Chronic Neck Pain : Postural Causes and A Unique Fix
Living An Anti-Inflammatory Life
What's the use of having a rare disease....if you can't learn from it?
Exercise, a Simple Diet, Managing Stress, and Sufficient Sleep: four non-drug treatments
that make a huge difference to your health.
You hear a lot about connections between chronic inflammation and chronic illness, and also about foods and supplements that fight inflammation, but not much about the cells that release the stuff—the molecules that directly cause inflammation and also signal other immune cells to gather and sustain that inflammation. Among those cell types are Mast Cells, which are found throughout the body, especially in tissues of the skin and gastrointestinal tract that interface with the outside environment, which includes the food/drink we take into out bodies and the air we breath with our lungs. Mast cells are among the first immune cells to detect tissue damage from injury, infection or other conditions such as allergy, ingestion of toxins, noxious chemical exposures, UV irradiation etc., and they respond by releasing inflammatory mediators that increase blood flow to the area, attract and activate other immune cells that help clear away infected/damaged cells, and start the repair process. Mast cells make over 50 kinds of inflammatory mediators. Some they make as needed such as cytokines, leukotrienes, prostaglandins, growth factors. Others are premade and stored in granules that crowd the mast cell's cytoplasm. These mediators include large amounts of histamine, proteases that break apart proteins, peroxidases that produce reactive oxygen molecules to fight infections, and lipases that break apart fats. (see the Biotrend Review: Mast Cell Function in Physiology–page 2 for a more complete list) Mast cells release their granule contents either by wholesale dumping/ degranulation or by slow leakage of specific mediators. Histamine, the most immediately dangerous mediator, is the cause of various degrees of anaphylaxis in those with severe allergies, and those with too many mast cells (mastocytosis) or have hyper-sensitive activated mast cells (MCAS/MCAD). Anaphylaxis is a systemic disorder with symptoms that affect more than 2 body systems such as skin (flushing or hives)+ cardiovascular (very low or very high blood pressure, abnormal heart rhythm, chest pain) + gastrointestinal (diarrhea, cramps) or urinary (pressure diuresis, burning) or neurological (headache, brain fog, dizziness) and others. The most severe version of anaphylaxis is anaphylactic shock caused by cardiovascular collapse.I have a Mast Cell Activation Disorder. Some of my mast cells are hypersensitive and when triggered they release large amounts of inflammatory mediators that effect my entire body. The symptoms include itchy skin, facial flushing, red eyes, diarrhea, heartburn, polyuria, heartburn, very low or very high blood pressure, high heart rate, mind going a-mile-a-minute, anxiety, ears buzzing (tinnitis), muscle twitching, leg spasms at night etc. The triggers are often substances or conditions that cause normal mast cells to release inflammatory mediators, but in most people the effects remain local and don't amplify into a body-wide, systemic reaction. (e.g. aspirin is a known mast cell degranulator but in a normal person stomach upset may be the only effect. For me, one aspirin would cause anaphylactic shock.) What follows are factors that help prevent my mast cells from triggering, and over the past couple years have actually made them less sensitive and more like a normal person's mast cells; these factors happen to correlate with well-known components of a healthy lifestyle.
The body like any machine, must be used in a way that keeps it
running smoothly, efficiently, and prevents it from degrading.
1. Get Plenty of Mild to Moderate Exercise: Helps to strengthen skeletal and heart muscle, improves immunity, decreases inflammation, helps to relax and to resist stress, helps with sleep, improves brain function, decreases cardiovascular risk factors, is associated with decreased risk of death and is as effective as many drug interventions in prevention of cardiovascular disease and diabetes. (ref) And reduces appetite.(ref)
• More positive effects of exercise: Sitting for hours weakens muscles, bones and hearts. Frequent moderate exercise (5 minute intervals to 60 mins sustained at 40-60% of maximal aerobic capacity) helps strengthen the body as well as the immune system. A 2012 study in the journal, Circulation, reported that physically active participants (at least 2.5 hr. per week of moderate to vigorous physical activity as assessed by questionnaire) at the start of the study had lower levels of inflammatory CRP (C-reactive protein) and IL-6 than sedentary participants, and over a ten year period lower levels were maintained. Increases in physical activity decreased inflammatory levels even more. See "Physical Activity and Inflammatory Markers Over 10 Years: Follow-Up in Men and Women from the Whitehall II Cohort Study" Hamer et al. Also see a recent study, Intensity versus duration of physical activity: implications for the metabolic syndrome. A prospective cohort study by Laursen et al. (2012). They reported that brisk walking speed reduced the risk of Metabolic Syndrome more effectively than longer, slower walks.
• Negative effects of too much exercise: But as often happens, too much of a good thing can have negative effects. Repeated bouts of very strenuous exercise can negatively effect the immune system. (see Exercise and the Immune System by Brolinson et al., Is it Time to Skip the Gym? by Robert Mocharla, MD, and Overtraining Syndrome by R. Budgett,) Dealing with chronic physical stress requires lots of energy both for metabolism and repair. But optimal maintenance of the immune system also takes a lot of energy. Immune cells such as white blood cells have a high turnover rate and constantly need to be replaced. Immune cells themselves are very metabolically active, making and storing large amounts of inflammatory mediators, or producing large amounts of immune-related products such as immunoglobulins (e.g. antibodies). Energy and resources being limited, the body must choose between spending it on the more immediate danger of physical stress, or the relatively long term need for an optimal immune system. Generally the immune system loses. The adrenals pump out cortisol in response to stress and inhibits the immune system.
Because of hypersensitive mast cells, I've often had episodes of inflammatory mediator release from aerobic exercise. Even in people with normal mast cells, the onset of vigorous exercise is accompanied by large but short-lived releases of cytokines from hard working tissues such as muscle and perhaps even lung tissue due to the drying and irritation of mucous membrane from rapid breathing. (I had a moderate reaction after doing several minutes of rapid "yogi" breathing, something I won't do again.) But even so, regular exercise in most people is consistently associated with lower levels of inflammatory mediators and reduced fatty tissue inflammation. Luckily, I found a way to exercise without the mast cell problems. In the article, "Exercise induced Anaphylaxis: A Serious but Preventable Disorder" by Miller et. al., they advise doing strenuous exercise before eating in the morning or five hours after eating. Timing meals and exercise in this way has allowed me to do 20 minutes workouts on an exercise-cycle and take a twice weekly physical fitness class that includes a half hour of step aerobics.
• Exercise as a form of hormesis: Hormesis is a stress placed on the body that has a beneficial effect at lower doses, but a toxic effect at higher doses. Following a low dose stress, cells increase their production of protective proteins such as growth factors and antioxidant enzymes. Examples of hormesis includes moderate exercise, dietary restriction, low doses of certain phytochemicals such as polyphenols, sulforaphnes and curcumin, and also occasional low level ionizing radiation (increase DNA repair efficiency). (see Hormesis Defined by Mark Mattson) Hormetic effects generally involve intermittent mild to moderate stress, but not chronic stress from which the body does not have time to recover. Also see Gettingstronger.org, "...a blog about the philosophy of Hormetism, based on the application of progressive, intermittent stress to... grow stronger physically, mentally and emotionally."
Increasing physical activity while simultaneously improving the diet helps with adherence to the diet. See Starting with two health behaviors may be better than one; and the abstract of original paper: Behavioral Impacts of Sequentially versus Simultaneously Delivered Dietary Plus Physical Activity Interventions: the CALM Trial by King et al (2013)
The body, like a car, should be fed fuel that doesn't gunk up the carburetor.
2. Limit or Avoid Certain Foods Depending on the Cause and the Severity of Reaction: If specific foods cause heartburn, abdominal distress or other reactions such as fatigue, headaches, redness of the eyes and/or swelling of eyelids or the delicate tissues beneath, leg spasms/cramps at night, heart palpitations etc., your gastrointestinal mast cells may be reacting by releasing inflammatory mediators. Don't just medicate the reaction, eliminate the food, at least temporarily. If the reaction is a mild one and the food very nutritious, perhaps try adding the food back at a later time, gradually increasing the amount, as long as there is no further reaction. For moderate to severe reactions consult an M.D. For multiple food intolerances, an elimination diet* is necessary:
"The only reliable way of finding out which food chemicals may be contributing to your symptoms is to eliminate all possible trigger substances at the same time, wait for symptoms to subside, and then reintroduce them one-by-one according to a systematic challenge protocol." [from page 19 of the RPAH Elimination Diet Handbook reproduced in part at http://allergy.net.au/, click on ‘Pages Navigation Menu,’ then click on ‘handbook’*Having a limited diet calls for special care. Some foods and supplements interfere with bioavailabilty of other nutrients and supplements. Check out what interferes with what on my Anti-Nutrients page, which is still under construction.
• Problem Foods: Though not everyone has the same ones. These may include:
- Foods you are allergic to by skin prick or RAST testing; the most common food allergies are to eggs, peanuts, tree nuts, shellfish, milk and wheat.
- Milk for adults who lack the enzyme, lactase, which enables digestion of lactose milk sugar. May be a cause of some cases of IBS. ref ref [This is a lifetime problem, which most likely cannot be overcome.]
- Spicy Foods, depending on the spice, and especially if it causes heartburn or stomach upset. Many spices directly degranulate mast cells. (these include all kinds of peppers, paprika, curry, cinnamon, cloves, anise, nutmeg)
- Histamine and –amine containing foods: heat-stable breakdown products of amino acids found in aged, ripened cheeses; processed, smoked and fermented meats such as sausages, luncheon meats, salami; shell fish, fin fish (if not gutted immediately and eaten quickly), canned fish, pickled and marinated foods, fermented foods such as soy sauce. sauerkraut. and may include yogurt (depends on bacterial culture used), alcohol, any food left too long at room temperature or stored too long in the refrigerator (Bacteria and fungi break down protein into amino acids and form histamine (from the amino acid histadine) and other bio-active amines), some fruits and vegetables such as bananas, avocados, pumpkin, eggplant and spinach; beverages such as red wine, beer, cider) (See Histamine-Restricted Diet at the International Chronic Urticaria Society website. Also see this U.K. Histamine Intolerance Website. (Problems with access to this website? Click here for the Histamine Intolerance Food list.)] [Seafood-related scrombotoxin poisoning from fish such as tuna, mahi-mahi etc is caused by high concentrations of histamine and other biogenic-amines formed when killed fish are kept at elevated temperatures too long.]
- Sulfur-containing glucosinolates in vegetables such as those in the cabbage/cruciferous/brassica family (for those with sulfur, sulfite, sulfate sensitivity or thyroid problems - if you have goiter or are taking thyroid replacement medication consult your physician about eating raw cruciferous vegetables.) Glucosinolates are water soluble so boiling the vegetables and discarding the cook water significantly reduces levels. Steaming, baking, and roasting do not reduce levels. see: Effect of storage, processing and cooking on glucosinolate content of Brassica vegetables, by Song and Thornalley. Glucosinolates are broken down by an enzyme that is released when the plant is cut or chewed. The breakdown products are absorbed by the body. These include isothiocyanates, which compete with iodine for uptake into the thyroid; and goitrins, which interfere with thyroxin production in the thyroid. Cooking heat destroys the plant enzyme so that symptomatic hypothyroid and goiter are generally only a problem when large amounts of raw brassica vegetables are eaten. However, the unchanged glucosinolate can still be broken down by intestinal bacteria and small amounts of thyroid toxin can be absorbed through the large intestine. See comprehensive information and table of Glucosinolate Content of Selected Cruciferous Vegetables: Isothiocyanates: Linus Pauling Institute. Epidemiological studies report lower risk of cancer with higher intake. For brief overview see Glucosinolates from Brassica vegetables: risks and benefits by Gary Williamson, University of Leeds, UK. [I have extreme sulfite/sulfate intolerance but have recently been able to eat cauliflower and broccoli with no reaction at all. In my case, at least, intolerance to cruciferous veggies was not permanent.]
- Foods that release histamine from mast cells:
– fruits such as most citrus, strawberries, papaya, pineapple, tomato, (fruits are more likely to contain natural salicylates and benzoates, both of which degranulate mast cells.);
– vegetables such as spinach (very high in oxalates, and some of those have formed irritating, needle-like crystals called raphides),
– wheat germ, raw egg white, kidney and pinto beans (contain toxic lectins, which are largely removed from raw beans by long soaking, discard of soak water, and boiling until well done) soy beans (contain multiple toxic anti-nutrients) and the solanacea family: potatoes, tomatoes, peppers ref
– vegetable oils high in salicylates such as olive oil and flax oil; coffee, tea, cocoa, alcohol, mint flavorings (salicylates),
– vinegar and foods containing vinegar such as ketchup, barbecue sauce;
– certain food additives (benzoates, food dyes like tartrazine, nitrites, sulfites, sulfates). See salicylatesensitivity.com for a Low Salicylate Food Guide
- Foods that block the histamine metabolizing enzyme (diamine oxidase-DAO) that is released by cells lining the gut and responsible for breaking down histamine in the food we eat and the histamine made by the bacteria living in our large intestine; includes alcohol, tea, and cocoa. (Some medicines can block DAO and also another enzyme, Histamine N-Methyl Transferase (HMT) which is present within cells. Such meds increase levels of histamine. See the List)
- Foods high in refined carbohydrate, especially those high in simple sugars, and includes honey, candy, dates, dried fruits and to a lesser degree many fruits
When I was able to eat sugary foods (can't now, due to my MCAD) I'd quickly become fatigued. The older I got the worse I'd feel.
– In the following study reported in "Effects of Dietary Composition on Energy Expenditure During Weight-Loss Maintenance" a diet high in carbohydrates (60% of calories) and low in fat (20%) reduced resting and total energy expenditure, and had unfavorable effects on metabolic syndrome components. Better was a lower percentage of carbohydrates (40%) and higher fat (40% of calories) diet, which increased resting and total energy expenditure and more favorably effected metabolic syndrome components. The very low carbohydrate (10%), high fat (60%) diet increased resting energy expenditure the most and improved metabolic syndrome components the most, but increased cortisol (stress-related) and C-reactive protein levels (more inflammation). [note: A moderate fat intake is important for absorption of important fat-soluble vitamins such as A, D, E and K. (My vitamin D levels increased to normal levels when I changed from low fat to whole milk)]
— Does too much sugar in the diet cause diabetes? It might; at least that's what population level data suggests. See the article: The Relationship of Sugar to Population-Level Diabetes Prevalence: An Econometric Analysis of Repeated Cross-Sectional Data by Basu et al. "Duration and degree of sugar exposure correlated significantly with diabetes prevalence in a dose-dependent manner, while declines in sugar exposure correlated with significant subsequent declines in diabetes rates independently of other socioeconomic, dietary and obesity prevalence changes. Differences in sugar availability statistically explain variations in diabetes prevalence rates at a population level that are not explained by physical activity, overweight or obesity."
— Diets high in simple sugars may contribute to endogenous production of oxalates and thus to calcium oxalate kidney stones. Sugars are a major source of glyoxal, which converts to glycolate via the glyoxalase system and requires glutathione. Glycolate appears to lead to oxalate – a problem for those who form calcium-oxalate kidney stones. ref Analysis from the Nurses Health Study II has shown that sugar increased kidney stone risk in young women by more than 30% ref.
- Foods that predispose to calcium-oxalate kidney stones (especially in those prone to forming kidney stones) and certain pain syndromes such as vulvar pain: Blood oxalate levels may be high in insulin resistance (ref), autism (ref, ref), and oxidative stress (ref). see Medscape article: "Oxalate in Renal Stone Disease"
— foods high in oxalates such as spinach, chocolate and most nuts (almonds are almost twice as high in oxalates as the next highest nut (cashews), ref)
— foods high in salt
— foods high in refined carbohydrates (see comprehensive Medscape article on Hyperoxaluria)
- Refined vegetable oils. Most of these contain large amounts of polyunsaturated fatty acids (PUFA), which undergo oxidation (turn rancid) in the presence of oxygen. PUFA oxidation speeds up at high higher temperature and is retarded at lower temperatures e.g. refrigeration. In the body PUFA undergo non-enzymatic lipid peroxidation to form various damaging oxidation products including glyoxal, which is converted to glycolate via the and then to oxalate—the excreted end product. Oxalate contributes to kidney stones in some. ref
- Fried, baked, roasted foods, all forms of dry heat, high temperature cooking. (I can only tolerate moist heat cooked foods. Baked or roasted chicken doesn't work for me, but slow simmered in water does). These foods promote formation of advanced glycation end products (AGEs) that directly bind to RAGE receptors on mast cells causing them to release inflammatory mediators. See the AGEs page for more information and refs. "Oral advanced glycation end products (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1" ref.
— Glyoxal, a precursor of AGEs is a highly reactive carbonyl molecule that is produced by several enzyme-independent pathways: spontaneous reaction of protein amino groups with reducing sugars, auto-oxidation of sugars, DNA oxidation, UV photo-damage, peroxidation of polyunsaturated fatty acids, conditions of oxidative stress and depletion of glutathione, and more. Glyoxal attacks amino groups of proteins, nucleotides, and lipids and is a strong carcinogen by Ames test and an in vitro genotoxin in mammalian cells. But only limited studies on carcinogenicity and birth defects.(review) ref Glyoxal plays a role in endogenous oxalate production in the body. "Glyoxal Formation and Its Role in Endogenous Oxalate Synthesis" ref Glyoxal is also found in fermented foods such as beer, wine, yogurt, soy sauce.
- Gluten-containing grains: wheat, rye, and barley. Gluten binds to and irritates the absorptive villi of the small intestine. Gluten increases intestinal permeability through zonulin signaling...more info
If you have a large number of food allergies or intolerances, ask your doctor for a referral to a registered dietician (not a nutritionist, who has no recognized credentials). For more detailed information on the variety of food intolerances see the Food Intolerances web page on this site.
•Desensitization: It may be possible to desensitize oneself to foods, supplements and medications that are important to health. Aspirin desensitization has been carried out on aspirin/nsaid sensitive asthma patients and also in mastocytosis patients, who over-produce prostaglandins, even though aspirin is a known degranulator of mast cells. See Rapid Desensitization for Hypersensitivity Reactions to Medications by Mariana Castells. Patients with various food allergies confirmed by skin testing have been desensitized using a standard protocol. See "Food Allergy: Oral Specific Desensitization by Nucera et al.
(I was able to desensitize myself to a Vit K supplement by starting with a dose of the powdered pill that did not elicit a reaction and slowly...very slowly... increased the amount over a month's time until I could tolerate one pill a day. [This vit K supplement had caused only a small reaction to begin with, so was a good candidate].)
Eating a wide variety of foods is probably important for maintaining a general state of tolerance to all kinds of food, especially those of plant origin. Lets face it, what plant wants to be eaten? Plants contain plenty of natural toxins/pesticides, without which they'd be quickly eaten into extinction by animals. What I did, in eliminating all foods I reacted too, even if the reaction was mild, may have worsened my intolerance as well as sensitized my body to other similar foods. The theory that living in a very clean environment doesn't present enough challenge to the immune system and causes it to turn on body and predispose us to autoimmune diseases, may be a similar phenomenon. For each individual food intolerance, the risks of reaction to that food should be weighed before totally eliminating it from the diet. I now believe that if a tiny amount of a food can be eaten without reaction then a gradual desensitization is possible. Of course one should only proceed under a doctor's care, especially if anaphylactic shock could result. Now I think that because I took the route of eliminating every food I had even the slightest reaction to, I not only ended up with three foods only, but my reactions to other foods - even those that are low in the substances I am sensitive too such as salicylates - became even more exaggerated.
— "Strictly avoiding allergenic foods has been an important strategy for protecting against allergic reactions, since even the smallest amount of an offending protein can cause symptoms to flare. However, this may prevent “natural immunotherapy,” whereby children are exposed to tiny amounts of food proteins over time so they can build tolerance. Some researchers have found that children are prone to outgrow certain allergies more quickly than others because they’re consistently exposed to the protein. ...Research is ongoing worldwide to determine how to induce tolerance. In the United States, researchers are using oral and sublingual immunotherapy..In some cases, an individual’s food allergy has returned when he or she didn’t consume the allergenic protein after a period of time. This suggests study participants didn’t achieve true tolerance and that researchers observed only a period of nonreactivity." See Outgrowing Food Allergies — Evidence Shows Multiple Factors Affect Outcome by Sherry Collins in Today's Dietitian.
— In the case of a food allergy that causes severe anaphylaxis. Any attempt at desensitization must be undertaken only with a doctor's care.
—Very importantly, certain intolerances such as in celiac disease, where gluten intake destroys the ability to absorb all nutrients, must be respected. Trying to reverse such an intolerance, especially one that have a genetic predisposition as in the case of celiac disease, is much too risky. I haven't seen any reports that that gluten desensitization has been attempted.
—Intolerances that are genetically determined can't be reversed. (e.g. a low functioning DAO gene for breakdown of histamine, deficiency of lactase, the enzyme that breaks down lactose, the sugar in milk). In those cases the best and healthiest route is avoidance unless a medicine or additive is available to make up for the missing genetic factor. (e.g. histaminase for histamine rich foods, lactase to break down lactose in milk and milk products)
Salt and High-Salt Foods: Studies show an increase in body-wide inflammation that could be one environmental reason for the increasing prevalence of autoimmune diseases. see abstracts of two articles published in the journal Nature in 2013: Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells by Kleinewietfeld et al. "mice fed with a high-salt diet develop a more severe form of EAE (Experimental autoimmune encephalomyelitis, is an animal model of M.S., Multiple Sclerosis).... Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells." And
Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1 by Wu et al. "We show here that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances TH17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. SGK1-deficient mice are resistant to EAE, owing to a defect in maintaining the TH17 phenotype."
—A study by Gaddy et al. (2013) shows that high salt intake and cagA proteins produced by H. pylori bacteria interact to increase stomach cancer risk (in gerbils). All the gerbils on a high salt diet and infected with normal H. pylori (cagA+) developed gastric cancer and higher levels of stomach inflammation. In contrast, 58% of H. pylori infected gerbils on a low salt diet developed gastric cancer and had less stomach inflammation.
—A study by Baudrand et al, (2013) High sodium intake is associated with increased glucocorticoid production (cortisol), insulin resistance and metabolic syndrome and a discussion of the article in Medpage Today.
—Dietary Salt Associated With MS Activity (2012)
—May increase incidence of calcium-oxalate kidney stones. High dietary sodium leads to less calcium reabsorption to the blood, leading to higher calcium excreted in urine. This excess calcium may bind to soluble oxalate in the kidney and predispose to calcium-oxalate stones. But the clinical studies are contradictory. ref
2.2 Ignore the deluge of daily contradictory news articles about salt, alcohol, sugar, other dietary substances and advice based on the latest, exciting, and perhaps counter-intuitive research findings. Maybe I am being overly paranoid but economic interests are so pervasive that we can't know for sure if an interesting or surprising news article about a dietary component or additive that's usually considered harmful, is actually fact or a positive spin by an advertising or public relations agency. Peer reviewed journal articles might be better, but even some of those may be tainted, as in the case of articles about pharmaceuticals that list well-known researchers as authors but are actually ghost-written, and planted in reputable medical journals to tout the benefits of new drugs or downplay side effects. (see Pharmageddon by David Healy, his shrill rant may be a turn-off, but some of the cases he cites are outrageous. Definition of pharmageddon: "the prospect of a world in which medicines and medicine produce more ill-health than health, and when medical progress does more harm than good")
See "Big Sugar's Sweet Little Lies," by Taubes and Couzens and There is no completely safe dose or form of alcohol by oncologist, Dr J. Salwitz, and in PLOS Medicine: Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews by Rastrollo et al. "...the best large randomized trials also support a direct association between SSB (sugar-sweetened beverage) consumption and weight gain or obesity." Conclusion: "Financial conflicts of interest may bias conclusions from SRs (published systematic reviews) on SSB (sugar-sweetened beverages) consumption and weight gain or obesity.
See this Essay in PLOS Medicine "Why Most Published Research Findings Are False" by John P. A. Ioannidis – Corollaries:
1) "The smaller the studies conducted in a scientific field, the less likely the research findings are to be true." 2) "The smaller the effect sizes in a scientific field, the less likely the research findings are to be true. e.g. Impact of smoking on cancer or cardiovascular disease (relative risks 3–20 x's) vs. genetic risk factors for multigenetic diseases (relative risks 1.1–1.5 x's)" 3) Research findings are more likely true when confirming pre-study odds, such as large phase III randomized controlled trials, or meta-analyses, than in hypothesis-generating experiments. 4) "The greater the flexibility in designs, definitions, outcomes, and analytical modes in a scientific field, the less likely the research findings are to be true. Flexibility increases the potential for transforming what would be “negative” results into “positive” results" due to bias" etc. 5) The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are to be true. 6) The hotter a scientific field (with more scientific teams involved), the less likely the research findings are to be true. Any new finding gets published fast to avoid being one-upped. But then the other teams try to confirm and refute as quickly as possible. "The term Proteus phenomenon has been coined to describe this phenomenon of rapidly alternating extreme research claims and extremely opposite refutations [ref]. Empirical evidence suggests that this sequence of extreme opposites is very common in molecular genetics."
See Who's Afraid of Peer Review? by John Bohannon. Different versions of a spoof research paper describing the anticancer properties of a chemical extracted from a lichen was sent to 304 open-access journals. More than half of the journals accepted the paper without noticing the very obvious flaws in experimental design and presentation of data. More than one third are based in India; the next largest base is the U.S. It was shocking that journals accepting the paper including ones published by Elsevier, Wolters Kluwer, and Sage. Of some comfort is that PLOS ONE, published by the Public Library of Science quickly rejected the paper on the basis of its scientific quality
See "Overstatement of Results in the Nutrition and Obesity Peer-Reviewed Literature" by Menachemic et al. Of 937 papers on nutrition or obesity published in 2001 and 2011 in leading specialty, medical, and public health journals, 8.9% of them had overreaching conclusions with a higher percentage of them in 2011 than in 2001. Unfunded studies and those with four or fewer coauthors were significantly more likely to have overstated results. (see commentary in Reuters - "Results from so-called observational studies - which can't prove cause-and-effect ....or generalized to a larger group of people when the study group was quite different... are often used to make potentially inappropriate recommendations without better data.") And then the inevitable hype by media magnifies the study's overstated results even more.
More reports on lack of reproducibility of research findings: Believe it or not: how much can we rely on published data on potential drug targets? by Prinz, Schlange and Asadullah of Bayer Pharmaceutical; Drug development: Raise standards for preclinical cancer research by Begley and Ellis (2012) of Amgen. Good overview at Reason.com Can Most Cancer Research Be Trusted?
All companies that sponsor research on their products have a marketing interest in showing those products in the best light. "This approach conflicts with scientific standards that require the symmetric and comparable reporting of safety and efficacy data. Selective reporting of the results of clinical trials can misrepresent the risk-benefit profile of drugs." Reporting Mortality Findings in Trials of Rofecoxib for Alzheimer Disease or Cognitive Impairment: A Case Study Based on Documents From Rofecoxib Litigation by Psaty and Kronmal (JAMA, 2008)
Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs from Harvard University Edmond J. Safra Center for Ethics, by Light, Lexchin and Darrow [Journal of Law, Medicine and Ethics Vol. 14, No. 3 (2013)]— "An extensive range of studies and lawsuits already documents strategies by which pharmaceutical companies hide, ignore, or misrepresent evidence about new drugs; distort the medical literature; and misrepresent products to prescribing physicians.... It is our thesis that institutional corruption has occurred at three levels.
First, through large-scale lobbying and political contributions, the pharmaceutical industry has influenced Congress to pass legislation that has compromised the mission of the Food and Drug Administration (FDA).
Second, largely as a result of industry pressure, Congress has underfunded FDA enforcement capacities since 1906, and turning to industry-paid “user fees” since 1992 has biased funding to limit the FDA’s ability to protect the public from serious adverse reactions to drugs that have few offsetting advantages.
Finally, industry has commercialized the role of physicians and undermined their position as independent, trusted advisers to patients."
2.3 Avoid Eating to Stomach Discomfort: Too much food distends the stomach and irritates stomach mast cells into releasing inflammatory mediators, in particular—histamine, which causes increased stomach acid and may lead to heartburn. Inflammatory mediator release or the effects on the stomach (don't know which one) may prompt abdominal cramping and distension from intestinal gas (common in IBS). Distension of the intestines further irritates gastrointestinal mast cells. Mediator release can also cause diarrhea.
— The Center for Mindful Eating urges the application of mindfulness to eating in order to counteract mindless overeating. See Mindful Eating — Studies Show This Concept Can Help Clients Lose Weight and Better Manage Chronic Disease. Also see "Mindful Eating as Food for Thought" (Gordinier, New York Times) and Mindless Eating.org. Also a very wonderful article by Dr. Pamela Peeke on WebMD: Secrets of Mindful Eating.("By slowing down your eating pace, you allow your own body/brain chemicals to work optimally ...studies have shown, far fewer calories consumed." Dr. Peeke also recommends Mindful Eating by Miraval Chef, Chad Luethje) —Playing ‘Tetris’ reduces the strength, frequency and vividness of naturally occurring cravings by Jessica Skorka-Brown et al.(2014) “Episodes of craving normally only last a few minutes, during which time an individual is visualising what they want and the reward it will bring. Often those feelings result in the person giving in and consuming the very thing they are trying to resist. But by playing Tetris, just in short bursts (3 minutes), you are preventing your brain creating those enticing images and without them the craving fades.” ref
—Often I still crave more food after I've finished my meal, probably because I've eaten too fast. And if I give in, I will become too full and uncomfortable, which will trigger a mast cell episode (MCAS). But I can ignore those cravings if I get involved in physical activity such as walking the dog or dancing to fast music. The cravings as Skorka-Brown explains above, only last a few minutes, and after that satiety sets in until the next meal. I can also put off eating in the morning by doing a strenuous activity that I must show up for, such as my exercise class. (this is how I avoid exercise-induced anaphylaxis) See 2.4 below.
2.35 Better to eat fewer, larger meals than snacking throughout the day:Hypercaloric diets with increased meal frequency, but not meal size, increase intrahepatic triglycerides [fatty liver]: A randomized controlled trial by Koopman et al. ABSTRACT: "American children consume 27% of calories from high-fat and high-sugar snacks. Both sugar and fat consumption have been implicated as a cause of hepatic steatosis [fatty liver] and obesity but the effect of meal pattern is largely underexposed. We hypothesized that a high meal frequency, compared to consuming large meals, is detrimental in the accumulation of intrahepatic and abdominal fat. To test this hypothesis, we randomized 36 lean, healthy men to a 40% hypercaloric diet for six weeks or a eucaloric control diet and measured intrahepatic triglyceride content (IHTG) using 1H-MRS, abdominal fat using MRI and insulin sensitivity using hyperinsulinemic euglycemic clamp with glucose isotope tracer before and after the diet intervention. The caloric surplus consisted of fat and sugar (high-fat-high-sugar; HFHS) or sugar only (high-sugar; HS) and was consumed together with, or in between the 3 main meals, thereby increasing meal size or meal frequency. All hypercaloric diets similarly increased BMI. Increasing meal frequency significantly increased IHTG (HFHS +45%; p=0.016 and HS +110%; p=0.047) whereas increasing meal size did not (2-way-ANOVA size vs frequency p=0.03). Abdominal fat increased in the HFHS-frequency group (+63.3 ± 42.8 ml; p=0.004) and tended to increase in the HS-frequency group (+46.5 ± 50.7 ml; p=0.08). Hepatic insulin sensitivity tended to decrease in the HFHS-frequency group only. Peripheral insulin sensitivity was not affected. Conclusions: A hypercaloric diet with high meal frequency increased IHTG and abdominal fat independent of caloric content and body weight, whereas increasing meal size did not. This study suggests that snacking, a common feature in the Western diet, independently contributes to hepatic steatosis and obesity. (Hepatology 2014)"
2.4 Fasting as a Form of Hormesis: (references to come) Because I cannot eat before exercising due to exercise–induced anaphylaxis, and since my fitness class doesn't begin until 10 am, I "fell" into intermittent fasting, not eating from 6:30 the previous evening to 11:30 – 12:00 the next morning. Currently, I fast until late morning most days of the week, and don't feel hungry at all as long as long as I'm exercising or working. I eat two and a half meals in a 7 to 6 hour period and don't eat after 6:30 in the evening. How do I feel? Energetic and healthy! I had begun gaining weight too fast because for the first time in 6 years of Mast Cell Activation Syndrome I'd been able to eat more than 3 foods; so I was binging on nuts and fruit, and gaining weight not as muscle but fat. I wanted to gain weight but not this fast and not as fat. I knew that if I began eating in the morning it would be an all day nosh. Intermittent fasting nipped my rapid weight gain in the bud. I realize that a good breakfast is supposed to be important, but maybe for some of us, it isn't.
2.5 Drink Adequate Amounts of Fluids: It's important to drink enough non-dehydrating fluids during the day—but only enough so urine is not strongly colored (helps prevent kidney stones too. ref). It's equally important not to drink too much hypotonic/low electrolyte fluids such as water because blood sodium can be diluted to the point that brain cells (and other cells) swell and brain damage results, a potentially fatal condition (see hyponatremia, also review of a book by Tim Noakes — Waterlogged: The Serious Problem of Over-hydration in Sports at humankinetics.com). Avoid diuretics (like caffeine and alcohol) unless a medication prescribed by a physician. Avoid salty and sugary foods that cause water to leave cells through osmosis, and cause thirst. Beverages that contain caffeine and alcohol, act as both diuretics and dehydrators.
2.6 Avoid constipation, which can be a source of inflammation and can be a trigger for mast cell degranulation. (This is from my own experience, and was a big surprise to me.) A small amount of magnesium citrate may help. Calcium supplements can be a cause of constipation, but I have not found milk to be. Balance calcium citrate with magnesium citrate to achieve normal bowel movements.
3. Stress Management
- How do you know when your level of stress might be a threat to health?
i) A negative situation is involved – difficult boss or customers, frequent criticism, not enough time, or chronic illness or pain that interferes with work, family, sleep etc.
ii) You have little control over the situation or think you don't.
iii) Frequent symptoms of "fight or flight" sympathetic nervous system activation such as dry mouth, anxiety, rise in blood pressure and heart rate, etc.
iv) You are gaining weight. (see abstract for Daily Stressors, Past Depression, and Metabolic Responses to High-Fat Meals: A Novel Path to Obesity (2014) Authors conclude that: "The cumulative 6-hour difference between one prior day stressor and no stressors translates into 435 kJ, a difference that could add almost 11 pounds per year. These findings illustrate how stress and depression alter metabolic responses to high-fat meals in ways that promote obesity."
- Stress and the immune system:
i) Psychological Stress and the Human Immune System: A Meta–Analytic Study of 30 Years of Inquiry by Segerstrom and Miller, 2004. A meta-analysis of over 300 studies concerning the relationship between psychological stress and the immune system. In brief: Acute stressors (lasting minutes, fight or flight response) tended to 1) increase some aspects of non-specific natural immunity resulting in inflammation (mediated by granulocytes such as mast cells in tissue, neutrophils in blood stream, natural killer cells and complement proteins; mainly involving less energy intensive activities such as cell redistribution and mediator release) and 2) decrease some aspects of specific immunity (more energy intensive and mediated by lymphocytes – specific cellular and antibody immunity). Chronic stressors tended to suppress specific cellular and humoral (antibody) responses, which are more energy intensive functions (e.g. ramping up antibody and white blood cell production). The kind of stressful situation (e.g. trauma, loss etc. for acute stressors; change in in social role, responsibilities, degree of control etc. for chronic stressors) had an effect. Physical frailty (age or chronic illness) tended to increase the effects of stress on immune function. Also see Stress, Energy, and Immunity: An Ecological View, by Segerstrom, 2007. Explores the immune system as an energetically costly system that may or may not have priority over other body systems during stressful situations, when demands tax, exceed or threaten available resources/energy.
ii) See Meditation or exercise for preventing acute respiratory infection: a randomized controlled trial. Barrett et al (2012) This study done in adults, 50 years or older. Results: "Mindfulness" meditation group—27 Acute Respiratory Infection (ARI) episodes and 257 days of ARI illness; Exercise group—26 episodes and 241 illness days; Control group—40 episodes and 453 days. Mean global severity was 144 for meditation, 248 for exercise, and 358 for control. Both the meditation group alone and the Exercise group alone had significantly fewer acute respiratory infections, fewer days of missed work and less severity than the control group.
- Rest and relaxation is anti-inflammatory:
i) see the article: "Inflammation: Implications for understanding the heart-brain connection" by Shishenbor et al. Discusses the beneficial effects of activating the parasympathetic nervous system (the rest, relax and digest part of the autonomic nervous system) in decreasing inflammation in damaged hearts, and the worsening caused by sympathetic (fight or flight, adrenaline release, part of the autonomic) activation. Several studies show that greater parasympathetic tone is associated with lower cardiovascular mortality. "In experimental models of inflammatory diseases, vagus nerve stimulation (major nerve of the parasympathetic) attenuates the production of proinflammatory cytokines and inhibits the inflammatory process."
ii) see Physiology and immunology of the cholinergic antiinflammatory pathway and The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation) The Cholinergic Anti-inflammatory Pathway helps to prevent the damaging consequences of excessive innate immunity. ref
- Activities that stimulate vagus nerve function and thecholinergic anti-inflammatory pathway (see Neural reflexes in inflammation and immunity)
i) Aerobic Exercise
ii) Supplemental fish oil, olive oil and other fats (also see Fat meets the cholinergic anti–inflammatory pathway). The mechanism appears to involve release of cholecystokinin (CCK) that triggers stimulation of gall bladder contraction, pancreas secretion, and activation of the vagus nerve, which signals the sensation of satiety in the brain. ref
iv) Meditation (Useful reference: Meditation: An In-Depth Guide)
v) Biofeedback Training
vi) Relaxation Training, and
vii) Diaphragmatic or Abdominal breathing, which is done by relaxing the belly to allow the diaphragm to descend further into the abdomen during an in-breath, thus allowing the lungs to fill with more air and the breathing rate to slow – Jon Kabat-Zinn, in his book Full Catastrophe Living (Revised Edition – 2013) states that when several hundred patients were asked about the single most important thing they got out of his stress reduction program, the majority said "The Breathing." [Babies do belly breathing. Many of us have forgotten to breath this way because we are trying to tighten our abs to keep our bellies from bulging out. Try standing taller with good posture while also relaxing the belly. The bulge is much less. Abdominal and chest organs are less crowded and breathing improves even more.]
— See the article: Diaphragmatic Breathing Reduces Exercise-Induced Oxidative Stress"Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin."
—See the abstract: Diaphragmatic breathing reduces postprandial oxidative stress. "Results show that in normal subjects, acute hyperglycemia induces free-radical production while reducing the antioxidant levels (p<0.05). Diaphragmatic breathing reduces heart rates (p<0.01), increases insulin (p<0.05), reduces glycemia (p<0.01), and reduces free-radical production as indicated by the higher antioxidants levels (p<0.05). Conclusions: "Diaphragmatic breathing, likely through the activation of the [vagus nerve and] parasympathetic nervous system, increases insulin, reduces glycemia, and reduces reactive oxygen species production."
viii) From my experience, vigorous exercise (combination aerobic and resistance training) followed by a stretching routine.
ix) Have a list of enjoyable activities ready so that "When anxiety hits at an inactive moment, you can go off and do something to occupy your mind." Because "...when unoccupied, the mind wanders, often to anxieties; whereas when engaged with an activity we enjoy, we feel better. Even neutral or somewhat wearing activities, like household admin, can be better than sitting around worrying. (from The Peaceful Mind: 5 Step Guide to Feeling Relaxed Fast at Jeremy Dean's Psyblog website)
- Changing the way you think about stress changes your response to stress.
i) In "Rethinking stress: The role of mindsets in determining the stress response" Crum et al. (2013) reported three studies about the stress response in investment bankers. (Surely a mentally debilitating job due to the unfettered and extreme "bipolar" reactions of stock markets to any sliver of news, rumor or not, reported by the news media, and the resulting volatility and risks to one's livelihood.) In one study, the bankers were shown three different videos: 1– "stress is enhancing"; 2 – "stress is debilitating"; 3 – neutral. After a few weeks, the bankers who'd seen the positive video reported they felt less stress at work, and levels of their stress hormone, cortisol had moderated. The author's conclude that "a stress-is-enhancing mindset is associated with moderate cortisol reactivity and high desire for feedback under stress. Together, these 3 studies suggest that stress mindset (what the individual believes) is a distinct and meaningful variable in determining the stress response." also see the article – Rethinking the Stress Mindset: Can You Find the Upside of Pressure?
ii) Psychological Processes Mediate the Impact of Familial Risk, Social Circumstances and Life Events on Mental Health by Kinderman et al. "Our results demonstrate that psychological processes of response style (specifically a greater tendency to ruminate) and self-blame (or an internal attributional style for negative events) powerfully determine the impact of familial histories of mental health problems, life events and traumas, and social deprivation in the aetiology of depression and anxiety and in the maintenance of well-being." Additional Commentary
iii) The Queen and I: Neural Correlates of Altered Self-Related Cognitions in Major Depressive Episode by Sarsam et al. Functional magnetic resonance imaging was used to analyze the brain while participants chose positive, negative and neutral adjectives to describe either themselves or the British Queen. Study participants experiencing depressive episodes displayed increased brain activity when they think about themselves, and used more negative and neutral words to describe themselves. Additional Commentary
- It's not the stressors, but how you react to them:
i) David Almeida, PhD, professor at Penn State says "Our research shows that how you react to what happens in your life today predicts your chronic health conditions 10 years in the future independent of your current health and your future stress." Alameda said," I like to think of people as being one of two types. With Velcro people, when a stressor happens it sticks to them; they get really upset and, by the end of the day, they are still grumpy and fuming. With Teflon people, when stressors happen to them they slide right off. It's the Velcro people who end up suffering health consequences down the road." See Social Strain and Cortisol Regulation in Midlife in the US by Friedman et al. Also see, Frontiers in the Use of Biomarkers of Health in Research on Stress and Aging by Piazza et all. and The Speedometer of Life: Stress, Health and Aging.
ii) Avoid ruminating over stressors. Rumination is the retelling of the story of the stressful event over and over to yourself. Each retelling calls forth the same strong emotions and as a consequence the same release of inflammatory mediators. The story of the stressor is just a sequence of events with a baggage of emotions like the script for a movie. Without the retelling of the story or the script, what happens to the emotions? Sometimes they simply dissipate along with the inflammatory effects. When my little dog was finally euthanized for heart failure, I held her in my lap as the vet injected the drug into her vein, and she simply went limp. My eyes welled with tears, but my heart raced and my face burned red from mast cell releases of histamine and inflammatory mediators into my bloodstream. Any worse and I'd have needed my EPI pen. And later, every time the memory came, the same histamine/inflammatory mediator symptoms and more. My defense was to force myself not to think about it, to simply let it go.iii) Rethinking Rumination a review by Nolen-Hoeksema et al. "...evidence now suggests that rumination is associated with psychopathologies in addition to depression, including anxiety, binge eating, binge drinking, and self-harm" ..."rumination is associated with the experience of depressive symptoms and that rumination in the context of depressed mood or major depression is associated with more negative thinking, poorer problem solving, diminished instrumental behavior, and reduced social support.
- Gaining a measure of self-control lowers stress. Some lessons from Willpower: Rediscovering the Greatest Human Strength, Baumeister and Tierney,)
i) Don't Procrastinate: for many of us an unfinished task preys on the mind until it's done. And when we finally begin, if there's a deadline involved, anxiety builds in the rush to get it finished. And the final result may not be anything we're proud of. Our health may suffer too. (Term Papers written at the last minute invariably get lower grades.) To help with mental stress begin a list of what needs to be done and steps to get started; at least that eases the mind.
ii) Know your limits: 1. "Your supply of willpower is limited", and 2. "Willpower and self-control are powered by the same resource that is used for many unrelated things." (The actual identity of the resource is not made clear but seems to be a combination of metabolic energy and refreshed brain synapses.) In the morning after a good sleep and healthy breakfast (not high glycemic: but complex carbs, protein, fat, to keep hunger away the longest), willpower is strongest. Then all day long, every little thing needing to be done and every decision, small or large, agonized over (like deciding to eat grilled instead of crunchy, fried chicken or taking the stairs instead of the elevator), eats away at self-control and willpower until very little is left by the end of the day. Then in front of the TV we're assaulted by snack food advertisements. Some even find it impossible to make the decision to drag themselves off the couch and go to bed at a decent hour. The more willpower exerted during a decision, the less is available for the next decision.
iii) Tips for dealing with willpower depletion:
a. Watch for symptoms of willpower depletion and replenish resources: Feeling more frustrated than usual ? or having a hard time making the simplest of decisions? Put off important decisions until after lunch or have taken a nap.
b. Pick your battles: Some things are not worth depleting energy reserves.
c. Make decisions about daily activities as easy as possible by turning routine decisions into automatic habits. Develop cues and rewards that automatically turn on healthy habits. (see The Power of Habit by Charles Duhigg)
d. Ironically, people with good willpower seem to use less of it. They tend to control/arrange their environments, so they're not continually fighting temptation. Having temptations close by, especially if in plain sight, requires energy to resist. And that energy is limited, no matter how much willpower one thinks one has. Perhaps there are exceptional people out there, but in general the more self-control one tries to apply, the more quickly it fails.
- Selected References:
i) Acute stress increases mediator release in mast cells and body–wide inflammation. See Theoharides and Cochrane, 2004 "Critical role of mast cells in inflammatory diseases and the effect of acute stress."
ii) Benefits of activating the parasympathetic (rest, relax and digest part of the autonomic nervous system) in decreasing inflammation in damaged hearts and lowering mortality, and the worsening caused by sympathetic (fight or flight, adrenaline release, part of the autonomic) activation. "In experimental models of inflammatory diseases, vagus nerve stimulation (major nerve of the parasympathetic) lessens the production of proinflammatory cytokines and inhibits the inflammatory process." ("Inflammation: Implications for understanding the heart-brain connection" by Shishenbor et al.
iii) "Chronic panic, phobia, and similar anxiety disorders may contribute to premature biological aging by shortening telomeres (loss of protective caps at the ends of our chromosomes), an observational study suggested." Chronic Anxiety Speeds Aging By Crystal Phend, Senior Staff Writer, MedPage Today Published: July 12, 2012. Original article: High Phobic Anxiety Is Related to Lower Leukocyte Telomere Length in Women, Okereke et. al. Another report found a similar correlation between work-related exhaustion and shortened telomeres: Work-Related Exhaustion and Telomere Length: A Population-Based Study by Ahola et al.
4. Make Sleep a Priority: According to a CDC study, nearly one third of workers in the U.S. get 6 hours or less of sleep a night. Insufficient sleep interferes with performance on the job or at school, can have fatal consequences (20% of vehicle crashes involve sleepy drivers) and makes it harder to enjoy life. Chronic sleep deprivation is also associated with heart disease, stroke, diabetes, obesity, depression, anxiety and over-eating. See Speigel et al (2004) – Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. And also: Why the Sleep-Deprived Crave Junk Food and Buy Higher Calorie Foods and The impact of sleep deprivation on food desire in the human brain (Greer et al. 2013) High-level brain regions required for complex judgments and decisions become blunted by lack of sleep, while activity of the more primal amygdala that controls motivation and desire are amplified. The more sleep deprived the study participants were, the greater the cravings for high calorie foods. refSchmid et al (see reference that follows) "...draw attention to 24-hour lifestyle and ongoing trends for use of technical devices for gaming, online shopping, social networking, or watching television as contributing factors for sleep disturbance. From a public-health perspective it will be most important to reduce voluntary sleep restriction caused by computer gaming, electronic social-media use, etc, in particular in teenagers..."
The Metabolic Burden of Sleep Loss by Schmid et al. (entire article is free with registration)
Summary: "In parallel with the increasing prevalence of obesity and type 2 diabetes, sleep loss has become common in modern societies. An increasing number of epidemiological studies show an association between short sleep duration, sleep disturbances, and circadian desynchronisation of sleep with adverse metabolic traits, in particular obesity and type 2 diabetes. Furthermore, experimental studies point to distinct mechanisms by which insufficient sleep adversely affects metabolic health. Changes in the activity of neuroendocrine systems seem to be major mediators of the detrimental metabolic effects of insufficient sleep, through favoring neurobehavioural outcomes such as increased appetite, enhanced sensitivity to food stimuli, and, ultimately, a surplus in energy intake. The effect of curtailed sleep on physical activity and energy expenditure is less clear, but changes are unlikely to outweigh increases in food intake. Although long-term interventional studies proving a cause and effect association are still scarce, sleep loss seems to be an appealing target for the prevention, and probably treatment, of metabolic disease." See also: Impaired Insulin Signaling in Human Adipocytes After Experimental Sleep Restriction: A Randomized, Crossover Study – Broussard et al (2012) "...show that cellular insulin sensitivity was reduced 30% in adipocytes from subcutaneous fat samples collected after 4 nights of sleep restriction (4.5 hours in bed) compared with 4 nights of normal sleep (8.5 hours in bed)." In this well done though small study (7 healthy adults), the authors conclude that sleep restriction results in an insulin-resistant state in human adipocytes. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity. Sleep may be more than its "restorative effects on the central nervous system," and may also be an important regulator of energy metabolism in peripheral tissues." See editorial in same issue: A New Challenge to Widely Held Views on the Role of Sleep by Cappuccia and Miller (2012). Also: A link between sleep loss, glucose metabolism and adipokines Padilha et al (2011).
— An observational study of sleep duration in adolescents showed that C-Reactive Protein levels (CRP is released by the liver in response to inflammatory mediators from immune cells and fat cells, and is associated with increased cardiovascular risk) were higher on weekdays when sleep averaged 6 hours and less on weekends when sleep averaged 7 and a half hours. The recommended sleep duration for this age group is 9 hours. See: Sleep Linked to CRP Levels in Teens, Hall et al. and also Nontraditional Risk Factors and Biomarkers for Cardiovascular Disease: Mechanistic, Research, and Clinical Considerations for Youth : A Scientific Statement From the American Heart Association. Balagopal et al.
— See also Diurnal Rhythms in Blood Cell Populations and the Effect of Acute Sleep Deprivation in Healthy Young Men by Ackermann et al, 2012. Granulocyte (major type of white blood cells) levels and diurnal (day-night) rhythmicity are directly affected by acute sleep deprivation; these changes mirror the body's immediate immune response upon exposure to stress. Also, Sleep restriction increases white blood cells, mainly neutrophil count, in young healthy men: A pilot study, Boudjeltia et al.: "Four hours of sleep on three consecutive nights resulted in significant increase in white blood cells, mainly neutrophils. Several studies have found an association between elevated white blood cell count and coronary heart disease. See White blood cell count: an independent predictor of coronary heart disease mortality among a national cohort. Brown et al., 2001.
— TH17 Cell Differentiation Is Regulated by the Circadian Clock by Yu et al. "TH17 cells are CD4+ T helper cells that produce the proinflammatory cytokine interleukin-17. In the intestines, TH17 cells protect the host from fungal and bacterial infections, and their proinflammatory function is linked with autoimmune diseases including inflammatory bowel disease. Yu et al. show that the molecular circadian clock directly regulates the differentiation of TH17 cells in the intestine, which suggest that both nutrition and light are important environmental factors that directly regulate the immune response." Additional Commentary: Why Late Nights Are Bad for Your Immune System
— To Study or to Sleep? The Academic Costs of Extra Studying at the Expense of Sleep, by O'Neel et al. Researchers at UCLA found that high schoolers, who stayed up late studying, risked having more trouble understanding subjects taught in class and doing poorly on tests, quizzes, and homework assignments, regardless of the total amount of students’ study time.
— Sleep and Alzheimer's Disease; "Among community-dwelling older adults, reports of shorter sleep duration and poorer sleep quality are associated with greater Aβ (beta amyloid) burden. Additional studies with objective sleep measures are needed to determine whether sleep disturbance causes or accelerates Alzheimer disease. " ref Amyloid Beta significantly increased during awake periods compared to sleeping periods in mouse models of Alzheimer's. "Sleep disturbances... could exacerbate a fundamental process leading to neurodegeneration, and optimization of sleep time could potentially inhibit aggregation of toxic proteins and slow the progression of AD"ref ref.
When Dreams and Nightmares disturb sleep: Nightmares are a problem for me. When I wake from one, my mast cells have already dumped their histamine; my face is burning, my ears buzz like crazy, my heart hammers away. What I don't know is whether the mast cell episode caused the nightmare or the nightmare caused the episode. Perhaps it's a little of both; whatever the cause, my dreams are more vivid and troubling when I've been exposed to more inflammatory mediators from a mast cell triggering situation during the day, and also have more trouble sleeping. (Histamine is a neurotransmitter, and directly increases arousal in the brain.) Some tips that may help with bad dreams and nightmares.....
• Avoid emotionally charged situations, including those involving people or entertainment, before bedtime. Many arguments are not worth having. Step back and ask yourself, will it change anything, or is it the same old script recycled many times over, with no one giving ground because of underlying resentments and the need to maintain some measure of control over their own lives. When it comes to older children and adults, natural consequences are best, unless a truly life threatening situation is likely.
• Use a White Noise Machine: Nightly use effectively reduces my mast cell releases, and if I miss even one night the mast cell releases come right back. Do I have fewer bad dreams? It's hard to tell, but definitely my reactions have lessened. (Sometimes white noise reminds me of sounds I've heard underwater. Perhaps white noise triggers a primal memory from before birth? I wonder, do babies sleep better with white noise machines?) • Try Imagery Rehearsal Therapy: A simple behavioral technique called Imagery Rehearsal Therapy (IRT) helps with chronic nightmares as well as symptoms of Post-Traumatic Stress Disorder (PTSD). In brief: 1) Write down a short description of a recent nightmare. 2) Think of a way to change the nightmare for the better 3) Each day set aside time to visualize the changed version of the nightmare. This sounds too simple to be effective, but an article in the Journal of the American Medical Association in 2001 showed that IRT significantly decreased chronic nightmares, improved quality of sleep and decreased PTSD symptoms in women who had moderate-to-severe PTSD from rape and other sexual assaults.
In most people levels of blood histamine rise at night—perhaps due to emotionally charged dreams or the higher histamine causes them? In the brain, histamine acts as an excitatory neurotransmitter for the arousal system (Excitatory effect of histamine on the arousal system and its inhibition by H1 blockers,Tasaka et al.). Could the arousal effect cause bad dreams from mast cell releases in the rest of the body? However histamine from mast cell releases in the body doesn't ordinarily cross the blood/brain barrier. But other inflammatory mediators might enter the brain, bind to brain mast cells and induce them to release excessive histamine. Interestingly I've heard people say that eating or drinking too much, which may irritate GI mast cells into releasing histamine, seems to cause not only stomach distress but bad dreams.
• Avoid Sleep Medications. All of them lose effectiveness over time and often need to be increased. Even after short term use, abruptly stopping a sleep medication causes a rebound effect that leads to one or more sleepless nights. Benzodiazepines (Xanax, Atavan, Valium) are particularly difficult to get off and must be tapered over many weeks to months to avoid unpleasant withdrawal symptoms. See Addictions and Recovery.org and Benzodiazepines: How They Work and How to Withdraw. Sleeping pills may make it easier to fall asleep, by 15 minutes, but total sleep time is still not much longer than 6 hours, or at best 30 mins longer than without the pills.
— Sleeping pills are only recommended for short periods of time, not long term. These drugs may have significant side effects such as memory loss, sleep walking, and fall. s Long term use also covers up the real reason for the insomnia, which could be a medical problem like sleep apnea, which may contribute to high blood pressure, heart disease, and diabetes. see The Sleep-Diabetes Connection. Long term use can also cause worsening of depression. see the article "10 things the sleep-aid industry won't tell you"
5. Don't Overuse Over The Counter (OTC) Medications That Degranulate Mast Cells and Inflame the Gut – Especially all NSAIDS: Avoid aspirin or other Nsaids (non-steroidal anti-inflammatories) if they cause heartburn, stomach upset or other reactions (e.g. tinnitis, facial flushing, heart palpitations). In particular, avoid high dose nsaids soon after an intermediate to long term course (more than 3 weeks) of oral corticosteroids. The cascade of inflammatory mediator release from mast cells caused by nsaids may not stop if one has a degree of adrenal insufficiency from the corticosteroids. (which is apparently what precipitated my mast cell activation disorder.)
Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes – Van Wijck et al. (2012) Conclusions: "This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that non-steroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged."
Intestinal permeability and inflammation in patients on NSAIDs – Sigthorsson et al (1998) Conclusions: "Intestinal permeability test dose composition is an important factor when assessing the effects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel."
Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine.– Bjarnason et al (1986) Abstract: Intestinal permeability was estimated in healthy subjects after ingestion of aspirin (1.2+1.2 g), ibuprofen (400+400 mg) and indomethacin (75+50 mg) at midnight and an hour before starting a 51chromium labeled ethylenediaminetetraacetate absorption test. Intestinal permeability increased significantly from control levels following each drug and the effect was related to drug potency to inhibit cyclooxygenase. Intestinal permeability increased to a similar extent after oral and rectal administration of indomethacin showing that the effect is systemically mediated. Prostaglandin E2 decreased intestinal permeability significantly but failed to prevent the indomethacin induced increased intestinal permeability. These studies show that non-steroidal anti-inflammatory drugs disrupt the intestinal barrier function in man and suggest that the morphological correlates of the damage may reside at the level of the intercellular junctions.
Present status and strategy of NSAIDs-induced small bowel injury. – Higuchi et al (2009)
Excerpt from Abstract: "Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. ...The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAID-induced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness."
6. Avoid Respiratory Irritants: especially fumes of volatile chemicals—alcohol from wine or liquor, vinegar (acetic acid) from salad dressing, barbecue sauce and pickled foods, ammonia from window cleaners, bleach from kitchen and bath cleaners, perfume and soot from candles and incense. In other words—avoid irritating air pollutants, indoor and outdoor. These all directly cause mast cell releases in the respiratory system.
7. Limit friction or pressure on skin, and treat dry itchy skin: The skin is a large organ and contains lots of mast cells. Avoid wearing tight clothes or compression hosiery (unless medically necessary). Try turning down the water temperature in showers, and moisturize skin afterwards. A bit of petroleum jelly spread over moist skin helps seal in moisture.
8. Avoid Excessive Sun Exposure to Skin or Eyes:
— Strong sunlight and ultraviolet light damage skin cells causing mast cell degranulation.
— UV and blue light damage the light-sensing retina of the eye. This is particularly important if one has a parent or other close relative with macular degeneration, or there's a genetic predisposition (23andMe genomic analysis can show this). Blue light can be minimized with amber colored blue-light filtering sunglasses. Cataract surgery, in particular, can make eyes more sensitive to blue light because the naturally yellowed lenses have been replaced with crystal clear artificial ones. In some cases (my mother for one) cataract surgery has been followed by rapid worsening of existing dry macular degeneration (drusen) or onset of wet macular degeneration (my mother). Supplementing with Zeaxanthin and Lutein (2 deep yellow anti-oxidant pigments found in some vegetables) may help protect the retina. Zeaxanthin preferentially deposits in the macula. And lutein deposits in the rest of the retina. Do not take both at the same time, but alternate because they inhibit each other from binding to the retina. (My experience has been that Zeaxanthin and Lutein have helped my photophobia from Mast Cell disease considerably.)
9. Don't Ignore Seasonal or Year Round Allergies: Take antihistamine med's at regular intervals as prescribed or recommended in order to keep mast cell degranulation at a minimum. Both histamine 1 blockers such as Zyrtec and Claritin, and histamine 2 blockers such as Zantac (ranitidine) bind to specific sites on Mast cells and help inhibit mast cell activity, which lowers releases of histamine and other inflammatory mediators. Zantac (generally used for heartburn, histamine increases stomach acid production) may help with allergies and itchy skin. (For grass and pollen allergy during the spring, use a surgical mask in problematic situations such as gardening and walking by a lawn being mowed.)
Notes on Markers of Inflammation:
— CRP (C-reactive protein) produced in the liver in response to interleukin-6, a cytokine released by fat tissue and arteriosclerosis plaques. CRP elevation has been shown to be an independent risk for cardiovascular and peripheral arterial disease, and associated with increased risk for hypertension, type 1 and type 2 diabetes, and may contribute to age-related macular degeneration (AMD). See "Review: The role of CRP and inflammation in the pathogenesis of age-related macular degeneration" by Colak et al.
— Low Vitamin B6
"Inflammation causes tissue-specific depletion of vitamin B6" Chiang et. al.
"Low Vitamin B6 Linked to Inflammation" WebMD Health News
"Association of plasma B-6 vitamers with systemic markers of inflammation before and after pyridoxine treatment in patients with stable angina pectoris" Ulvik et al.
"Dietary Folate, Methionine, Riboflavin, and Vitamin B-6 and Risk of Sporadic Colorectal Cancer" de Vogel et. al.
"Low Intake of Vitamin B-6 Is Associated with Increased Risk of Colorectal Cancer in Japanese Men" Ishihara et. al.
— kynurenine-to-tryptophan ratio
— white blood cell count
*A new test for depression measures nine biomarkers in blood, many of them from the "inflammation" family. “Chronic inflammation [is] part of a risk factor or part of the process of depression itself,” says George Papakostas, a psychiatrist and director of treatment-resistant depression studies at Massachusetts General Hospital. See the article "Blood Test Accurately Distinguishes Depressed Patients from Healthy Controls.
Accurately Distinguishes Depressed Patients from Healthy ControlsSee also Research on Psychiatric Disorders Targets Inflammation – About one third of depressed patients have treatment resistant depression and are resistant to medications such as serotonin reuptake inhibitors (SSRI's). These patients tend to show an increase in inflammatory markers such as inflammatory cytokines and c-reactive protein., and it is these patients who had improvement on anti-cytokine therapy.