment of your teeth and jaws, which is crucial for overall oral health. Orthodontic treatments play a pivotal role in correcting misalignments and achieving that ideal bite. Let’s delve into the world of orthodontics and explore the various treatments available to attain a straight and harmonious smile.
The Importance of a Perfect Bite
A perfect bite, or occlusion, occurs when the upper and lower teeth fit together correctly when the jaws are closed. This alignment allows for efficient chewing, reduces the risk of tooth wear and fracture, prevents jaw pain and dysfunction, and enhances facial aesthetics. However, many individuals experience malocclusions, or bite problems, which can range from minor misalignments to more severe issues like overbites, underbites, and crossbites.
Understanding Orthodontic Treatments
Orthodontic treatments aim to correct these bite abnormalities and improve the alignment of teeth and jaws. Here are some common orthodontic treatments used to achieve a perfect bite:
1. Braces: Braces are the most traditional orthodontic treatment and have been used for decades to straighten teeth and correct bite issues. They consist of metal brackets bonded to the teeth and connected by wires, which apply gentle pressure to gradually move the teeth into the desired position. Braces are highly effective in treating a wide range of orthodontic problems, including overcrowding, gaps between teeth, and misaligned bites.
2. Invisalign: Invisalign is a modern alternative to traditional braces that utilizes clear, removable aligners to straighten teeth. These custom-made aligners are virtually invisible and offer greater comfort and convenience compared to braces. Invisalign is particularly popular among adults and teens who prefer a discreet orthodontic solution. While it may not be suitable for all orthodontic issues, Invisalign can effectively treat mild to moderate bite problems.
3. Retainers: Retainers are orthodontic devices used to maintain the results achieved by braces or Invisalign. After completing active orthodontic treatment, patients are typically required to wear retainers to prevent teeth from shifting back to their original position. Retainers can be removable or fixed, depending on the patient’s needs. By wearing retainers as directed by their orthodontist, patients can preserve their straightened teeth and perfect bite for years to come.
4. Palatal Expanders: Palatal expanders are devices used to widen the upper jaw to correct crossbites and create more space for crowded teeth. These appliances are commonly used in growing children and adolescents to address skeletal issues that contribute to malocclusions. Palatal expanders work by applying gentle pressure to the palate, gradually widening it over time. Early intervention with palatal expanders can prevent the need for more invasive orthodontic treatments later in life.
5. Jaw Surgery: In some cases of severe malocclusions or skeletal discrepancies, orthognathic surgery, or jaw surgery, may be necessary to achieve a perfect bite. Jaw surgery involves repositioning the upper and/or lower jaws to improve their alignment and function. This procedure is typically performed in conjunction with orthodontic treatment to achieve optimal results. While jaw surgery is a more complex and invasive treatment option, it can provide life-changing benefits for individuals with severe bite problems.
Conclusion
Achieving a perfect bite is not just about having straight teeth; it’s about ensuring the proper alignment of teeth and jaws for optimal oral health and function. Orthodontic treatments offer effective solutions for correcting bite abnormalities and achieving a straight and harmonious smile. Whether it’s traditional braces, Invisalign, retainers, palatal expanders, or jaw surgery, there are various options available to address different orthodontic issues. By consulting with an experienced orthodontist, you can embark on a journey towards a healthier and more confident smile.
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928,789,149,158,940,700 | Modeling malaria infection and immunity against variant surface antigens in Príncipe Island, West Africa
Bandeiras, Cátia and Trovoada, Maria Jesus and Gonçalves, Lígia A. and Marinho, Cláudio R.F. and Turner, Louise and Hviid, Lars and Penha-Gonçalves, Carlos and Gomes, M. Gabriela M. (2014) Modeling malaria infection and immunity against variant surface antigens in Príncipe Island, West Africa. PLoS ONE, 9 (2). pp. 1-10. e88110. ISSN 1932-6203
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Abstract
After remarkable success of vector control campaigns worldwide, concerns about loss of immunity against Plasmodium falciparum due to lack of exposure to the parasite are relevant since an increase of severe cases in less immune individuals is expected. We present a mathematical model to investigate the impact of reducing exposure to the parasite on the immune repertoire against P. falciparum erythrocyte membrane protein 1 (PfEMP1) variants. The model was parameterized with data from Príncipe Island, West Africa, and applied to simulate two alternative transmission scenarios: one where control measures are continued to eventually drive the system to elimination; and another where the effort is interrupted after 6 years of its initiation and the system returns to the initial transmission potential. Population dynamics of parasite prevalence predict that in a few years infection levels return to the pre-control values, while the re-acquisition of the immune repertoire against PfEMP1 is slower, creating a window for increased severity. The model illustrates the consequences of loss of immune repertoire against PfEMP1 in a given setting and can be applied to other regions where similar data may be available. | {
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-2,559,085,845,839,180,000 | Home / Finance / Health and Fitness / Disease Illness / Sun Exposure & UV Rays: The Basic Facts
Sun Exposure & UV Rays: The Basic Facts
The human body benefits from sun exposure. And a little bit of tan protects you from the sun. Right? Wrong!
The body does indeed benefit from sun exposure. But a little bit of tan does not necessarily protect you from the sun. Let’s see why.
The sun’s rays are a major source of vitamin D and help the body’s systems acquire much needed calcium for building healthy bones. However, most people don’t need to spend large amounts of time exposed to the sun in order to get their required amount of vitamin D.
In fact, the body’s health can actually suffer negative effects when it’s exposed too long to the sun’s rays, especially if it’s unprotected. Results can vary from skin and eye damage to immune system suppression and ultimately cancer, even for the young.
So let’s look at the basic facts about sun exposure.
There are three kinds of invisible ultraviolet (UV) rays in the sun that reaches earth: UVA, UVB, and UVC. When these rays come in contact with our skin, affects of UVA and UVB can be – tans, burns and other reactions (e.g. like acne and cancer).
It’s also notable that the effects of all UV rays are not the same. Depending upon the season, time of day and place on the planet in relation to the sun – (i.e. your altitude and latitude), the rays’ intensities vary. For example, during summertime, UV rays are at their strongest. Between 10 a.m. and 4 p.m., the rays are strongest. And close to the equator and at high altitudes (where air and cloud cover are less, resulting in increased harmful penetration of UV rays into the environment), the rays are also strongest.
In order to protect ourselves from the harmful UV rays, let’s look at the skin’s first defense – melanin.
Melanin is a chemical present in a variety of colors and concentrations in most people’s skin that helps with defense from the sun. Melanin reacts with UV rays and absorbs them. Or rather, to be more specific, the rays act upon melanin, causing the melanin to spread out or grow, increasing its presence in response to the sun’s exposure. The result? A ‘sun tan’. The darker the skin color, the more melanin the skin has for protection. And ‘tanning’ for darker color is included here; ‘color’ does not have to refer to just the original skin color.
A word of caution
Tanning may look great on the surface, – but the amount and length of time a person is exposed to the sun, determines the amount of possible damage. It also determines the future risk of damage that’s likely.
For example, people who are exposed to the sun in huge doses like ship crews, field workers and beach surfers, are at higher risks for skin damage than indoor workers. What happens is that when the amount of UV exposure is greater than what the skin’s melanin can handle, sunburn can result. And those with lighter, fairer skin, who have less melanin, absorb less UV, suffering less protection.
Since research has shown that UV damage from the sun is the main cause of skin cancer, (with as high as 20% of some populations developing skin cancer during their lifetime), we need to take a proactive approach in relation to sun exposure to avoid harmful skin damage.
As we say colloquially here in Australia – “Slip, Slop, Slap”. (I.e. ‘Slip’ on a shirt, ‘Slop’ on a hat, ‘Slap’ on a sunscreen). Look after the skin you’ve got, because you’re the one who will be living with it!
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8,856,824,116,720,913,000 | Question: Does metformin 500 mg help get pregnant?
Metformin can help improve your rate of ovulation, increasing your chances of getting pregnant. And metformin has benefits even after you get pregnant. It can reduce your risk of developing type 2 diabetes due to the blood sugar problems caused by PCOS.
How does metformin increase fertility?
Doctors find the use of metformin in fertility treatment effective because it helps in the following way: Sensitises insulin receptor to the available Insulin. Induce Ovulation: Menstrual cycles become regular with Metformin administration and ovulation is induced as a result in some PCOS patients.
How quickly does metformin work for PCOS?
Daily Metformin for 2 Years, But Most Benefit Seen in First 6 Months.
Does metformin help with egg quality?
When insulin is high as in the setting of insulin resistance or hyperinsulinemia, the follicles may not grow properly. This can lead to poor quality eggs and even interfere with ovulation. Metformin alone has been show to improve fertility and increase a womans chances of getting pregnant and having a baby.
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Characterization of chronic HCV infection-induced apoptosis
Abstract
Background
To understand the complex and largely not well-understood apoptotic pathway and immune system evasion mechanisms in hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) and HCV associated chronic hepatitis (CH), we studied the expression patterns of a number of pro-apoptotic and anti-apoptotic genes (Fas, FasL, Bcl-2, Bcl-xL and Bak) in HepG2 cell line harboring HCV- genotype-4 replication. For confirmation, we also assessed the expression levels of the same group of genes in clinical samples obtained from 35 HCC and 34 CH patients.
Methods
Viral replication was assessed in the tissue culture medium by RT-PCR, quantitative Real-Time PCR (qRT-PCR); detection of HCV core protein by western blot and inhibition of HCV replication with siRNA. The expression level of Fas, FasL, Bcl-2, Bcl-xL and Bak was assessed by immunohistochemistry and RT-PCR whereas caspases 3, 8 and 9 were assessed by colorimetric assay kits up to 135 days post infection.
Results
There was a consistent increase in apoptotic activity for the first 4 weeks post-CV infection followed by a consistent decrease up to the end of the experiment. The concordance between the changes in the expression levels of Fas, FasL, Bcl-2, Bcl-xL and Bak in vitro and in situ was statistically significant (p < 0.05). Fas was highly expressed at early stages of infection in cell lines and in normal control liver tissues followed by a dramatic reduction post-HCV infection and an increase in the expression level of FasL post HCV infection. The effect of HCV infection on other apoptotic proteins started very early post-infection, suggesting that hepatitis C modulating apoptosis by modulating intracellular pro-apoptotic signals.
Conclusions
Chronic HCV infection differently modulates the apoptotic machinery during the course of infection, where the virus induces apoptosis early in the course of infection, and as the disease progresses apoptosis is modulated. This study could open a new opportunity for understanding the various signaling of apoptosis and in the developing a targeted therapy to inhibit viral persistence and HCC development.
Background
Hepatitis C virus (HCV) is a major worldwide causative pathogen of chronic hepatitis, cirrhosis, and hepatocellular carcinoma [1]. Egypt has the highest prevalence of HCV infection in the world where 15% of the total population are infected [24]. Although the exact mechanisms of HCV pathogenesis, such as viral persistence, hepatocytes injury, and hepatocarcinogenesis are not fully understood, yet an accumulating body of evidence suggests that apoptosis of hepatocytes is significantly involved in the pathogenesis [5, 6].
Apoptosis plays a pivotal role in the maintenance of cellular homeostasis through removal of aged cells, damaged cells, and overgrowing new cells [7]. Failure of apoptosis induced by various stimuli is one of the most important events in tumor progression as well as in resistance to cytotoxic therapy [8]. In mammalian cells, apoptosis can be induced via two major pathways. First, the death receptor pathway (extrinsic pathway), which is triggered by binding Fas ligand (FasL) to Fas (CD95) with subsequent activation of caspase-8, which in turn activates the effectors caspases 3, 6, 7 [912]. This pathway is considered an important apoptotic system in cancer [13] because FasL is one of the effector molecules of cytotoxic T cells. The second apoptosis pathway (the intrinsic pathway) is induced by mitochondria in response to DNA damage, oxidative stress and viral proteins [5]. Mitochondria-dependent apoptosis is amplified by pro-apoptotic genes (Bax, Bad, Bak and others) whereas molecules like Bcl-2 or Bcl-xL act as anti-apoptotic. These proteins converge at the mitochondrial permeability transition pore that regulates the release of apoptotic regulatory proteins, such as procaspase-9, and cytochrome C [14].
There have been many studies indicating that apoptosis of hepatocytes plays a significant role in the pathogenesis of HCV infection [15], although various apoptotic pathways were proposed [16]. For example, many studies demonstrated that HCV core protein suppresses apoptosis mediated by cisplatin, c-myc, TNF-α, or the Fas signaling pathway [17], whereas others showed that the core protein sensitizes Fas, TNFα, or serum starvation-induced apoptosis [18]. The precise mechanisms for the involvement of the HCV core protein on the apoptotic pathways are not fully understood. For example, core protein-dependent inhibition of TNF-α and CD95 ligand-induced apoptosis has been described in a hepatoma cell line [19, 20]. In other models, overexpressed HCV core protein did not prevent CD95 ligand induced apoptosis in hepatoma cells or transgenic mice overexpressing HCV core protein [17, 21]. Until recently, the lack of an infectious HCV tissue culture system did not allow to study the impact of HCV infection on hepatocyte apoptosis [22].
The present study was performed to determine the changes in apoptotic machinery accompanying HCV infection both in vitro and in vivo. For the in vitro study, we developed a HCV replication system in HepG2 cell line, which may reflect to some extent the in vivo situation. Successful infection and propagation of the virus was assessed by detection of HCV-RNA using nested RT-PCR with specific primers, detection of increased titer by real time PCR, and virus passage to naïve cells. The HCV-HepG2 cell line was then used to study the long term effect of HCV infection on the apoptosis regulatory genes (Fas, FasL, Bak, Bcl-2, and Bcl-xL). This was correlated with the apoptotic activity in the cells by determining the expression levels of caspases 3, 8, and 9. We further assessed protein expression and mRNA levels of the same group of genes in liver tissues tissue samples obtained from patients with chronic hepatitis (CH) and hepatocellular carcinoma (HCC).
Methods
Patients
The present study included 69 cases that are HCV-RT-PCR positive and HBV-PCR negative in both liver tissues and serum samples. These cases were divided into two groups: group 1 (HCC; n = 35), samples were collected from patients diagnosed and treated at the National Cancer Institute, Cairo University, between December 2005 and August 2008; group 2 (CH; n = 34), samples were collected from HCV associated chronic hepatitis (CH) patients admitted to Kasr Al-Aini School of Medicine, Cairo University, in the same period and enrolled in routine diagnosis or therapeutic procedures. The mean age of CH patients was 47.5 years and M:F ratio was 1.5:1, whereas the mean age of HCC was 51.6 years and M:F ratio was 1.3:1.
All cases of CH were graded and staged according to the modified Knodell scoring system [23] and all HCC cases were graded according to the World Health Organization (WHO) classification criteria and staged according to the American Joint Committee on Cancer [24]. The percent of normal to tumor ratio were more than 80% in all studied cases to overcome the nominalization effect of the tumor stroma and/or necrosis as well as the cirrhotic tissues factors in the studied specimens. Table 1 illustrates the clinico-pathological features of the studied cases. Normal liver tissue samples were obtained from liver transplant donors (15 samples) and were used as controls. A written consent was obtained from all patients and normal liver donors prior to enrollment in the study and the ethical committee of NCI approved the protocol, which was in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Table 1 Clinical features of the studied groups of patients.
HepG2 cell culture
HepG2 cells were used to establish the in vitro HCV replication. HepG2 culturing and infection were carried out according to previous protocols [25]. Briefly, HepG2 cells were maintained in 75 cm culture flasks (Greiner bio-one GmbH, Germany) containing Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 4.5 g/L glucose and 10 g/L L-glutamine (Bio Whittaker, a Combrex Company, Belgium), 50 ml/L fetal calf serum (FCS), 10 g/L penicillin/streptomycin and 1 g/L fungizone (250 mg/L, Gibco-BRL life Technologies, Grand Island, NY (USA). The complete culture medium (CCM) was renewed every 3 days, and cells were passaged every 6-10 days. A total of 3 × 106 cells were suspended in 10 ml CCM and incubated at 37°C in 5% CO2.
Viral inoculation and sample collection
Viral inoculation and cell culture were performed as previously described [26]. Briefly, cells were grown for 48 h to semi-confluence in complete culture medium, washed twice with FCS-free medium, and then inoculated with 500 μl serum obtained from HCV infected patients (500 μl patient sera and 500 μl FCS-free DMEM/3 × 106 cells). The HCV genotype was characterized as genotype-4 with 9 quasispecies based on our previously described method [27]. The viral load in the used serum was quantified by real time PCR. The average copy number was 58 × 107copies/ml. After 180 min, Ham F12 medium (Bio Whittaker, a Combrex Company, Belgium) containing FCS was added to make the overall serum content 100 ml/L in a final volume of 10 ml including the volume of the human serum, which used for infection as mentioned above. Cells were maintained overnight at 37°C in 5% CO2. The next day, adherent cells were washed with CCM and incubation was continued in CCM with 100 ml/L FCS. Throughout the culture duration, the assessment of HCV replication were confirmed by a detection of viral core protein using western blotting, by RT-PCR amplification of sense and antisense strands of the virus by real time PCR and by the inhibition of HCV replication using siRNA knockout as we previously reported [28].
Western blot analysis of HCV core antigens in HepG2 cells
Lysates containing 100 μg of protein from uninfected and infected HepG2 cells were subjected to SDS-PAGE, as previously described [26, 27]. After three washes, membranes were incubated with diluted peroxidase-labeled anti-human IgG/IgM antibody mixture at 1:5000 in PBS (3 g/L) for previously treated strips with the anti-core antibody (Novocastra, Novocastra Laboratories, UK) for 2 h at room temperature. Visualization of immune complexes on the nitrocellulose membranes was performed by developing the strips with 0.01 mol/L PBS (pH 7.4) containing 40 mg 3,3',5,5'-tretramethylbenzidine and 100 μl of 30 ml/L hydrogen peroxide (Immunopure TMB substrate Kit, PIERCE, Rockford, IIIinois, USA).
Quantification of human GAPDH mRNA
The integrity of the cellular RNA preparations from HCV infected HepG2 cells was analyzed by 18s and 28s bands on agarose gel and by automated gel electrophoresis (Experion Software Version 3.0, Bio-Rad), which was also used for measuring the RNA concentration in addition to spectrophotometer at 260 nm (nanoDrop, USA). GAPDH mRNA levels were quantified by real time RT-PCR using TaqMan technology with GAPDH specific primers. Amplification of human GAPDH transcripts was performed using the TaqMan EZ RT-PCR kit (Applied Biosystems, Foster City, CA). The target template was the purified cellular RNA from HepG2 cells at 1, 2, 3, 4, 5, 6, 7 and 8 days post-infection with HCV, in absence and presence of siRNA. The RT-PCR was performed using a single-tube, single-enzyme system. The reaction exploits the 5'-nuclease activity of the rTth DNA polymerase to cleave a TaqMan fluorogenic probe that anneals to the cDNA during PCR 50 μl reaction volume, 1.5 μl of RNA template solution equivalent to total cellular RNA from 2.5 × 105 cells were mixed with 200 nM forward primer, 200 nM reverse primer, 300 nM GAPDH probe, 300 μM from each of dATP, dCTP, dGTP and 600 μM dUTP, 3 mM manganese acetate, 0.5 μl rTth DNA polymerase, 0.5 μl Amp Erase UNG, 1× Taqman EZ buffer and amplified in the sequence detection system ABI 7700 (Applied Biosystems, Foster City, CA). The RT-PCR thermal protocol was as follows: Initial UNG treatment at 50°C for 2 minutes, RT at 60°C for 30 minutes, deactivation of UNG at 95°C for 5 minutes followed by 40 cycles, each of which consists of denaturation at 94°C for 20 seconds and annealing/extension at 62°C for 1 min.
Northern Blot Analysis
To construct a HCV RNA transcription vector total RNA was extracted from all cell types at days 1, 2, 3, 4, 5, 6, 7 and 8 post-transfection, 5 μg of total RNA were loaded onto the gel. HCV sequences from nt 47 to 1032 were cloned after RT-PCR into pSP 64 [poly(A)] vector (Promega), resulting in plasmid PMOZ.1.HCV then confirmed by DNA sequence analysis. HCV template RNA was transcribed in vitro from MOZ.1.HCV. Briefly, 5 mg of plasmid DNA was linearized with a BglII. The linear plasmid DNA was purified from an agarose gel and then incubated with 50 U of SP6 RNA polymerase for 2 h at 37°C in the presence of 500 mM (each) ribonucleoside triphosphates (GTP, ATP, UTP, and CTP), 100 U of RNAsin, 10 mM dithiothreitol, 40 mM Tris-HCl (pH 7.5), 6 mM MgCl2, 2 mM spermidine, and 10 mM NaCl in a total reaction volume of 100 μl. After transcription reaction, DNA template was degraded by two rounds of digestion with RNase-free DNase (Boehringer) for 30 min at 37°C with 10 U of enzyme. Upon completion of digestion, two rounds of extraction with phenol-chloroform-isopropyl alcohol and then ethanol precipitation were done. HCV RNA transcripts, which contained a poly(A) tail, were further purified on an oligo(dT) cellulose column. RNA concentration was determined spectrophotometrically at A260 with UV light. An aliquot was analyzed by agarose gel electrophoresis to assess its integrity.
Sensitivity of RT-PCR assay
HCV RNA synthesized in vitro was diluted with TE (Tris-EDTA) buffer at a concentration of approximately 106 copies per ml and was stored at -20°C. Serial 10-fold dilutions of these stock solutions were made in water just prior to RT-PCRs. One hundred copies were routinely detected. Both probes were purified using MicroSpin G-50 columns (Amersham Pharmacia). Blots were visualized and quantified as previously described [29].
Detection of plus and minus-strand RNA by nested RT-PCR
Detection of plus- and minus- HCV strand was performed as previously reported [26, 30]. The One Step real-time PCR system (Applied Biosystems) was used.
Molecular detection of HBV
DNA extraction and PCR amplification from fresh tissues and PCR amplification were performed as previously described [31].
Determination of caspase activity
HepG2 cells were harvested on different dates. After lysis and protein concentration, cell lysates containing 200 μg of total protein was used to measure the activities of caspases 3, 8 and 9 using ApoTaget colorimetric Assay kits (BioSource international, Inc. Camarillo, CA) according to the manufacturer instructions.
RNA extraction from liver tissues
Total RNAs were extracted using a SV total RNA isolation system (Promega, Biotech) according to manufacturer's instructions. The extracted total RNA was assessed for degradation, purity and DNA contamination by a spectrophotometer and electrophoresis in an ethidium bromide-stained 1.0% agarose gel. Ten samples of normal human DNA and RNA were extracted from normal liver tissues and were used to optimize the best conditions for the multiplex PCR of B-actin gene (621-bp fragments) versus each of the studied genes. Negative RT-PCR control was used against each sample [32].
c-DNA synthesis
Reverse transcription (RT) of the isolated total RNA was performed in 25 μl reaction volume containing 200 u of Superscript II RT enzyme (Gibco-BRL, Gaithersburg, MD, USA.), 1× RT-buffer [250 mM Tris-HCl pH 8.3, 375 mM KCl, 15 mM MgCl2], 1 mM dithiotheritol, 25 ng from random primer, 0.6 mM deoxynucleotide triphosphates, 20 U RNAsin (Promega, USA.), 100 ng of extracted RNA. Samples were then incubated at 50°C for 60 min followed by 4°C until the PCR amplification reaction [32].
PCR amplification of the studied genes
Primer sequences, PCR conditions of the studied genes (Fas, FasL, Bcl-2, Bcl-xL and Bak), and the expected PCR DNA band length are listed in Table 2. The PCR and quantitation were performed in a 50 μL reaction volume containing 5 μL of the RT reaction mixture (c-DNA), 2.5 units Taq polymerase (Gibco-BRL, Gaithersburg, MD, USA), 1× PCR buffer (500 mM KCl, 200 mM Tris-HCl, 1.5 mM MgCl2, 1 mg/mL bovine serum albumin (BSA)), 200 mM each of the deoxyribonucleotide triphosphate and 0.25 mM of each primer. Amplification of the β-actin gene (621 bp fragment) was performed to test for the presence of artifacts and to assess the quality of RNA. A water control tube containing all reagents except c-DNA was also included in each batch of PCR assays to monitor contamination of genomic DNA in the PCR reagents. Negative RT-PCR control was used against each sample [32].
Table 2 Primer sequences of the studied genes.
Quantification of the studied genes
Fifteen microliters of each PCR product were separated by electrophoresis through a 2.0% ethidium bromide-stained agarose gel and visualized with ultraviolet light. Gels were photographed and the bands were scanned as digital peaks. Areas of the peaks were then calculated in arbitrary units with a digital imaging system (Photo-documentation system, Model IS-1000; Alpha Innotech Co., San Leandro, CA, USA). To evaluate the relative expression levels of target genes in the RT-PCR, the expression value of the normal pooled liver tissues was used as a normalizing factor and a relative value was calculated for each target gene amplified in the reaction. Non-expression in any of the studied genes was considered if there was a complete absence, or more than a 75% decrease in the intensity of the desired band in comparison to the band of normal pooled liver tissue [24, 25]. Samples were assayed in batches that included both cases and controls. The absence of bands was confirmed by repeating the RT-PCR twice at different days and by consistent presence of β-actin gene amplification [32].
Immunohistochemistry
Protein expression of the studied proteins was assessed using the following monoclonal antibodies Fas (C236), FasL (sc-56103), Bcl-2 (sc-56016), and Bcl-xL (sc-8392) (all from Santa Cruz Biotechnology, inc. Germany). Briefly, from each tumor block, a hematoxylin and eosin-stained slide was microscopically examined to confirm the diagnosis and select representative tumor areas. Tissue cores with a diameter of 1.5 mm were punched from the original block and arrayed in triplicate on 2 recipient paraffin blocks. Five μm sections of these tissue array blocks were cut and placed on positive charged slides to be used for IHC analysis. Sections from tissue microarrays were deparaffinized, re-hydrated through a series of graded alcohols, and processed using the avidin-biotin immunoperoxidase methods. Diamino-benzidine was used as a chromogen and Mayer hematoxylin as a nuclear counterstain. A case of follicular lymphoma was used as a positive control for Bcl-2, Fas and FasL whereas a case of colon cancer was used as a control for Bcl-xL. Results were scored by estimating the percentage of tumor cells showing characteristic cytoplasmic immunostaining for all examined markers [33].
Protein expression was classified compared to normal hepatic tissue samples. Positive expression was further classified according to the level of expression into mild: ≥ 10%- < 25%, moderate: ≥ 25%- < 50% and high expression: ≥ 50% but during statistical analysis they were broadly classified into negative or positive expression.
Statistical analysis
The results were analyzed using the Graph Pad Prism software (Graph Pad Software, San Diego, CA, USA). For gene expression analysis the Mann-Whitney U Test was used for numeric variables and Chi square or Fisher's exact Test were used to analyze categorical variables. P-value was considered significant when ≤ 0.05.
Results
All studied cases were positive for HCV infection by both ELISA and HCV RT-PCR in serum and liver tissue but were negative for HBV infection by serological markers and PCR both in serum and liver tissues. The level of pro-apoptotic genes expression was measured in HCV infected HepG2 cell line as an in vitro model as well as in HCC and CH tissue samples.
Infection of HepG2 cell line with hepatitis C virus
In this model, we observed a good correlation between persistence of HCV infection in HepG2 cell line and the appearance of certain morphological changes in the infected cells such as visible cell aggregation and granulation that took place 21 days post infection suggesting successful viral transfection, as shown in Figure 1. Successful HCV genotype-4 replication in HepG2 cells were also confirmed by western blot for the detection of viral core protein as shown in Figure 2a, as well as inhibition of HCV replication by 100 nM siRNA previously developed in our lab [28], illustrated in Figure 2b.
Figure 1
figure1
(A): Non-infected HePG2 cells. (B): Infected HePG2 cells. Scale bar = 100 μm.
Figure 2
figure2
Expression levels of the viral core and GAPDH. (A) The expression level of the viral core and GAPDH in HepG2 cells infected by HCV genotype-4 from day 1 to day 8. (B) The expression level of the viral core in HepG-2 cells infected by HCV genotype-4 from day 1 to day 8. Upper row show HCV-core expression in un-transfected cells. Lower row showed the HCV- core expression in siRNA-Z5 transfected cells.
Quantification of HCV RNA was performed both in cell free media and cell lysates at days 1, 2, 3, 7, 14, 21, 28, 35, 42, 52, 59 and 116 post HCV infection. HCV RNA was detected in all of these days except days 35, 52 for cell free media and days 21, 28 for cell lysates. HCV-RNA was quantitatively detected in all days except days 2, 3, 14, 45 (Table 3).
Table 3 Changes in apoptotic and pre apoptotic genes expression in HCV infected HepG2 cell line in vitro.
Apoptotic genes expression in HCV-infected HepG2 cells
No changes in the expression level of Bcl-2 gene post-HCV infection was observed compared to the control (HCV free HepG2 cells) (Figure 3A). The expression of Bcl-xL and Bak genes (Figures 3B, C, respectively) fluctuated 3 weeks post infection then, the levels of their expression was similar to the control levels at the end of the experiment. Interestingly, there was a good correlation between Fas, FasL genes expression and HCV infection. The expression of Fas gene was visible until the third measurement (day 3) post infection and then disappeared by the end of the experiment. In contrast, the expression of FasL was not visible until day 21 post infection then the visibility progressively increased until the end of the experiment (Table 3 Figures 3D, E).
Figure 3
figure3
Data on gene amplification. Ethidium bromide-stained 2% agarose gel (A) for Bcl2 gene amplification. Lanes 1 and 2 showed negative RT-PCR control; lane 3 showed positive amplification of CH case; lane 4 showed negative amplification of CH case; lane 5 showed positive amplification of HCC case; lane 6 showed negative amplification of HCC case; lane 7 showed positive amplification of HepG2 without HCV infection; lane 8 showed positive amplification of HepG2 with HCV infection. (B) For Bcl-Xl gene amplification. Lane 1 showed HepG2-positive amplification with HCV infection at day 28; lane 2 HepG2-negative amplification without HCV infection; lane 3 and 4 showed positive amplification of CH case; lane 5 showed positive amplification of HCC case; lane 6 & 7 showed negative RT-PCR control. (C) For Bak gene amplification. lane 1 HepG2-positive amplification with HCV infection at days 59; lane 2 HepG2-negative amplification without HCV infection lane 3 showed HepG2-negative amplification with HCV infection at days 35; lane 4 showed positive amplification of CH case; lane 5 showed positive amplification of HCC case of CH; lane 6 negative RT-PCR control. (D) for Fas gene amplification, first lane: MW, lanes 1 and 2: negative RT-PCR control, lane 3 showed HepG2-positive amplification without HCV infection, lane 4 HepG2- showed negative amplification with HCV infection at day 21, lane 5 showed negative case of HCC, lanes 6 and 7 showed positive amplification of CH and lane 8 showed positive amplification of HCC case. (E) for FasL gene amplification, lane 1: negative RT-PCR control; lanes 2 and 3 showed HepG2-positive amplification with HCV infection at days 28 and 35 respectively; lane 4 showed HepG2-negative amplification without HCV infection; lane 5 showed negative case of CH; lanes 6 and 7 showed positive amplification of CH, lanes 8 and 9 showed positive amplification of HCC case. (F) Amplification plot of RT-PCR for housekeeping gene using Taqman probe.
Caspases activity in HCV-infected HepG2 cells
As shown in Figure 4, recognizable changes were observed in caspases 3, 8 and 9 throughout the course of HCV infection. There was an initial increase in their levels starting from day six to day 30 then all caspases levels were dramatically decreased until day 135 post-infection.
Figure 4
figure4
Changes in caspases expression levels in vitro.
Apoptotic genes expression in the studied cohorts of patients
There was a significant difference in the RNA expression level of both Bcl-xL and Bcl-2 genes between HCC and CH (26%, 80% versus 0%, 59%; respectively, p < 0.0001, = 0.0068). As well as between HCC cases and normal distant tumor (NDT) (p < 0.001) (Figure 5). Similarly, a significant difference was found in the Bak gene expression between HCC and CH patients (69% versus 47%, p = 0.0025) as well as between HCC and NDT (p < 0.0001). The FasL was significantly expressed in CH compared to HCC (47% versus 23%, p < 0.001). None of the CH cases studied revealed Bcl-xL gene expression.
Figure 5
figure5
The expression level of the apoptotic genes in the different studied groups. NB: CH = Chronic hepatitis, HCC = Hepatocelullar carcinoma, NAT = Normal distant to tumor.
Apoptotic proteins expression
Positive immunostaining for Bcl-2, Bcl-xL, Fas and FasL proteins was detected in 29 (85.9%), 12 (34.3%), 21 (60%) and 9 (25.7%) the studied samples of the 35 HCC cases examined compared to 18 (52.9%), 0 (0%), 18 (52.9%) and 18 (52.9%) of samples of the 34 CH cases; respectively. The concordance between immunohistochemistry and RT-PCR ranged from 86% to 94% (Figure 6).
Figure 6
figure6
Cases of chronic hepatitis (CH) and hepatocellular carcinoma (HCC). Data from cases of CH showing (A) high membranous expression of FasL, (B) moderate cytoplasmic expression of FAS and (C) moderate cytoplasmic expression of Bcl-2. Cases of HCC showing (D) High membranous expression of FasL, (E) Marked expression of FAS, (F) high expression of Bcl-2, and (G) Marked expression of Bcl2 in tumor tissues with loss of expression in adjacent non neoplastic region. Scale bar = 100 μm (A, C, D, G) and 200 μm (B, E, F).
Clinical correlations
In HCC cases, Fas-RNA and protein expression were significantly associated with the presence of cirrhosis (p = 0.0027) and with poorly differentiated tumors (p < 0.0001). Bak gene expression was significantly associated with the presence of invasion (p = 0.05), absence of cirrhosis (p < 0.0001) and with well differentiated tumors (p < 0.0001). The expression level of Bcl-2-RNA and protein was significantly associated with poorly differentiated tumors (p < 0.0001) (Table 4).
Table 4 Correlation between gene expression and clinicopathological features in hepatocellular carcinoma cases.
Table 5 shows that in CH patients Fas expression was significantly associated with high hepatitis grade (p = 0.05), whereas FasL expression was significantly associated with the presence of necrosis as well as with high hepatitis grade and stage (p = 0.015, 0.015 and 0.006; respectively). In contrast, Bcl-2 expression was significantly associated with the presence of cirrhosis (p < 0.0001).
Table 5 Correlation between gene expression and clinicopathological features in CH patients
Discussion
An important cause of morbidity and mortality worldwide is the infection by HCV. Progress in understanding HCV biology has remained challenging due to the lack of an efficient cell culture system for virus growth. Establishment of self-replicating full-length HCV genomic replicons from genotypes in cultured cells has provided an important tool for the study of HCV replication mechanisms. This study discusses the system for the HepG2 cell line harboring HCV- genotype-4 replication and examines the expression levels of group of genes in clinical samples obtained from HCC and CH patients. Other studies have reported another systems for HCV replication, the first with HCV GT1 H77 in immortalized human hepatocytes (IHH) [34] and the other system of HCV GT2 JFH1 in human hepatoma cell line (Huh7) [35]. Kanda et al. suggested that IHH support HCV genome replication and virus assembly by examined HCV core protein-mediated IHH for growth of HCV [34]. Their study described the generation of cell culture-grown HCV from genotype 1a and discuss the concept of HCV replication and assembly of genotype 1a in IHH and speculated that cellular defense mechanisms against HCV infection are attenuated or compromised in IHH [34]. It was reported the HCV production from a HCV-ribozyme construct of genotype 1a (clone H77) in Huh-7 cells with no determination for the virus infectivity [35]. Furthermore, subgenomic replicons of the JFH1 genotype 2a strain cloned from an individual with fulminant hepatitis replicate efficiently in cell culture. The JFH1 genome replicates efficiently and supports secretion of viral particles after transfection into a Huh7, providing a powerful tool for studying the viral life cycle and developing antiviral strategies [35].
Apoptosis has been demonstrated as an important mechanism for viral clearance. In HCV-infected liver, viral persistence is observed despite enhanced hepatocyte apoptosis [5]; however, it is not clear whether this apoptotic effect is due to a direct cytopathic effect of the virus, immunological reactions or a contribution of the molecular mechanisms causing liver damage during HCV infection [22, 36]. For understanding the impact of HCV infection on the apoptotic machinery during disease progression, we studied the expression patterns of Bcl-2, Bcl-xL, Bak, Fas, FasL in HCV- genotype-4 infected HepG2 cell line as well as in human tissue samples obtained from patients with HCC and CH as a result of chronic HCV infection. We also analyzed the expression levels of caspases 3, 8 and 9 in tissue culture medium and in HCV infected cells by a colorimetric assay, and viral replication by both RT-PCR and Real-Time PCR for up to 135 days post-infection.
The results of the present study showed that HCV infection disrupted the process of apoptosis through down regulation of Fas and up-regulation of FasL genes expression. However, in tissue samples a higher expression of Fas and FasL genes were detected in CH compared to HCC patients, which explains the presence of severe inflammation in chronic HCV infection and its oncogenic potential. In this regard, previous studies demonstrated that enhanced FasL gene expression induces T-cell apoptosis [15], which favors viral persistence and indirectly increases the probability of progression to HCC [36]. In addition, the FasL gene exerts proinflammatory activities via IL-1β secretion that is responsible for neutrophils infiltration [37].
In contrast, other studies [3840] demonstrated that the ratio of Fas/FasL was significantly lower in HCC than in CH tissue samples or non tumor hepatic tissues. This was attributed to the fact that tumor cells possess more than one safe guard against Fas mediated apoptosis. First, the reduced expression or loss of certain molecules that are involved in the Fas mediated apoptosis pathway such as FADD (Fas-associated protein with death domain), FLICE (FADD like interleukin-1β-coverting enzyme, caspase-8) or FAF (Fas associated factor), or the induction of molecules that would inhibit Fas mediated apoptosis such as FAP (Fas associated phosphatase) [7]. Second, the expression of sFas RNA and FAP-1 may neutralize Fas mediated apoptosis [41] and third, Fas mutation could be expected. Many investigators suggested that one of the possible mechanisms by which HCV core protein inhibits apoptosis is through a direct binding to downstream domain of FADD and cFLIP leads to viral persistence and cells proliferation [5]. Consequently, it is conceivably possible that the observed decreased apoptosis relative to cell proliferation of infected hepatocytes could be part of the signaling mechanisms in the pathogenesis of HCC [42].
It has also been reported that the extrinsic (Fas-FasL) pathway plays an important role in liver cell injury directly via HCV infection or indirectly through immune attack of HCV- infected cells with subsequent recruitment and activation of stellate cells and macrophages, resulting in fibrosis and cirrhosis [43]. Also, I was found that during HCV infection, HCV-specific T cells migrate to the liver and recognize viral antigens on the hepatocytes [38]. These immunologically active cells, which are probably induced due to inflammation rather than viral infection, become activated and express FasL that transduces the apoptotic death signal to Fas bearing hepatocytes, resulting in their destruction [38]. Therefore, neither Fas expression nor the degree of liver injury correlates with the intra-hepatic viral load [15, 44]. In such case, the TNF or the IFN-δ might be responsible for the up regulation of Fas expression in infected hepatocytes and FasL in lymphocytes [45].
Alternatively, the hepatocytes which are likely type II cells in which direct activation of caspase 8 (extrinsic pathway mechanism) is not sufficient to induce apoptosis amplification by a mitochondrial pathway (intrinsic mechanism) are highly required. Accordingly caspase 8 activation causes the proapoptotic cleavage of Bid, which induces cytochrome c release from the mitochondria, which subsequently binds to Apaf-1 and procaspase 9 forming apoptosome complex [29]. In the present study, we assessed the activation of caspases 8, and 9, which represent both death receptor-mediated and the mitochondrial apoptosis pathway and caspase 3 which is an executioner caspase. Our data showed a positive correlation between Fas mediated apoptosis and caspases activation. In HCV infected cells, we observed a loss of caspases after 4 weeks post HCV infection. Some studies provided evidence that monitoring of caspases activation might be helpful as a diagnostic tool to detect the degree of HCV mediated inflammatory liver damage and to evaluate efficacy of HCV therapy [36, 37]. However, it was reported that the extent of caspase activation correlates with the grade of the disease but not with surrogate markers, such as serum transaminases or viral load [36]. This observation indicates that caspase activation is not directly related to HCV mediated damage and suggests the involvement of HCV mediated immune response with Fas triggered hepatocyte apoptosis giving rise to several amplification loops [36]. Similar findings were reported by others, who indicated in their study that the core protein could stimulate caspase-independent apoptosis at later stages of the disease giving relevance to the release of HCV particles from the host cells and to viral spread [46].
It has been shown that some HCCs are resistant to Fas-mediated apoptosis directly through the expression of HCV proteins or indirectly through up-regulation of Bcl-2 family members [36]. Our data showed that both Bcl-2 and Bcl-xL RNA expression were significantly higher in HCC than in CH and NDT indicating late involvement of those genes in the cascade of HCV-associated hepatocarcinogenesis. We were also able to detect Bcl-2 gene expression in HepG2 cells starting from day 1 post-infection until the end of the experiment, whereas the expression of Bcl-xL was not visible until day 28 when it started to be expressed and its expression was closely associated with the presence of HCV in tumor cells (Table 3) suggesting that Bcl-2 is tumor related whereas Bcl-xL is a viral related. In this context, Bcl-2 was linked to inhibition of apoptosis via interfering with either the recruitment of procaspase 8 to Fas receptors [47] or by preventing the release of cytochrome C [5]. It has also been shown that the HCV core protein inhibits apoptosis at the mitochondrial level through augmentation of Bcl-xL expression with consequent inhibition of caspase 3 activation [16]. The HCV core protein could induce apoptosis in the Fas death way although this is achieved through the activation of Bax and Bak, both are important mediators of p53 mitochondrial function [5, 36]. Our results showed an increase in Bak-RNA expression at an early stage of HCV infection of HepG2 cells, which is also observed in tissue samples obtained from both CH and HCC patients compared to NDT samples. Our results provided enough evidence that the Bak gene can induce apoptosis in HCC cells even in the presence of high levels of the anti-apoptotic Bcl-2 gene family members, which is in agreement with the findings of others [48].
The results of gene expression in tissue samples show a significant correlation between Fas expression in HCC cases and the presence of cirrhosis or poorly differentiated tumors. We observed that FasL expression was significantly associated in CH patients with the grade of inflammation and the stage of fibrosis as well as with the presence of severe necro-inflammatory changes. Based on these results we conclude that aberrant expression of Fas and FasL in HCV-infected patients could be considered a marker for increased disease severity with a higher possibility of progression into cirrhosis and/or HCC. Similar results were also reported by others [49], who indicated that FasL may contribute to malignant transformation of hepatocyte as it was significantly expressed in the peri-cancerous lobules and cirrhotic nodules [42]. Similarly, Bcl-2 expression was significantly associated with poorly-differentiated tumors as well as with the presence of cirrhosis in CH patients. Similar findings were reported previously by some of us [32]. In this study, Bak expression was significantly associated with absence of cirrhosis and well-differentiated tumors, thus Bak gene could be considered a good prognostic marker.
The impact of HCV infection on modulating apoptotic machinery pathway(s) differs during the course of infection, as the disease progresses apoptosis is inhibited leading to cell immortalization and HCC development. HCV infection could exert a direct effect on hepatocytes by inducing Fas-FasL pathway with subsequent inactivation of caspases or indirectly by immune attack on hepatocytes resulting in HCV mediated liver injury, viral persistence and cirrhosis in CH patients with an increasing possibility of hepatocarcinogenesis especially with increasing proliferation rate and acquisition of genetic damage.
Alternatively, HCV infection could induce apoptosis at the early phase of infection followed by modulation of apoptosis by disturbing Fas/FasL. This in turn would cause an inactivation of caspases 3, 8, and 9, up-regulation of Bcl-2 family members, impairment in Bak gene expression and increasing the expression of FasL leading to inhibition of apoptosis in HCV infected patients. This signaling cascade favors cell survival with persistence of HCV infection and enhances the possibility of HCC development. A combination of these effects initiates a circle of hepatocyte damage and repair, which is the hallmark of HCV infection that might progress to HCC. Our study could provide an insight for understanding apoptosis and developing molecular target therapies that could inhibit viral persistence and HCC development. Further studies are still required to clarify the interaction between other HCV proteins in the apoptotic machinery system and the possible involvement of other apoptotic pathways in HCV associated HCC development.
Conclusions
Chronic HCV infection modulates the apoptotic machinery differently during the course of infection, where the virus induces apoptosis early in the course of infection, and as the disease progresses apoptosis is modulated. This study could open a new opportunity for understanding the various signallings of apoptosis and in the developing a targeted therapy to inhibit viral persistence and HCC development. Nevertheless, further studies are mandatory to clarify the interaction between other HCV proteins in the apoptotic machinery system and the possible involvement of other apoptotic pathways in HCV associated HCC development.
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Acknowledgements
Grant support from the National Cancer Institute Grant Office and Research Center, Cairo University, Egypt.
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Correspondence to Abdel-Rahman N Zekri.
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Authors' contributions
ARNZ made substantial contributions to conception and design, carried out the tissue culture and molecular genetic studies and gave the final approval of the version to be published. AAB carried out pathological and the immunohistochemistry studies. MMH carried out the tissue culture and molecular genetic studies, participated in the design of the study and performed the statistical analysis. ZKH participated in the molecular studies and participated in the statistical analysis, interpretation of data and drafted the manuscript. MK participated in pathological studies. SAL participated in drafting the manuscript. GMS participated in the statistical analysis. AREZ provided all clinical samples and data. SSD participated in drafting the manuscript and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
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• HepG2 Cell
• Viral Persistence
• Chronic Hepatitis Patient
• Immortalize Human Hepatocyte
• Infected HepG2 Cell | {
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-8,944,429,554,313,342,000 | Create an Asthma Action Plan
Photo source: Shutterstock.com, By Orawan Pattarawimonchai
If you have asthma, you should have an Asthma Action Plan. Asthma Action Plans help you prevent and control asthma attacks.
The first step is to meet with your primary care provider. Your primary care provider, or a provider familiar with your asthma, should always help create your plan.
Your plan will be divided into three sections. The first section describes what it feels like when your asthma is under control, and what you can do to keep it that way. For example, when your asthma is under control, your plan may tell you to take maintenance medicine prescribed by your doctor at a specific dose.
The second section describes your asthma as it gets worse, and tells you exactly what to do to regain control. It is important to include a description of what it feels like when your asthma is worsening to make it easy to identify when you need to take action. The actions should be written out in detail and include what medicine to take, what the dose should be, and how often to monitor yourself.
The third section describes what to do when your asthma becomes a medical alert. It has a plan for taking medicine and going to the emergency room. When you experience the symptoms described in this section of your plan, it is extremely important to get medical help.
There are several Asthma Action Plan example forms available for free. Download them from https://www.cdc.gov/asthma/actionplan.html or ask if your doctor already has a form. Remember that all your information needs to be filled out specifically for YOUR needs, and meeting with a medical provider familiar with your asthma is necessary.
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2,865,517,308,138,579,000 | Differential Diagnosis of Acute Vertigo
Benign paroxysmal positional vertigo (BPPV) is characterized by brief spinning sensations, usually lasting less than 1 minute, which are generally induced by a change in head position with respect to gravity.
BPPV must be distinguished from other, more serious causes of acute or episodic vertigo. A history taking and neurologic examination often allow for differentiation among stroke, vestibular neuritis, and BPPV.
Differential Diagnosis of Acute Vertigo
Cause Onset and Course Nystagmus Auditory Symptoms Other Features
BPPV* Recurrent, transient, positional; usually provoked by turning over or getting in and out of bed Positional, with mixed vertical torsional nystagmus in BPPV involving posterior canal and horizontal nystagmus in BPPV involving horizontal canal None Recent inciting event possible (e.g., recumbent position at dentist’s office or hair salon, prolonged bed rest, head trauma); history of similar episodes
Stroke Spontaneous, usually sustained; may be worsened by positional change Spontaneous, with beating in various or changing directions Occasional Neurologic symptoms or signs may include headache and vertical misalignment of eyes; results of head impulse test typically normal†
Vestibular neuritis Spontaneous, sustained; may be worsened by positional change Spontaneous, predominantly horizontal None May be preceded by viral illness; results of head-impulse test abnormal†
Vestibular migraine Recurrent, spontaneous; duration for minutes to hours; may be positional Rare, but when present usually positional Occasional Migrainous headaches, motion sickness, family history
Meniere’s disease Recurrent, spontaneous; typical duration for hours Spontaneous, horizontal Fluctuating hearing loss, tinnitus Ear pain, sensation of fullness in ear
* BPPV denotes benign paroxysmal positional vertigo.
† In the head-impulse test, the result is considered abnormal when a corrective movement (saccade) is required to maintain straight-ahead fixation after the head has been rotated to the side.
References:
1. Kim JS, Zee DS. Clinical practice. Benign paroxysmal positional vertigo. N Engl J Med. 2014 Mar 20;370(12):1138-47 [Medline]
2. von Brevern M. Benign paroxysmal positional vertigo. Semin Neurol. 2013 Jul;33(3):204-11. [Medline]
Created Jul 23, 2014.
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49,372,255,589,698,970 |
Abstract Title
RETINAL GANGLION CELLS ARE RESISTANT TO AMPA RECEPTOR MEDIATED EXCITOTOXICITY
Presenter Name
Yong Park
Abstract
Glaucoma is an age-related disease that affects nearly 70 million people worldwide. It is characterized by damage to the cells in the back of the eye which eventually die and cause gradual vision loss. The mechanism to how glaucoma occurs is yet unknown but there are many speculations. A protein molecule called the AMPA receptor is speculated to play a role in glaucoma by causing the death of these cells in the back of the eye. In our study, we are isolating the cells from the back of the eye of rats to study the role of the AMPA receptor and how it truly functions. Understanding basic functions of this protein molecule can one day help us develop drugs targeting AMPA receptors and therefore possibly protecting the dying cells in glaucoma.
Purpose (a):
The ionotropic glutamate receptors (iGluR) have been hypothesized to play a role in glaucoma pathogenesis by mediating excitotoxic death of retinal ganglion cells (RGC). Previous studies on iGluR in the retina have been focused on two broad classes of receptors: NMDA and non-NMDA receptors including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and Kainate receptor. In this study, we examined the specific excitotoxic effects of activation of the AMPAR in RGCs in-vitro.
Methods (b):
Purified rat RGCs were isolated from P3-P5 Sprague-Dawley rats by a double immunopanning technique using an antibody to Thy 1.1. RGCs were cultured for 7 days before s-AMPA (100μM) treatments. s-AMPA excitotoxicity was determined by Caspase3/7 luciferase activity assay, immunoblot analysis for α-fodrin and Live (calcein AM)/Dead (ethidium homodimer-1) assay. Gap-43 expression was assessed by immunocytochemistry.
Results (c):
Treatment of cultured RGCs with s-AMPA (100μM) for 24, 48 and 72h, both in the presence and absence of trophic factors (BDNF and CNTF), did not alter caspase 3/7 activity and cleavage of α-fodrin (neuronal apoptosis marker), compared to untreated controls. A significantly higher (p<0.05) cell survival of RGCs (85.3±1.5% alive cells) was observed after a 72h treatment with 100μM s-AMPA compared to control untreated RGCs (74.8±3.1% alive cells). Quantification of s-AMPA (100μM) – mediated excitotoxicity in purified RGCs incubated for 24h in an oxygen/glucose deprived (0.5% oxygen) medium demonstrated no statistically significant differences in cell survival compared to control RGCs maintained under either normoxia or hypoxia. Additionally, immunocytochemical analysis showed increased GAP-43 staining in RGCs after 24h of treatment with s-AMPA (100μM).
Conclusions (d):
These results indicate that purified RGCs in-vitro are not susceptible to AMPA excitotoxicity as previously hypothesized. Activation of AMPAR increased GAP-43 expression, suggesting AMPAR could possibly increase neurite outgrowth. The ability of AMPA receptors to promote neuroprotection of RGCs remains to be confirmed.
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RETINAL GANGLION CELLS ARE RESISTANT TO AMPA RECEPTOR MEDIATED EXCITOTOXICITY
Glaucoma is an age-related disease that affects nearly 70 million people worldwide. It is characterized by damage to the cells in the back of the eye which eventually die and cause gradual vision loss. The mechanism to how glaucoma occurs is yet unknown but there are many speculations. A protein molecule called the AMPA receptor is speculated to play a role in glaucoma by causing the death of these cells in the back of the eye. In our study, we are isolating the cells from the back of the eye of rats to study the role of the AMPA receptor and how it truly functions. Understanding basic functions of this protein molecule can one day help us develop drugs targeting AMPA receptors and therefore possibly protecting the dying cells in glaucoma.
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5,127,594,311,700,071,000 | Computation of reliable textural indices from multimodal brain MRI: Suggestions based on a study of patients with diffuse intrinsic pontine glioma
Jessica Goya-Outi, Fanny Orlhac, Raphael Calmon, Agusti Alentorn, Christophe Nioche, Cathy Philippe, Stéphanie Puget, Nathalie Boddaert, Irène Buvat, Jacques Grill, Vincent Frouin, Frederique Frouin
Résultats de recherche: Contribution à un journalArticleRevue par des pairs
29 Citations (Scopus)
Résumé
Few methodological studies regarding widely used textural indices robustness in MRI have been reported. In this context, this study aims to propose some rules to compute reliable textural indices from multimodal 3D brain MRI. Diagnosis and post-biopsy MR scans including T1, post-contrast T1, T2 and FLAIR images from thirty children with diffuse intrinsic pontine glioma (DIPG) were considered. The hybrid white stripe method was adapted to standardize MR intensities. Sixty textural indices were then computed for each modality in different regions of interest (ROI), including tumor and white matter (WM). Three types of intensity binning were compared di: constant bin width and relative bounds; dii : constant number of bins and relative bounds; diii : constant number of bins and absolute bounds. The impact of the volume of the region was also tested within the WM. First, the mean Hellinger distance between patient-based intensity distributions decreased by a factor greater than 10 in WM and greater than 2.5 in gray matter after standardization. Regarding the binning strategy, the ranking of patients was highly correlated for 188/240 features when comparing di with diii, but for only 20 when comparing di with dii , and nine when comparing dii with diii. Furthermore, when using di or diii, texture indices reflected tumor heterogeneity as assessed visually by experts. Last, 41 features presented statistically significant differences between contralateral WM regions when ROI size slightly varies across patients, and none when using ROI of the same size. For regions with similar size, 224 features were significantly different between WM and tumor. Valuable information from texture indices can be biased by methodological choices. Recommendations are to standardize intensities in MR brain volumes, to use intensity binning with constant bin width, and to define regions with the same volumes to get reliable textural indices.
langue originaleAnglais
Numéro d'article105003
journalPhysics in Medicine and Biology
Volume63
Numéro de publication10
Les DOIs
étatPublié - 10 mai 2018
Modification externeOui
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3,519,436,278,630,596,600 | Should I Use Steroids on My Skin?
Topical steroids are creams, ointments and lotions which contain steroid medications and are most commonly used in the treatment of skin conditions such as eczema and psoriasis to reduce skin inflammation.
These steroid treatments are often offered as a first course of action in treating skin conditions. But are they the magic miracle solution they appear to be?
Steroid creams come in different potencies and the greater the strength, the greater the risk of side-effects with continued use. Which is why many experts advise against the long-term use of topical steroids.
HOW DO THEY WORK?
Topical steroids are absorbed into the skin cells. They stop these cells from producing various inflammation-causing chemicals that are normally released when the skin reacts to allergens or irritation.
By preventing inflammatory chemicals from being released, corticosteroids reduce inflammation and relieve its related symptoms such as redness and itching.
LOCALISED EFFECTS
• Stinging or burning feeling following treatment
• Skin thinning
• Stretch-marks - long-term use has in some cases led to permanent skin bruising, discolouration, or spidery blood vessels
• Topical steroids can also induce rosacea, which may include the eruption of erythema, papules, and pustules
• Increased hair growth where the skin is being treated.
• Some people have developed an allergy to the contents of the treatment, which in some instances can make the inflammation worse
• Because topical steroids change the way the immune system work, they can inhibit the skin’s ability to fight off bacterial and fungal infections
SYSTEMIC EFFECTS
• In some cases the topical steroid gets through the skin and into the bloodstream, which is primarily a concern in children who are on strong doses as this can affect their growth
• Fluid build-up in the legs
• Increase in blood pressure
• Bone damage and thinning
• Cushing's syndrome: although rare, symptoms include rapid weight gain, skin thinning and mood changes
• Glaucoma is a disease in which the pressure inside the eye increases to the point of damaging the optic nerve. There are isolated reports of people developing glaucoma after long-term use of topical steroids around the eyes. How this happens is not completely understood, but it is believed that enough of the steroid can be absorbed in the surrounding tissue to leech into the eye itself.
HOW LONG SHOULD I USE STEROIDS FOR?
It's advised by medical professionals that topical steroids should not be used continuously for more than two to four weeks, then the frequency should be tapered to twice weekly use. Problems can begin to occur when you try and taper off usage. Steroid creams are only ever targeting the symptoms on the surface of the skin - the underlying condition still exists.
Topical corticosteroids withdrawal (sometimes called “topical steroid addiction” or “Red Skin Syndrome”) is the adverse effect that can occur when topical steroids are inappropriately used or overused, then stopped. It can result from prolonged, frequent, and inappropriate use of moderate to high potency topical corticosteroids, especially on the face and genital area.
TSW might sound like a new phenomenon but topical steroid addiction was actually identified back in the seventies, according to a study called "Steroid addiction" published in the International Journal of Dermatology forty years ago.
HOW TO PREVENT TOPICAL STEROID WITHDRAWAL
1. Don't use steroids in the first place
When you're deliberating whether to begin a course of topical steroid treatment, remember this might not be the magical quick fix you're looking for. Whilst the temptation of temporary remission is there, consider the long-term implications when making this difficult decision.
2. Don't go cold turkey when coming off topical steroids
This means slowly cutting down on your applications, rather than stopping suddenly. For example, use a lower strength steroid, then only use it every second day for a week, then every third day for two weeks, and so on until you are applying them once a week. After about a 6 weeks of slowly cutting down on topical steroids, stop using them.
3. Feed your skin with nutrients
It's important to give your body what it needs during this time of hormonal imbalance and healing. TSW can take months or even years to recover from, if you do not have extra nutritional support. Nutritional support reduces the risk of loss of hair, eyebrow loss and "elephant skin" and it helps patients with TSW recover faster. Follow the plan and recipes in my book RADIANT - specifically designed to heal skin from within.
LIST OF STEROID TREATMENTS
Brand name Name of corticosteroid Potency Other active ingredients
Alphaderm cream Hydrocortisone 1% Moderate
Aureocort ointment Triamcinolone acetonide 0.1% Potent Urea (humectant moisturiser)
Betacap scalp application Betamethasone valerate 0.1% Potent
Betnovate cream/ointment/lotion Betamethasone valerate 0.1% Potent
Betamethasone and clioquinol cream/ointment Betamethasone valerate 0.1% Potent Clioquinol (antiseptic)
Betamethasone and neomycin cream/ointment Betamethasone valerate 0.1% Potent Neomycin (antibiotic)
Betnovate RD cream/ointment Betamethasone valerate 0.025% Moderate
Bettamousse Betamethasone valerate 0.12% Potent
Calmurid HC cream Hydrocortisone 1% Moderate Urea, lactic acid (humectant moisturisers)
Canesten HC cream Hydrocortisone 1% Mild Clotrimazole (antifungal)
Clarelux foam Clobetasol propionate 0.05% Very potent
Cutivate cream/ointment Fluticasone propionate Potent
Daktacort cream/ointment Hydrocortisone 1% Mild Miconazole (antifungal)
Dermacort cream Hydrocortisone 0.1% Mild
Dermovate cream/ointment Clobetasol propionate 0.05% Very potent
Dermovate scalp application Clobetasol propionate 0.05% Very potent
Clobetasol, neomycin and nystatin cream/ointment Clobetasol propionate 0.05% Very potent Neomycin, nystatin (antibiotic + antifungal)
Dioderm cream Hydrocortisone 0.1% Mild
Diprosalic ointment Betamethasone dipropionate 0.05% Potent Salicylic acid (keratolytic)
Diprosalic scalp application Betamethasone dipropionate 0.05% Potent Salicylic acid (keratolytic)
Diprosone cream/ointment Betamethasone dipropionate 0.05% Potent
Diprosone lotion Mometasone furoate 0.1% Potent
Elocon cream/ointment Mometasone furoate 0.1% Potent
Etrivex shampoo Clobetasol propionate 0.05% Very potent
Eumovate cream/ointment Clobetasone butyrate 0.05% Moderate
Eumovate eczema and dermatitis cream Clobetasone butyrate 0.05% Moderate
Eurax hydrocortisone cream Hydrocortisone 0.25% Mild Crotamiton (anti-itch)
Fucibet cream Betamethasone valerate 0.1% Potent Fusidic acid (antibiotic)
Fucidin H cream/ointment Hydrocortisone acetate 1% Mild Fusidic acid (antibiotic)
Haelan cream/ointment/tape Fludroxycortide Moderate
Locoid cream/ointment/crelo/ lipocream/scalp lotion Hydrocortisone 17-butyrate 0.1% Potent
Lotriderm cream Betamethasone dipropionate 0.064% Potent
Metosyn cream and ointment Fluocinonide 0.05% Potent
Mildison lipocream Hydrocortisone 1% Mild
Modrasone cream/ointment Alclometasone dipropionate 0.05% Mild
Nerisone cream/oily cream/ointment Diflucortolone valerate 0.1% Potent
Nerisone forte oily cream/ointment Diflucortolone valerate 0.3% Very potent
Nystaform HC cream/ointment Hydrocortisone 0.5%, 1% Mild Nystatin, chlorhexidine (antifungal + antiseptic)
Synalar cream/ointment/gel Fluocinolone acetonide 0.025% Potent
Synalar 1 in 4 cream/ointment Fluocinolone acetonide 0.00625% Moderate
Synalar 1 in 10 cream Fluocinolone acetonide 0.0025% Mild
Synalar C cream/ointment Fluocinolone acetonide 0.025% Potent Clioquinol (antimicrobial)
Synalar N cream/ointment Fluocinolone acetonide 0.025% Potent Neomycin (antibiotic)
Timodine cream Hydrocortisone 0.5% Mild Dimeticone, nystatin, benzalkonium chloride (barrier +antifungal +antiseptic)
Trimovate cream Clobetasone butyrate 0.05% Moderate Oxytetracycline, nystatin (antibiotic + antifungal)
Ultralanum plain cream/ointment Fluocortolone Moderate
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1,921,809,865,856,670,000 | What Leads to Workers’ Back and Head Pain?
Work Is a Pain in The…
Back pain and headache are common health complaints among workers in almost every industry, and are responsible for substantial suffering and disability, along with lost productivity. Two recent studies attempted to determine which risk factors are more likely to lead to musculoskeletal pain and headaches among workers.
Studying Office Workers
The first study examined office workers with a high degree of computer usage. Questionnaires were used to determine the musculoskeletal symptoms reported by the employees and the associated risk factors. The leading areas of pain among computer users were found to be the shoulder, neck, and upper back regions, with more than 60% of surveyed workers reporting pain in at least one of these areas.
Physical and Psychological Issues
High psychological distress was significantly associated with upper back and shoulder complaints, while a high workload was found to be significantly associated with lower back complaints. Women were more likely to report shoulder pain. The researchers concluded by emphasizing the importance of developing an intervention that addresses both physical and psychological complaints.
The second study focused on headaches as a possible outcome of the types of occupational and psychological factors examined in the first study. The aim of the study was to determine the occupational psychological, social, and mechanical factors that predicted the presence and severity of headaches among workers. The factors most strongly related to headache severity were role conflict, lower decision control, control over work intensity, job satisfaction, and higher quantitative demands.
Chiropractic Can Help
Stress has been shown to worsen chronic pain so managing stress could play a significant role in minimizing symptoms. Studies suggest that chiropractic can help the body cope with stress while improving the symptoms of headache and back pain.
References
Chiung-Yu Cho, Yea-Shwu Hwang, Rong-Ju Cherng. Musculoskeletal symptoms and associated risk factors among office workers with high workload computer use. Journal of Manipulative and Physiological Therapeutics 2012; (10.1016/j.jmpt.2012.07.004).
Christensen JO, Knardahl S. Work and headache: A prospective study of psychological, social, and mechanical predictors of headache severity. Pain 2012; doi 10.1016/j.pain.2012.07.009.
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-4,095,466,659,524,424,000 | Are you getting enough Iodine?
Woman holding mug and looking out to sea. Are you getting enough iodine?
Are you getting enough iodine?
When you hear the word iodine, you may think of the tablets used to disinfect water on camping trips or the yellow liquid used for disinfecting cuts and grazes when we were younger. Or you may just remember it from the periodic table in chemistry class.
Iodine is one of the most important life-sustaining elements. For more than 100 years, it has been known as the element that is necessary for thyroid hormone production. However, it is so much more than that.
Iodine is found in each and every one of the trillions of cells in the body, and responsible for the production of all the other hormones in the body.
It is a powerful antibiotic, and has potent antibacterial, antiviral properties.
It has strong anti-inflammatory effects by neutralising free radicals and is necessary for proper immune system function. Working together with other minerals like Selenium, it has many therapeutic benefits for a range of modern illnesses and diseases.
It is estimated by the World Health Organisation (WHO) that more than half of the world’s population live in an area of iodine deficiency, and that this has risen 400% in the last few decades due to soil depletion and an increase in environmental contaminants that have replaced it.
Our body does not make iodine, so we need to access it from the foods we eat. But if the nutrients are not in the soil to begin with, it cannot be in the food we eat, and this can lead to common deficiencies.
Iodine deficiency in New Zealand
Soil in coastal areas are naturally iodine-rich, as are the dairy products produced by the cows that graze there. Fresh produce such as fruits and vegetables that are grown in coastal areas are also rich in iodine.
Despite being a coastal nation, New Zealand soils are low in iodine, and this is reflected in our locally grown produce.
This can be due to intensive farming, lack of crop rotation and the use of fertilisers. Coupled with changes to our diet, the reduced use of iodised salt in the household, the prevalence of processed foods, many New Zealanders are now lacking important nutrients such as iodine that are key to good health.
The WHO’s research has suggested deficiencies in both Australia and New Zealand are re-emerging, when they were previously thought to be iodine sufficient.
This research suggests that we may be consuming less than 60% of what is recommended. While we all need iodine, it is especially important for women who are trying to fall pregnant, are currently pregnant or who are breastfeeding, as the body demands more during this time due to increased thyroid hormone production, and the requirements of the developing baby.
Woman smiling and leaning on fence in countryside.
Research suggests that we may be consuming less than 60% of what is recommended.
Properly evaluating and treating iodine deficiency will help people support thyroid health and immune system function, increase their energy levels, and help improve general health and wellbeing. This can be achieved by some simple changes to their diet or daily supplementation in consultation with their health practitioner. It can be as little as a couple of drops of potassium iodide in a glass of water each day to get you feeling better, and help you avoid some of the common but serious health problems we are seeing today in New Zealand and around the world.
The best results are seen with a holistic approach, and increasing the intake of important vitamins, minerals and electrolytes through a wholefood diet.
The hungry thyroid
The thyroid is often referred to as a ‘hungry’ part of the body, in reference to its high nutritional demands.
This butterfly-shaped endocrine gland surrounds the windpipe and is important for metabolism, regulating digestion and your heart rate. It facilitates energy production and mental agility. The thyroid also helps with fat burning too, by determining how quickly and efficiently kilojoules are burned up, and it assists in the breakdown of proteins. Thyroid function also assists the suppleness and strength of our hair, skin and nails.
Iodine is an essential ingredient in all thyroid hormones, including T4 (thyroxine) and T3 (triiodothyronine). It is important to maintain sufficient amounts of iodine, and they are required to be synthesised in adequate amounts. In a low thyroid state, known as hypothyroidism, the thyroid gland can’t make enough thyroid hormone to keep the body running normally. The metabolic state is therefore reduced which can lead to weight gain.
When the thyroid gland is releasing excess amounts of thyroid hormone, it is known as hyperthyroidism, which is an overactive or elevated metabolic state which can result in fatigue, irregular heartbeat, unexplained weight loss and brain fog.
When you have an adequate intake of iodine, your body contains 20-50g, and 75% of that amount is stored in the thyroid. However large amounts are also stored in other parts of the body, including the salivary glands, the breasts, ovaries, and the brain. In the brain it concentrates in the substantia nigra, the part of the brain that is associated with Parkinson’s disease.
One of the first signs of deficiency is an enlarged thyroid gland.
The lack of iodine causes the gland to expand in an attempt to extract as much iodine in the bloodstream as possible. If your iodine intake is low, this will be reflected in low levels of thyroid hormone. You may then experience fatigue, dry skin, constipation, systemic inflammation, a hoarse voice, delayed reflexes and some cognitive impairment.
It is best to consult your doctor or health professional should you identify any of these symptoms. Anybody taking thyroid medication should always discuss their condition with a health professional before taking supplementary iodine.
The role of selenium
Selenium, another important mineral and antioxidant, plays a significant role in regulating thyroid function and iodine metabolism. The thyroid contains more selenium by weight than any other organ in the body.
Selenium is a required component for the production of the enzyme glutathione peroxidase, which protects the body from damage with antioxidant capabilities.
Without this enzyme, the thyroid gland is susceptible to damage from oxidants, there would be no activation of thyroid hormone without selenium.
Pregnant woman lying on bed. Pregnant and breastfeeding women require more iodine.
Pregnant and breastfeeding women require more iodine.
The need for iodine before pregnancy
The consequences of iodine deficiency are most serious for women who are trying to fall pregnant, who are currently pregnant or are breastfeeding.
Thyroid hormones balance the function and development of the body’s major organs and influence the progress of the developing baby.
Research has shown that a lack of iodine can cause fetal and neonatal mental disabilities and growth problems, along with speech and hearing issues. Cognitive function and neurological development can be impaired when iodine levels are low.
Pregnant and breastfeeding women also require more iodine due to increased thyroid hormone production.
It is recommended that women take iodine supplements from the point of planned pregnancy and through the full duration of pregnancy as well as breastfeeding. Avoid kelp or seaweed supplements as they may be contaminated with heavy metals such as mercury. Multi-vitamin, multi-mineral and pre-natal supplements may or may not contain enough iodine, so it’s best to check.
Women with pre-existing thyroid conditions should always check with their health professional before taking a supplement.
How do I know if I’m deficient?
Under most states of iodine sufficiency, approximately 90% of dietary iodine eventually is excreted in the urine, with exception being the lactating female due to iodine excretion in the breast milk. Because of this, urine is the best biological fluid to use for assessment of deficiency.
If you are concerned there may be deficiency, you could undertake an iodine-loading test, otherwise known as a urinary iodine concentration (UIC) where you take a prescribed dose of iodine, then collect 24 hours of urine to undergo analysis with a health professional.
The principle of this test is that if you’re iodine sufficient, most of the dose will be excreted, and if there is a deficiency present, it will be instead be absorbed by the body.
Can I get enough iodine from salt?
Iodised table salt was implemented in many regions and countries around the world when iodine deficiency was recognised. In New Zealand in the 1920’s, the government allowed manufacturers to voluntarily add iodine to table salt. This was mainly to safeguard against thyroid enlargement (goitre) and the severe mental retardation of cretinism, although the incidence of these conditions was very rare in New Zealand.
Closeup image of unrefined, unprocessed sea salt. A better option than table salt.
Unrefined, unprocessed sea salt is a better option than table salt.
In recent decades we have seen people consume less salt due to health concerns, while some avoid salt entirely. Salt used in processed foods is often non-iodised to save on costs, so is not a source of iodine despite the sodium content.
In recent times we are seeing a prevalence of sea salt, or kosher salt, promoted as a healthier alternative. However, sea salt is a poor source of iodine, and we should look for unrefined, unprocessed sea salt, with some products now enriched with New Zealand sea kelp. The iodine in salt is not very bioavailable in our bodies, it is better absorbed through liquid and food sources.
Other sources of dietary iodine
It can be difficult to identify sources and the quantity of iodine in most foods. However, it is naturally present in seawater, so therefore seafood is a good source, especially seaweed, shellfish and saltwater fish. It’s also naturally present in soil, and found in eggs and dairy, including yoghurt, cow’s milk, ice cream and cheese.
If you don’t have access to shellfish or other seafood, or if the soil is deficient due to intensive farming, you’ll need to access it from other sources.
Iodine levels in milk can vary according to the soils in which the animals have grazed and factors such as the groundwater used in irrigation, fertilisers used and the feed for the livestock. Interestingly, organic milk is estimated to contain roughly 30-40% less iodine than conventional milk, owing to alternative processing methods.
It is difficult for most people to obtain adequate iodine by eating foods that are natural sources of iodine.
That said, in 2009, Iodine fortification of bread became mandatory with the exception of organic bread, non-yeast-leavened bread and bread mixes. When salt was iodised in the 20th century, this significantly improved the iodine levels within the New Zealand population, but recently deficiencies have again become apparent, hence the need for the fortification of foods.
Iodine dosage guidelines
There is no single dose of iodine that is effective for everyone. The best approach is working with a health professional that is knowledgeable about iodine.
If you eat seafood and other iodine-rich foods, use iodised salt, take a multi-vitamin or mineral supplement, you may be able to obtain adequate levels.
Recommended daily allowances range from 100-250mcg a day, with the exception of pregnant or breastfeeding women, who may require more than 300mcg per day due to increased hormone production in early pregnancy, increased urinary iodine excretion, and the transfer of iodine to the fetus or the nursing infant when feeding.
Some leading iodine experts suggest significantly larger daily doses, even up to 12mg. In Japan, the average daily intake is 12-13 milligrams due to increased consumption of seaweed and other seafood.
Iodine Liquid Mineral: Just 2 drops a day = 255mcg of Potassium Iodide
Iodine Liquid Mineral: Just 2 drops a day = 255mcg of Potassium Iodide
Summary
Iodine is one the most basic elements of all life on earth, it is present in the ocean, marine life and in every one of the trillions of cells in our body. The role it plays in our everyday wellbeing cannot be overstated. As our bodies can’t produce iodine, there are simple steps we can take to make sure we can rebalance and replenish our mineral levels, and avoid deficiencies.
References:
Brownstein, MD. D. Iodine. Why You Need It And Why You Can’t Live Without It. 2014
Reader’s Digest. The Healing Power of Vitamins, Minerals & Herbs. 2000
Schauss, Alexander G. Minerals, Trace Elements, & Human Health. Life Sciences Press. 1995
Kohrle J. The Trace Element Selenium and The Thyroid Gland. Biochimie. 1999
Smallridge RC, Ladenson PW. Hypothyroidism In Pregnancy: Consequences To Neonatal Health. J Clin Endocrinol Metab. 2001
Iodine. Ministry of Health Manatū Hauora Website.
Editors: de Benoist, Bruno. Andersson, Maria. Iodine status Worldwide. WHO Global Database on Iodine Deficiency. World Health Organisation, Geneva. 2004
Ministry of Health Manatū & Australian National Health and Medical Research Council. Nutrient Reference Values for Australia and New Zealand Including Recommended Dietary Intakes. 2006, updated 2017.
Disclaimer:
The information in this article is not intended as a medical prescription for any disease or illness. Nothing stated here should be considered medical advice. Use as directed. If symptoms persist, consult your healthcare professional. | {
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-5,724,000,926,567,237,000 | Bioengineered Extracellular Vesicles - Potential Boon for Delivering Biotherapeutics
by Deepti Tayal, Ph.D. Contributor Biopharma insight
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771 Comments 0
Topics: Novel Therapeutics
Because of endogenous properties, extracellular vesicles (EVs) have shown impressive potential as remedial modalities; nevertheless, more bioengineering refinement is expected to address clinical and business limitations.
EV-based treatments are now being evaluated for immunomodulation, tissue regeneration, recovery, and as delivery vectors for combination therapy. Moreover, EVs are critical parts of paracrine motioning in stem/progenitor cell-based treatments, can be utilized as a medication conveyance strategy or can be utilized as independent therapeutics. T cells that have been genetically modified can be utilized for everything from cancer immunotherapy to HIV treatment however getting T cell-designated drugs to patients is troublesome.
Why Extracellular Vesicles as Delivery Agents?
Extracellular vesicles (EVs) are nanoscale particles secreted by all cells that naturally encapsulated and transfer proteins and nucleic acids, making them an appealing and clinically relevant platform for constructing biomimetic delivery vehicles in the upcoming years. There are technologies for genetically engineering cells to develop multifunctional EV vehicles without the use of chemical compounds. High affinity profiling domains on the EV surface to accomplish, efficacious T cell binding, a protein tag to confer active cargo stacking into EVs, and fusogenic glycoproteins to enhance EV uptake and fusion with recipient cells are also demonstrated. These technologies operate very well together by delivering Cas9-sgRNA complexes to primary human T cells. These methodologies might lead to well enable vesicles to target to a variety of cells for efficient delivery as Cargoes.
Extracellular vesicles (EVs) are indeed a significant emerging strategy for trying to deliver biomolecular cargo. Intercellular interaction is influenced by EVs, which deliver their components to recipient cells to affect cellular activity. Unique characteristics including non-toxicity and non-immunogenicity, and the ability to design and develop surface and luminal cargo stacking, make vehicles an appealing platform for delivering a variety of therapeutics. Cargo can be integrated into vesicles by upregulating it in producer cells so that it can be loaded during EV biogenesis, or by physically or chemically modifying vesicles after production. Cells that have been genetically modified to produce functionalized EVs may even be implanted to continuously produce such EVs.
For various tumor types, immune checkpoint blockade therapy has emerged as a viable anticancer method. Immune checkpoint molecules have been used to develop several anticancer medicines. Recent years have seen huge turn of events and interpretation of EV-related therapeutics, advancing to pre-clinical and clinical investigations. Further, the limit of EVs to move natural and drug particles to explicit tissues and cell types has brought significant interest up in their improvement as biocompatible medication conveyance frameworks.
Recent Development: Bioengineered Vesicles !
Recently, I came across one research article where researchers at Northwestern University discovered a set-up of advances for hereditarily designing cells to create multifunctional EV vehicles — without utilizing chemical modifications that confound biomanufacturing. Researchers have focused on high affinity areas on the EV surface to accomplish explicit, effective restricting to T cells, distinguish a protein tag to present dynamic freight stacking into EVs, and show fusogenic glycoproteins to expand EV take-up and combination with recipient cells. These advancements have the capability of conveying Cas9-sgRNA edifices to alter essential human T cells. These methodologies could empower focusing on vesicles to a scope of cells for the proficient conveyance of freight.
Using Genetically encoded multifunctional integrated nanovesicles (GEMINI), EVs can be efficiently bound to specific target cells, uptake, and fused with a recipient cell to release cargo into the cytoplasm.
Although genetically modifying T cells can enable applications ranging from cancer immunotherapy to HIV treatment, T cell-targeted therapeutic delivery remains tricky, and in this case, extracellular vesicles could be of great benefit.
GEMINI- Extracellular Vesicles (EV) cargo proteins are expressed in producer cells to facilitate incorporation into a variety of vesicle populations, including macrovesicles that bud from the cell surface and exosomes that are produced by endosomal invaginations into multivesicular bodies. Surface-displayed targeting and fusion proteins aid in the binding and uptake of cargo by recipient cells, followed by cargo release via cell surface fusion or endosomal escape.
The above research work is to address the limitations during the process of enabling target delivery of biomolecules to T cells- cargo loading into EVs during biogenesis, EVs binding to specific target cells, uptake, and fusion of EV with recipient cell to release cargo into the cytoplasm. EVs derived from mesenchymal stem cells (MSCs) are already being studied in regenerative medicine for potential use in nano delivery.
Various therapeutic strategies encompassing bioengineered extra vesicles will strengthen preclinical and clinical tests in the future. Extracellular vesicle-based therapeutics hold the best clinical guarantee when a mix of local and designed aspects are used. Local extracellular vesicles (EVs) hold intrinsic restorative potential — they are biocompatible, stable, and because of their targeting, work with remedial use. However, there are huge difficulties related with their commercialization and clinical turn of events, with designed EVs permitting modified content, expanded creation, and targeting for better therapeutics results
Topics: Novel Therapeutics
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-6,829,662,972,619,096,000 | Altering the intestinal microbiota for therapeutic benefit in uveitis
Review Article
Altering the intestinal microbiota for therapeutic benefit in uveitis
Phoebe Lin
Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
Correspondence to: Phoebe Lin, MD, PhD. Associate Professor of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, 515 SW Campus Drive, Portland, OR 97239, USA. Email: linp@ohsu.edu.
Abstract: An intestinal dysbiosis is connected to a number of inflammatory diseases through various mechanisms relating to its effect on immune cell function and differentiation. This is a review of the literature summarizing our current understanding of intestinal microbial contributions to non-infectious uveitis and strategies to target the intestinal microbiome to treat uveitis. Several groups have demonstrated an intestinal dysbiosis associated with certain types of non-infectious uveitis. Additionally, approaches to treat uveitis by modifying the intestinal microbiota, such as oral antibiotics or administration of oral short chain fatty acids (SCFAs), which are intestinal bacterial metabolites produced by fermentation of dietary fiber, can successfully treat uveitis in mouse models. This reduction in severity of ocular inflammation occurs via the following mechanisms: enhancement of regulatory T cells, decreasing intestinal permeability, and/or affecting T cell trafficking between the intestines and the spleen. Other strategies that are directed at the intestinal microbiota that might be effective to treat uveitis include dietary changes, probiotics, or fecal microbial transplantation. The commensal gut bacteria are influential in systemic and intestinal mucosal immunity and thus contribute to the development of extraintestinal inflammation like uveitis. Targeting the intestinal microbiome thus has the potential to be a successful strategy to treat non-infectious uveitis.
Keywords: Non-infectious uveitis; microbiome; short chain fatty acids (SCFAs)
Received: 18 December 2019; Accepted: 16 July 2020; Published: 15 September 2020.
doi: 10.21037/aes-19-114
Introduction
Non-infectious uveitis is a group of heterogeneous disorders for which the etiologies have not been completely elucidated. These conditions seem to arise from a combination of genetic and environmental factors that are currently poorly characterized, but that have in common an imbalance resulting in an increased effector arm of the immune system relative to the regulatory arm of the immune system. Disruptions in both innate and adaptive immunity can result in ocular inflammation, as can aberrations in ocular immune privilege. Additionally, an immune reaction to as of yet unidentified infectious agents can result in what appears clinically like non-infectious uveitis. While the majority of therapeutics tested in recent clinical trials to treat non-infectious uveitis were either an ocular steroid formulation for a potent but nonspecific anti-inflammatory approach with potential ocular side effects, or a biologic treatment targeting the effector arm of the immune system, very little has been investigated which targets enhancing the regulatory arm of the immune system to potentiate immune homeostasis or regulating intestinal immunity to affect systemic immunity. Targeting the intestinal microbial changes associated with non-infectious uveitis has the potential to influence regulation of systemic immunity thus reestablishing immune homeostasis in the eye.
Intestinal microbiota in health and disease
A significant segment of the human immune system is housed in the gastrointestinal tract, which also is home to the majority of the human commensal microbiota (referring not just to commensal bacteria, but also commensal viruses, parasites, fungi, and archaea). The microorganisms that reside normally in the gastrointestinal tract were previously thought to be passive bystanders, but are now known to be active contributors to normal post-natal intestinal mucosal and systemic immune system development. In fact, the gut microbes are important in maintaining immune homeostasis in childhood and adulthood. Over the past decade, it has emerged that the gut microorganisms can influence both innate and adaptive immunity. A disruption in the intestinal microbial constituents, termed an intestinal dysbiosis, has thus been connected to the development of numerous inflammatory diseases including, but not limited to, ankylosing spondylitis (AS), atherosclerotic disease, rheumatoid arthritis (RA), type 1 diabetes, psychiatric, and CNS disorders (1-4).
Intestinal microbiota effects on adaptive immunity
These associations between immune-mediated disease and the commensal microbiota exist, in part, due to their influence on the differentiation of certain adaptive immune cell types. For example, some strains of bacteria (5,6) foster differentiation of T helper 17 cells (Th17), which can become pathogenic under certain conditions, and are found at inflamed tissue sites in diseases such as non-infectious uveitis or arthritis. Other commensal bacteria, on the other hand, can promote differentiation of regulatory T cells (Tregs) in the large intestine (7,8) which are thought to be protective against undue inflammation. Furthermore, short chain fatty acids (SCFAs), which are gut bacterial products of fermentation of dietary fiber, appear to promote Tregs as well, and were found in one study to reduce inflammatory colitis, and in another study, to reduce CNS inflammation in a mouse model of multiple sclerosis (MS) (9,10).
Several theories hypothesize how the gut microbiome causes inflammation at extraintestinal tissue sites such as the eye or joints: (I) the T-cell threshold model says that maladaptive immunodifferentiation with disproportionate numbers of potential effector immune cell types such as Th17 cells compared with immunoregulatory cell types such as Tregs can occur due to an imbalance in the abundance of gut microbial strains which promote one arm of the immune system over the other. This state decreases the threshold for T-cell activation by increasing the pool of Th17 cells that can traffic to other tissue sites from the GI tract, and can become pathogenic in certain local settings. (II) The molecular mimicry model is best explained as autoreactive T cell activation via cross-recognition of self-antigens with intestinal microbial antigens. (III) The leaky gut hypothesis is described by a scenario in which an intestinal dysbiosis results in disruption of intestinal barrier function leading to leakage of microbial components, microbial metabolites, or whole bacteria or other microorganisms into the systemic circulation, which then causes an aberrant immune response at an extraintestinal tissue site such as the eye.
Intestinal dysbiosis in disease states
Specific microbial changes have been described in several inflammatory diseases including AS, RA, and MS. For example, new onset RA patients who are treatment-naïve, have an increased relative abundance of Prevotella copri in their GI tract, but decreased Bacteroides species (4,11). P. copri was inversely correlated with the “shared-epitope” genes in RA which confer genetic risk. These results show that an intestinal dysbiosis favoring Prevotella is associated with disease development in non-genetic RA, which comprises the vast majority of RA (4). In MS, in which a subset of patients have anterior or intermediate uveitis and retinal vasculitis, there were reductions in Clostridia that usually foster Treg differentiation (3). Lending credence to the causative nature of this intestinal dysbiosis was data showing that fecal microbial transplants from MS patients into mice promoted worse CNS inflammation (12). In human HLA-B27 transgenic rats, we have demonstrated an increase in the relative abundance of Paraprevotella, a bacterial genus within the same family as Prevotella, as well as decreased Rikenellaceae (13) in the gut. Acute anterior uveitis occurs in approximately 30% of AS patients, of whom up to 90% are HLA-B27 positive. In AS patients, both Prevotellaceae and Lachnospiraceae bacteria are enhanced in the ileum compared to healthy control subjects (1).
In this review, we summarize the literature on how changes in the intestinal microbiota are associated with non-infectious uveitis and discuss how to thus direct novel treatment strategies for uveitis targeting the intestinal microbiome.
Alterations in the intestinal microbiota in non-infectious uveitis
Multiple investigators have shown the significance of the intestinal microbiome in non-infectious uveitis. For instance, Nakamura and colleagues were among the first to show that an intestinal bacterial signature was associated with severe, compared to mild, intraocular inflammation phenotypes in a mouse model of inducible uveitis called experimental autoimmune uveitis (EAU) (14). This same group demonstrated that an increase in intestinal permeability takes place before peak intraocular inflammation occurs in this model (15). Horai et al. showed in their study utilizing a mouse model of uveitis that expresses a transgene for a retina-specific T cell receptor, that a bacterial antigen from the small intestines activated retina-specific T cells, thus giving credence to the molecular mimicry model of autoimmune uveitis (16). However, to date, the intestinal bacterial antigen mimic for the retinal peptide that promotes uveitis has not been found (17).
Intestinal dysbiosis in non-infectious uveitis patients
Huang and colleagues showed that in acute anterior uveitis patients there was an intestinal dysbiosis compared to control subjects, while Ye et al. revealed that transferring the fecal microbiota from patients with Behcet’s disease into mice worsened uveitic inflammation (18,19). In a more recent study, uveitis patients were found to be enriched in intestinal Prevotella and Streptococcus strains but depleted in other bacteria such as Lachnospiraceae and Bifidobacterium (20). Furthermore, Jayasudha and colleagues describe the results of a case control study of 14 idiopathic or Vogt-Koyanagi-Harada uveitis patients compared to healthy control subjects who had significant differences in intestinal fungal diversity, including enrichment in Malassezia restricta, Candida albicans, Candida glabrata, and Aspergillus gracilis in uveitis patients (21).
Therapeutic targeting of the intestinal microbiota
There are several methods that can potentially be utilized to treat uveitis by altering the gut microbiome. The oral antibiotics, metronidazole and vancomycin, substantially reduced the severity of uveitis in EAU via alterations in the gut microbiota which drove their relative abundances closer to the non-disease state. This phenomenon was accompanied by increased Tregs in the intestinal lamina propria and extraintestinal lymphoid tissues later in the course of disease (14). An independent group of investigators ultimately found comparable results using the oral antibiotics metronidazole and ciprofloxacin (22).
Another approach to target the microbiota is to administer intestinal bacterial metabolites, such as SCFAs, known to promote immune homeostatic immunodifferentiation. Our group found that exogenous administration of oral SCFAs decreased intraocular inflammation by upregulating Tregs in the large intestine and extraintestinal lymphoid tissues as well as by inhibiting migration of Th1 cells from the gut to the spleen (23). These studies imply that striving to reestablish immune homeostasis by promoting Treg differentiation can potentially be a valuable tool to treat uveitis, although other mechanisms influenced by the gut microbiome, such as intestinal permeability and gut-extraintestinal lymphoid tissue T cell trafficking can also be important targets. We have also found that diets rich in certain fermentable fibers that allow for increased endogenous intestinal bacterial production of SCFAs, can protect against uveitis by decreasing intestinal permeability and by increasing regulatory T cells in the gut (unpublished data, Nakamura et al.). Additionally, our group has demonstrated that immunosuppressive agents commonly used to treat uveitis patients, such as mycophenolate and methotrexate, when given orally, may likely partially exert its effect via beneficial changes in the intestinal microbiota as well (unpublished data, Llorens-Belles et al.).
Thus far, we have outlined several potential approaches in therapeutic intervention targeting the intestinal microbiota for treatment of uveitis, including antibiotics that reverse the intestinal dysbiosis associated with uveitis, bacterial metabolite SCFAs to block migration of effector T cells from the gut, and dietary changes that promote SCFA production that also decrease intestinal permeability (Figure 1). All have in common that they can increase Tregs in the intestinal tract and elsewhere in the body. Additional potential approaches might utilize the following strategies: live bacterial strains, or probiotics, given orally to stimulate immune homeostasis through Treg differentiation. The latter approach appears to have good potential as demonstrated in pre-clinical experiments (24,25); and finally, replacing a community of dysbiotic intestinal bacteria with a healthy community via fecal microbial transplantation. Fecal microbial transplantation was demonstrated to be curative in antibiotic-refractory Clostridium difficile colitis in large clinical trials (26), although this approach can potentially bring new challenges, such as outlining suitable donor characteristics and regulating donor material testing to avoid transmission of infection or disease.
Figure 1 Targeting the intestinal microbiota to treat uveitis. Various approaches can be considered, from re-establishing intestinal immune homeostasis by increasing regulatory T cells (Tregs), reducing intestinal permeability, or by re-setting a maladaptive dysbiosis with various strategies (fecal microbial transplant, antibiotics, immunosuppressive agents, probiotics) to reduce inflammation via multiple mechanisms.
Conclusions
Increasing evidence reveals the significance of the gut microbiome in non-infectious uveitis, potentially as a contributor to the pathogenesis of disease, perhaps representing the intersection of genetic risk and environmental factors that trigger disease. Larger comprehensive studies will be crucial to verify which microbial cohorts are beneficially adaptive vs. maladaptive in uveitis, and to determine the timing in the course of disease that the dysbiosis is most important. With additional knowledge in this area, it seems feasible that one might prevent disease progression or recurrence using one or several strategies altering the gut microbiome such as through diet, specific antibiotic regimens, probiotics, oral supplementation of certain bacterial metabolites, or via fecal microbial transplantation.
Acknowledgments
I would like to thank lab members Christina Metea, Yukiko Nakamura, Cathleen Janowitz, and Ariel Balter, as well as collaborators Mark Asquith, Lisa Karstens, Jim Rosenbaum, Tammy Martin, and Michael Klein.
Funding: This study was supported by a National Eye Institute Grant K08 EY022948, a Collins Medical Trust Grant, and a Research to Prevent Blindness Career Development Award (PL). This study was also supported by core grant P30 EY010572 from the National Institute of Health (Bethesda, MD) and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY). PL is also the recipient of an Alcon Research Institute Young Investigator Award and OHSU Physician-Scientist award, as well as recipient of a Thome Foundation award.
Footnote
Provenance and Peer Review: This article was commissioned by the Guest Editor (Steven Yeh) for the series “Innovations in the Diagnosis and Management of Uveitis” published in Annals of Eye Science. The article has undergone external peer review.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aes-19-114). The series “Innovations in the Diagnosis and Management of Uveitis” was commissioned by the editorial office without any funding or sponsorship. PL reports grants from Alcon, other from Mallinckrodt, other from Clearside, outside the submitted work. The author has no other conflicts of interest to declare.
Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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doi: 10.21037/aes-19-114
Cite this article as: Lin P. Altering the intestinal microbiota for therapeutic benefit in uveitis. Ann Eye Sci 2020;5:26.
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Toxicol Lett. 2008 Sep;181(1):19-24. doi: 10.1016/j.toxlet.2008.06.868. Epub 2008 Jul 5.
Enzyme-based assay for quantification of chlorpyrifos oxon in human plasma.
Author information
1
Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University of Munich, Goethestrasse 33, 80336 Munich, Germany.
Abstract
Chlorpyrifos oxon (CPO) is the active metabolite of the pesticide chlorpyrifos that inhibits cholinesterases at high reaction rates. Chlorpyrifos is of major concern because it causes some ten thousand fatalities each year, mostly due to suicidal attempts. Notwithstanding, toxicokinetic studies on chlorpyrifos in humans are scarce and CPO has not been detected hitherto in human blood. Knowledge of the concentration and the time course of CPO in poisonings would be helpful to better design antidotal strategies, particularly with oximes. Owing to the exceptionally fast covalent binding to butyrylcholinesterase we searched for an enzyme-based assay for CPO determination. We succeeded in a simple procedure where CPO is titrated with purified equine butyrylcholinesterase. The assay requires less than 0.2 mL EDTA plasma and allows the quantification of CPO down to 0.5 nM. CPO is first extracted from plasma with n-pentane, thereby largely excluding the majority of the more hydrophilic pesticide oxons from possible cross-reactions. When chlorpyrifos incorporation is ascertained the assay may be considered largely specific. The new procedure enabled the assessment of the extent of reversible binding of CPO to human albumin, amounting to 85% under physiological conditions. The assay allowed the quantification of CPO in the plasma of a poisoned patient, where the active metabolite was about two orders of magnitude lower than chlorpyrifos. Similar to the parent compound its oxon showed the same tendency to persist for longer periods, thus calling for a change of the usual oxime dosage regimen.
PMID:
18655824
DOI:
10.1016/j.toxlet.2008.06.868
[Indexed for MEDLINE]
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-8,066,611,700,697,902,000 | Taking warfarin (Coumadin®) doesn’t mean you should avoid green vegetables
January 03, 2017 by Joel Fuhrman, MD
Health Concerns: Atrial Fibrillation
Patients on the medication warfarin (brand name Coumadin®), prescribed to prevent blood clots by thinning the blood, also called anticoagulants (an·ti·co·ag·u·lants), are often told by their health professionals not to eat vitamin K-rich foods, such as leafy green vegetables. Since I advocate a diet rich in leafy greens, broccoli, and other foods rich in vitamin K, my dietary recommendations often contradict dietitians, nurses, and doctors who advise their patients taking warfarin to avoid vitamin K-containing foods entirely.
In this post, I explain how to follow a healthful diet when taking warfarin. First, you need to know more about warfarin.
How warfarin works
The reason health professionals recommend patients on warfarin avoid vitamin K-containing foods is because it produces blood-thinning effects by acting as a vitamin K antagonist. Warfarin is similar in structure to vitamin K, which means it can compete with vitamin K and interfere with vitamin K-dependent enzymes, which are needed to produce clotting factors.
When you ingest more vitamin K from green vegetables, you can decrease the effectiveness of warfarin. A higher dose of the drug will then be required to maintain the recommended degree of interference with blood clotting.
Warfarin is most often prescribed for patients with atrial fibrillation, a common arrhythmia (irregularity in heart rate). When you have this abnormal heart rhythm, the turbulent flow of blood increases the likelihood of the formation of an embolus (a traveling clot) that can move to the brain and cause a stroke. Warfarin therapy also is used by people who have experienced a serious blood clot.
Side effects
Since warfarin is a drug given to prevent clots, the major side effect is bleeding. When taking warfarin, you will not stop bleeding easily if you sustain a cut. If involved in a serious car accident, you will more likely bleed to death. If you have a stomach ulcer or a broken blood vessel in your digestive tract while taking warfarin, you can bleed to death.
The main problem with this medication is its very narrow therapeutic range—too much, and you can suffer from a major bleeding episode; too little, it is ineffective at preventing strokes and other embolic events. Patients have to be closely monitored with regular blood tests to have their warfarin dose adjusted accordingly. According to current estimates, 30 percent of patients on warfarin tend to stop taking the medicine within the first year because of frustration with blood tests, dosage changes, and side effects.1
In addition to a major bleed, a serious but more infrequent complication of warfarin therapy is drug-induced limb gangrene and skin necrosis. Other adverse reactions that occur infrequently include white blood cell diseases, hair loss, allergic reactions, diarrhea, dizziness, hepatitis and abnormal liver function, skin rash, headache, nausea and/or vomiting, and itching.2
The risk of bleeding was thoroughly investigated in a 2003 meta-analysis which pooled data from 33 separate studies that examined the bleeding rates of patients who received at least three months of anticoagulation therapy. Major bleeding occurred at a rate of 7.22 per 100 patient-years, and fatal bleeding occurred at the rate of 1.3 per 100 patient-years.3 That means if 10 people were put on warfarin therapy for ten years each, seven out of the ten would have suffered a bleeding event and one would have died from taking warfarin.
Newer anticoagulants have been introduced that are viable options. One advantage of these drugs is that they don’t require the same frequent blood testing; another is that vitamin K does not interfere with their mechanism of action. They also carry a lesser risk of serious bleeding events. However, in many cases, warfarin is still the recommended blood thinner for patients who have atrial fibrillation and are at high risk of stroke.4-6
How to eat healthfully while on warfarin
A Nutritarian diet lowers body weight, blood pressure, cholesterol, blood sugar and can reverse atherosclerosis. Its effects have been documented in medical journal reports and explained in detail in my book, The End of Heart Disease.
When you naturally lower blood pressure and cholesterol through a Nutritarian diet, while flooding your body with antioxidants and phytochemicals, you have the potential to recover from atrial fibrillation. As your atherosclerosis melts away it also lowers your risk of forming a dangerous clot. It is likely that a Nutritarian diet can be even more protective against a serous event than warfarin or other medications. The healthier you get and the longer you follow dietary excellence, the more the risk benefit ratio moves away from using blood thinners, such as warfarin. In the short run, while your body is just starting to repair the damage, you could still require warfarin.
If you are on warfarin you can eat a Nutritarian diet, but carefully measure the amount of green vegetables, making sure only one serving of salad and one serving of cooked greens are consumed each day. The key is to eat the same basic amount each day, so your dose of medication can be adjusted and stabilized. Often, the person’s health will improve so much over six to twelve months, that it can be possible to safely stop taking warfarin. In my 25+ years practicing nutritional medicine, I have had many people resolve their atrial fibrillation following this life-saving approach.
The studies on blood thinners that show that patients in poor heath with multiple risk factors, such as obesity, diabetes and high cholesterol, who are at high risk of stroke, benefit from warfarin. These studies evaluate high-risk patients on the typical disease-creating American diet, not low-risk patients on a plant-rich diet that is loaded with vegetables, beans, berries, nuts and seeds. It is most likely that a person eating such a healthful Nutritarian diet, who resolves those risk factors would change the risk-benefit ratio significantly enough to make warfarin contraindicated, even if their atrial fibrillation continues.
For those who absolutely must take warfarin because of a recent thrombotic event, the danger of not eating a healthful diet exceeds the risk of increasing the warfarin dose slightly to accommodate the more healthful diet. As one’s diet changes to include more plant foods, less processed food and animal products, one’s cholesterol and blood pressure decreases, greatly reducing one’s risk of a heart attack or embolic stroke. A 2015 study in The American Journal of Lifestyle Medicine, survey data concluded that people who started a Nutritarian diet and adhered at least 80 percent, decreased their LDL cholesterol by 42 mg/dl, and those that started out with hypertension, reduced their systolic blood pressure by 26 mm Hg.7
As long as the amount of vitamin K-rich greens you eat is consistent day-to-day, your doctor can adjust your warfarin dose to accommodate it, to avoid fluctuations in the effectiveness of the drug. To keep the vitamin K amount constant, it is sensible to eat one large raw salad a day and one serving of dark green vegetables such as asparagus and string beans, but leave out the very dark green leafy vegetables, such as steamed kale, collards, and spinach. It is permissible to add some dark green leafy vegetables to a soup. The goal is to keep your vitamin K level stable, so the amount of blood thinning does not become dangerous. A dangerous level of blood thinning can occur if the dose of warfarin is adjusted to a high vitamin K intake and then the patient does not eat much vitamin K-rich food for a few days.
No medication can protect you as much as eating healthfully. Do not let anything deter you from eating a Nutritarian diet-style, as it is the most important intervention that can keep you safe and alive.
References
1. Gomes T, Mamdani MM, Holbrook AM, et al. Persistence with therapy among patients treated with warfarin for atrial fibrillation. Arch Intern Med 2012, 172:1687-1689.
2. Medline Plus: Warfarin [https://medlineplus.gov/druginfo/meds/a682277.html]
3. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003, 139:893-900.
4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014, 64:e1-76.
5. Gomez-Outes A, Lecumberri R, Suarez-Gea ML, et al. Case Fatality Rates of Recurrent Thromboembolism and Bleeding in Patients Receiving Direct Oral Anticoagulants for the Initial and Extended Treatment of Venous Thromboembolism: A Systematic Review. J Cardiovasc Pharmacol Ther 2015, 20:490-500.
6. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014, 124:2450-2458.
7. Fuhrman J, Singer M. Improved Cardiovascular Parameter With a Nutrient-Dense, Plant-Rich Diet-Style: A Patient Survey With Illustrative Cases. Am J Lifestyle Med 2015.
Joel Fuhrman, M.D. is a board-certified family physician, six-time New York Times bestselling author and internationally recognized expert on nutrition and natural healing, who specializes in preventing and reversing disease through nutritional methods. Dr. Fuhrman coined the term “Nutritarian” to describe his longevity-promoting, nutrient dense, plant-rich eating style.
For over 25 years, Dr. Fuhrman has shown that it is possible to achieve sustainable weight loss and reverse heart disease, diabetes and many other illnesses using smart nutrition. In his medical practice, and through his books and PBS television specials, he continues to bring this life-saving message to hundreds of thousands of people around the world.
Comments (0):
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Mirty
01/10/2017 04:48 PM
Thank you so much for this post of yours. I have been taking Warfarin because of an atrial fibrillation, I am supposed to stop taking it next March, more or less, and I am looking forward for it! Of course no cause of that atrial fibrillation event has been detected yet, as it usually happens. I can just hope it is not going to happen again! I am 52.
katmcc
01/10/2017 05:17 PM
I was diagnosed with A-Fib a couple of months ago. Have been a nutritarian for almost 5 yrs. All my blood tests (lipids included) are low normal range except platelets that are way below normal. My regular doc put me on a tiny dose of a beta blocker. Some side effects but my heart has stopped pounding when fatigued.
She sent me to a Cardiologist who was neither impressed with my diet, my blood results, my weight within normal range or anything else...She just wanted to force me to take a blood thinner. I declined after pointing out the risks I worried about. A week or so later I decided to take a daily baby aspirin Is there anything that can be done to reverse A-fib?
jryates replies:
01/10/2017 06:00 PM
Have you considered ablation of the heart? My wife was in full time afib and ablation delivered her from the malady. At times she has short relapses and Dr demands her to stay on warfarin but for the most part her afib is gone.
Heidi P replies:
01/10/2017 06:09 PM
Per Dr. Fuhrman "Ablation is an option, but it does not slow the damage from improper diet, which continues degrading the heart. A nutritarian diet is the most effective way to extend lifespan, and in the process it often resolves atrial fibrillation. "
This reply was last edited on 01/13/2017 05:38 PM
cfleming
01/10/2017 05:38 PM
I was so glad to read the article. I've just had Eliquis prescribed because I have a small clots in each lung I was stressed out because I thought I had to give up my dark greens.I'my going to be consistent and continue my nutrient rich life style
WHAT A RELIEF!!
molardoc
01/10/2017 05:47 PM
I passed out from afib attack 1.5 years ago. Doc switched me to Flecianide 100mg 2xday. Not one attack since, but it could happen. Been on warf for 10 years for afib. I monitor my own INR at home. Very stable.
jryates
01/10/2017 06:04 PM
This is a wonderful, comprehensive evaluation that should give a lot of hope to patients. I have been on warfarin for many years and can't safely go off due to having two pulmonary embolii with no diagnosis as to the cause. I would dearly love to not take warfarin but the risk is too great. Thanks for this! I am 80 now.
aimar
01/10/2017 07:18 PM
I taking a baby aspirin everyday which is 80mg. for blood thining. I suppose i should cut back on that because i into a nutritarin diet where i eat a huge amount of salad greens and lots of green produce every day. I also think i getting extra K vitamins eating fermented foods i make using Dr. Mercola's starter which he claims increases the K vitamins in fermented foods. I will talk with my primary doctor who gets most his patients on a baby aspirin every day.
dharr47
01/11/2017 12:21 AM
Thank you for this interesting post. My son has been on daily warfarin for 20 years, but it is due to heriditary protein C deficiency that runs in his dad's family. Other newer drugs do not seem to be tested on persons with this heriditary blood disorder. He was diagnosed when he was young and developed clots in his leg, and a wise doc took the family history and figured out specifically what to test for. He has been hospitalized twice. He wishes he could use the nutrarian diet becaused he loves to cook, but has run into problems because his INR will get too low or sometimes too high. We were in the emergency room just yesterday with an INR of 6.3. No doc seems to be interested in helping him eat better. However, the advice to avoid kale, spinach and collards is very helpful.
Transforming
01/11/2017 03:07 AM
What about Plavix and aspirin? Is it the same caution as the other medication mentioned?
Dr. Ferreri replies:
01/11/2017 12:09 PM
Vitamin K does not interfere with Plavix or aspirin.
JulieBBB
01/11/2017 12:32 PM
What about long term warfarin treatment for Wegeners disease.? It seems to be an autoimmune condition. Could this be treated with a nutritarian diet?
??
Dr. Ferreri replies:
01/16/2017 10:02 AM
From Dr. Fuhrman:
It may be possible to help Wegener’s patients with my autoimmune protocol (https://www.drfuhrman.com/learn/library/position-papers/1/autoimmune-diseases) and enable a better outcome. Many patients with Lupus have made recoveries and the diseases are related.
Since this disease is potentially fatal, the drug management still needs to be done by a rheumatologist specializing in this disorder.
The medications used for the disease can cause other secondary problems, and that is another reason why it is critical to combine medical treatment with a strict nutritarian diet to lessen the side effects and morbidity of treatment and to lessen the amount of treatment required. Over time, if improvement is evident, medication can be reduced.
Jeremiah63
01/11/2017 06:09 PM
Wow! This information has thrown me for a loop. My daughter has just been taken off warfrin and put on Eliquis. She has had other medicines as well. I think her doctors are just experimenting with different kinds of blood thinners. She has had blood clots twice, transfusions twice and one infusion. This article is both alarming and informative, however we don't know where or how to get help. Is there a doctor in Atlanta who specialize in this area? We want to follow Dr. Furhman's lead and advice. Please respond.
Nancy L
01/18/2017 08:10 PM
This article, is just what I needed. I knew to keep my green consumption even, so as not to affect the warfin, but, I had a blood clot at 49, with no identiyable cause (except high cholestrol). Was on warfin for one year, but the last 4 years, just baby asprin 2, 81 mg. As I eat healthier and the Cholestol goes into a healthy range, will I ever get ti eat dark green leafy vegetables again?
Twosiam
09/20/2017 08:02 AM
I've been vegan for 2.5 years but only cut out the vegan junk food for the last 9 months. I'm reliably nutrairian now but still have a lot of weight to lose and only do moderate exercise. I'm 65 and have afib but never had an embolism or clot. I take Dilitiazem for the afib but after a recent episode of afib that sent me to the ER, my cardiologist is pushing me to take Warfarin. The statistics of how much it helps prevent stroke beyond a baby aspirin seem really weak to me and I love growing and eating collards. What factors should I consider in making a decision whether or not to take this drug?
Noniee replies:
02/24/2018 09:38 PM
LooseBox
06/01/2018 09:23 AM
Want to follow suitable diet but have an unbelievable amount of stents......On Clopidogrel and aspirin daily. Low Vit D but okay when summer comes, with apparent osteoporosis..................I adore salads and greens and just about to upgrade my reasonable diet.......but concerned about Vit K uptake. Any suggestions welcome. Thank you
sunnyk57
11/13/2018 03:03 PM
Hi, I have been reading the interesting comments on diets with vitamin k containing vegetables while on warfarin, and other medications. Most people seem to be on warfarin for afib/clotting concerns. What would be your advice for those on warfarin and aspirin who have an artificial heart valve? Also, is it possible for those who have an artificial valve to take one of the newer medications that don't interfere with warfarin? I also miss the greens I used to love. Thanks for your help. | {
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Passiflora (Passiflora incarnata L.)
Jun 15, 2023
Passiflora incarnata flor sedativo
Nomes comuns Wild Passion Flower, Maypop (EN), Passiflore (FR), Flor-da-paixão, Maracujazeiro (PT), Passion fruit (Hindi)
Sânscrito Mamataphala,
Nome botânico Passiflora incarnata L. (Passifloraceae)
Parte utilizada Partes aéreas
Distribuição geográfica e habitat – A Passiflora incarnata é uma planta nativa do leste e sul da América do Norte. Cresce nos campos, beiras de estradas, cercas e matas abertas, savanas, pastagens, dunas, em vários tipos de solo e em altitudes até 1.000 metros. Esta e outras espécies da mesma família são amplamente cultivadas pelos seus frutos comestíveis, enquanto outras são cultivadas como ornamentais graças às suas flores espetaculares. É uma trepadeira lenhosa, perene, que pode crescer até 9 m de altura, as folhas são trilobadas, dentadas, de um verde profundo e brilhante, o caule é arroxeado. As flores são perfumadas, roxas por fora e brancas por dentro, os frutos, doces e aromáticos, são em forma de bola ou ovóides, roxos ou amarelo-esverdeados.
A palavra Passiflora vem da palavra latina “Passio” porque em 1529, os conquistadores espanhóis descreveram suas flores como símbolos da “paixão de Cristo”.
Utilização – A Passiflora incarnata é uma planta há muito usada pelos nativos americanos. Os Cherokee do Tennessee designam-na de ocoee; o rio Ocoee e o vale recebem o nome desta planta, que é a flor silvestre do estado do Tennessee. Há milhares de anos que esta planta é um alimento básico e uma planta medicinal para aquela tribo.
Tem um longo historial de utilização na medicina tradicional à base de plantas para o tratamento de insónia e ansiedade na Europa, e tem sido usado como chá sedativo na América do Norte. Além disso, esta planta tem sido usada para fins analgésicos, antiespasmódicos, antiasmáticos, vermífugos e sedativos no Brasil; como sedativo e narcótico no Iraque; e para o tratamento de distúrbios como dismenorreia, epilepsia, insónia, neurose e neuralgia na Turquia. Na Polónia, esta planta tem sido usada para tratar a histeria e neurastenia; na América, tem sido usado para tratar diarreia, dismenorreia, neuralgia, queimaduras, hemorroidas e insónia ;para curar indivíduos afetados por dependência de opiáceos na Índia.
De acordo com a Comissão E do Conselho Consultivo Científico do Instituto Federal do Medicamento e dos Dispositivos Médicos Alemão, a Passiflora incarnata está indicada para irritabilidade, distúrbios do sono e agitação nervosa e no British Herbal Compendium para tratamento de casos de dismenorreia, nevralgia e taquicardia nervosa
Utilização tradicional em Ayurveda– No âmbito da Medicina Ayurvédica, esta planta é mencionada nos escritos médicos antigos como um apoio promissor para a impotência masculina, declínio na libido em mulheres pósmenopausa, irregularidades menstruais. Neste contexto, é ainda uma das plantas utilizadas em diversas fórmulas como sedativo, ansiolítico e hipotensor.
Rasa (sabor): amargo Virya (energia): arrefece
Vipaka (efeito pós-digestivo): picante
Doshas: aumenta Vata e reduz Pitta e Kapha
Nota importante: A informação que levamos até si é elaborada com o maior cuidado e rigor, No entanto, com a mesma não se pretende diagnosticar, tratar, curar ou prevenir qualquer doença e a mesma não substitui a avaliação e diagnóstico efetuados por um Profissional de Saúde.
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-2,381,057,098,102,156,300 | Moon Diet for Weight Loss – Truth or Delusion?
Лунна диета{:en]Moon diet | LuckyFit
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If looked for ways to lose a few kilos in a short period of time at least once, you have probably come across the so called moon diet for weight loss on the Internet. We suppose you wonder whether this diet is really effective or it is just another diet which has become a sensation for a while and has no effect at all.
Moon diet for weight loss | LuckyFit
What kind of diet is it and why is it called a “moon diet”?
The influence of the Moon on the mental and physiological status of people has been known since ancient times and is described in the literature of almost all peoples of the world. Modern science also seeks and finds many confirmations and new facts about the influence of this celestial body on all living organisms.
It turns out that if we know the main phenomena that occur in a particular phase of the Moon, we can control almost all processes in our lives – from the creation of a family and treatment of serious diseases to weight loss.
The moon diet is a detox diet based on the phases of the Moon (new moon, first quarter, full moon and last quarter). This diet is followed for a very short period of time (24 hours only) according to the lunar phase cycle and this way your body gets rid of the accumulated harmful toxins naturally.
Why precisely use Moon phases?
Moon phases have an electromagnetic effect on water. Moon phases affect ocean and sea tides but they can also have an effect on the human body as it contains 70% water.
The moon’s gravitational pull is strongest when it reaches a new phase and if just then you follow the moon diet, you can lose between 1 and 3 kilos of your weight.
How to follow this diet?
To put it simply, if you follow a moon diet you don’t eat any solid food and consume only liquids within 24 hours. In order to be effective, this diet must be followed in the first 24 hours when the moon enters a new phase.
Juices for moon diet | LuckyFit
What does this mean?
We already mentioned that the phases of the moon are four in total. We also mentioned that the Moon’s gravitation pull is strong during these phases, so then it has the strongest effect on our bodies. This is why it is so important to start the diet exactly at the time when the natural satellite of the Moon enters a new phase and stop it at the same hour the next day.
Based on the peculiarities of the physiological processes that occur in our bodies in each moon phase, the moon diet achieves harmony between natural phenomena and the behavior of human nutrition which results in natural weight loss, cleansing and healing of the body.
The moon diet can be followed only one day per month (at full moon), twice a month (at new moon and full moon) or at all 4 lunar phases (i.e. 4 times per month for 24 hours).
What can you consume during this diet and what not?
You should consume no solid food but only liquids within 24 hours. To increase the effect of this diet, it is good to consume a lot of water (at least 3-4 litres per day). Besides water, you can have freshly prepared vegetable or fruit juices (but with no other additives such as salt or sugar).
Vegetable and fruit juices are recommended as they provide the body with additional nutrients. Tea consumption is allowed but with no added flavors such as sugar or honey).
You are not allowed to drink liquids containing sugar, fat or salt and this means you can’t consume alcohol, carbonated beverages, milk, coffee / tea with sugar.
Why exactly moon diet?
Because this is a wonderful way to free your body of accumulated toxins and the water that is retained due to improper and unhealthy diet, stress and so many other reasons. The moon diet is a perfect way to regularly let your body get rid of all harmful elements and gradually move to a healthy diet.
The truth is that by following a 24-hour liquid-only diet you stimulate kidney function, eliminate toxins, strengthen your immune system and the body gets rid of excess water.
By following the moon diet for 24 hours only, you will lose between 1 and 3 kilos of your weight and if the detox regime is followed once at each of the 4 moon phases, the effect will be even greater.
If you follow the liquid diet, efficiency is really guaranteed but it is good to know that the lost kilograms are mainly due to detoxification of the body and if after this diet you go back to your usual diet again, the effect of the diet will be temporary. Therefore, experts advise that after a 24-hour fasting you should gradually go to a normal diet by eating light food at first (vegetable soups, rice with vegetables, fruit salads, fish, lean meat, etc.).
After the 24-hour consumption of liquids, it is good to do exercise, improve your eating habits (take less fat and sugar and drink plenty of water) for an even greater effect.
Relaxed woman | LuckyFit
Does this diet have real health benefits?
Actually, there are real benefits of this weight-loss diet and it is not just because you lose some kilos in a short period of time. The truth is that this diet is a perfect way to detoxify your body which needs to get rid of the accumulated toxins and improve the function of the liver, the stomach and the digestive system. In addition:
• This diet is very easy (and cheap) to follow;
• If you strictly stick to the diet, weight loss is guaranteed;
• It does not prevent you in any way from performing your usual duties (you don’t have to count calories or consume food under a given diet plan);
• You can combine it with physical exercise to achieve a greater effect.
Does the moon diet have any contraindications?
You are not recommended to follow this weight-loss diet for more than 24 hours as if you keep fasting long, the lack of protein and carbohydrates may lead to serious health complications. The diet is not recommended for people who have blood pressure problems, metabolic disorders and for pregnant women and nursing mothers. | {
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-5,426,470,045,682,819,000 | Methylenomycins
Structural Formula Vector Image
Title: Methylenomycins
Literature References: Members of a family of cyclopentenoid antibiotics related structurally to sarkomycins, q.v., and having in vitro activity vs gram-positive and gram-negative organisms. Isoln from Streptomyces violaceoruber, physical, chemical, biological properties: M. Arai et al., JP Kokai 73 19796 (1973 to Sankyo), C.A. 78, 157861 (1973); T. Haneishi et al., J. Antibiot. 27, 386 (1974). Structures of methylenomycins A and B: eidem, ibid. 393. Crystal and molecular structure of (±)-A: B. H. Toder, A. B. Smith, J. Cryst. Mol. Struct. 8, 1 (1979). Stereospecific total synthesis of (±)-A: R. M. Scarborough et al., J. Am. Chem. Soc. 99, 7085 (1977); eidem, ibid. 102, 3904 (1980); and absolute configuration: K. Sakai et al., Tetrahedron Lett. 1979, 2365. Stereospecific total synthesis and absolute configuration of (+)-A: J. Jernow et al., J. Org. Chem. 44, 4210 (1979). Revised structure and total synthesis of B: eidem, ibid. 4212. Concise synthesis of B: M. Mikolajczyk, R. Zurawinski, Synlett 8, 575 (1991). Prepn of analogs of A and structure-activity correlations: T. Haneishi et al., J. Antibiot. 27, 400 (1974). Toxicity: eidem, ibid. 386. Methylenomycin A is the first example of an antibiotic in which all information required for synthesis is carried by a plasmid, SCP1: L. F. Wright, D. A. Hopwood, J. Gen. Microbiol. 95, 96 (1976). Review of biosynthesis: U. Hornemann, D. A. Hopwood, Antibiotics vol. IV, J. W. Corcoran, Ed. (Springer-Verlag, New York, 1981) pp 123-131. General review: A. Terehara et al., Heterocycles 13, 353-371 (1979).
Derivative Type: Methylenomycin A
CAS Registry Number: 52775-76-5
CAS Name: [1S-(1a,2a,5a)]-1,5-Dimethyl-3-methylene-4-oxo-6-oxabicyclo[3.1.0]hexane-2-carboxylic acid
Molecular Formula: C9H10O4
Molecular Weight: 182.17
Percent Composition: C 59.34%, H 5.53%, O 35.13%
Properties: Colorless crystals from chloroform/carbon tetrachloride, mp 115° (dec). mp of the (±)-form: 88.5-89°; after subl (70-75°, 0.025 mm Hg), 107.5-108°. [a]D20 +42.3° (c = 1 in chloroform). uv max (methanol): 224 nm (e 6300). Sol in benzene, chloroform, ethyl acetate, acetone, methanol, water. Slightly sol in n-hexane, CCl4. pKa¢ 3.65. LD50 in mice (mg/kg): 1500 orally, 75 i.p. (Haneishi).
Melting point: mp 115° (dec); mp of the (±)-form: 88.5-89°
pKa: pKa¢ 3.65
Optical Rotation: [a]D20 +42.3° (c = 1 in chloroform)
Absorption maximum: uv max (methanol): 224 nm (e 6300)
Toxicity data: LD50 in mice (mg/kg): 1500 orally, 75 i.p. (Haneishi)
Derivative Type: Methylenomycin B
CAS Registry Number: 52775-77-6
CAS Name: 2,3-Dimethyl-5-methylene-2-cyclopenten-1-one
Molecular Formula: C8H10O
Molecular Weight: 122.16
Percent Composition: C 78.66%, H 8.25%, O 13.10%
Properties: Neutral colorless oil. uv max (methanol): 240 nm (e 7650). Sol in ether, benzene, chloroform, ethyl acetate, acetone, alcohols. Slightly sol in n-hexane, petr ether. LD50 in mice (mg/kg): 260 orally, 245 i.p. (Haneishi).
Absorption maximum: uv max (methanol): 240 nm (e 7650)
Toxicity data: LD50 in mice (mg/kg): 260 orally, 245 i.p. (Haneishi)
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p-BromoacetophenoneSilver SelenideAllopregnane-3β,17α,20α-triolRhenium Trioxide
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"rps_doc_openwebtext_importance_length_correction": -285.59246826171875,
"rps_doc_wikipedia_importance": -221.17987060546875,
"rps_doc_wikipedia_importance_length_correction": -221.17987060546875
},
"fasttext": {
"dclm": 0.019352320581674576,
"english": 0.5810636878013611,
"fineweb_edu_approx": 2.4703783988952637,
"eai_general_math": 0.5112550854682922,
"eai_open_web_math": 0.5504533648490906,
"eai_web_code": 0.002364099957048893
}
} | {
"free_decimal_correspondence": {
"primary": {
"code": "547.0",
"labels": {
"level_1": "Science and Natural history",
"level_2": "Chemistry",
"level_3": "Chemistry, Organic"
}
},
"secondary": {
"code": "615.0",
"labels": {
"level_1": "Industrial arts, Technology, and Engineering",
"level_2": "Medicine",
"level_3": "Materia medica, Drugs, and Pharmacy"
}
}
},
"bloom_cognitive_process": {
"primary": {
"code": "2",
"label": "Understand"
},
"secondary": {
"code": "3",
"label": "Apply"
}
},
"bloom_knowledge_domain": {
"primary": {
"code": "1",
"label": "Factual"
},
"secondary": {
"code": "2",
"label": "Conceptual"
}
},
"document_type_v1": {
"primary": {
"code": "3",
"label": "Reference/Encyclopedic/Educational"
},
"secondary": {
"code": "-1",
"label": "Abstain"
}
},
"extraction_artifacts": {
"primary": {
"code": "0",
"label": "No Artifacts"
},
"secondary": {
"code": "3",
"label": "Irrelevant Content"
}
},
"missing_content": {
"primary": {
"code": "0",
"label": "No missing content"
},
"secondary": {
"code": "4",
"label": "Missing Images or Figures"
}
},
"document_type_v2": {
"primary": {
"code": "8",
"label": "Documentation"
},
"secondary": {
"code": "10",
"label": "Knowledge Article"
}
},
"reasoning_depth": {
"primary": {
"code": "1",
"label": "No Reasoning"
},
"secondary": {
"code": "2",
"label": "Basic Reasoning"
}
},
"technical_correctness": {
"primary": {
"code": "4",
"label": "Highly Correct"
},
"secondary": {
"code": "5",
"label": "Exceptionally Correct"
}
},
"education_level": {
"primary": {
"code": "4",
"label": "Graduate/Expert Level"
},
"secondary": {
"code": "3",
"label": "Undergraduate Level"
}
}
} | b755ed28a90d11d590ef646404f4afc5 |
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