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Fight Chronic Inflammation

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Fight Chronic Inflammation and Associated Pain

Non-drug treatments for fighting chronic inflammation: a simple diet with greens, other vegetables and whole fruit—mainly berries; an active life style that includes aerobic and strength training, and limits long, uninterrupted periods of sitting; managing stress; and sufficient sleep.

Certain life styles promote chronic inflammation in the body and contribute to arthritic joint pain and poor musculo-skeletal condition. Chronic inflammation also increases the risk of chronic illnesses including cardiovascular disease, diabetes, depression, osteoporosis and associated fracture risk.

— 1. Diet
— 2. Physical Activity
3. Stress
4. Sleep
5. Miscellaneous
6. Food Intolerances
7. Anti-Nutrients and Pro-Nutrients
8. Metabolic Pathways: Methylation, Folate, Histamine etc.
9. Risk Alleles (23andMe)

There are numerous articles and recommendations by the National Institutes of Health, medical societies, well-known hospitals (Johns Hopkins, Mayo Clinic etc) on the benefits of anti-inflammatory life styles for increasing the well-being of those with chronic illness and pain, including arthritis, autoimmune disease, cardiovascular disease, cancer, diabetes and psychiatric disorders including depression. The four pillars of an anti-inflammatory life style are diet, exercise, stress reduction and sleep.

1. Diet

Evidence that a healthy diet reduces risk of rheumatoid arthritis:
     • Diet and Risk for Rheumatoid Arthritis Commentary by Kevin Dean (2017) Evidence that a long term diet conforming to "healthy eating patterns" reduces risk of rheumatoid arthritis in :

Evidence that a whole foods, plant-based diet improves joint pain from rheumatoid and osteo-arthritis:

     • "Rheumatoid arthritis treated with vegetarian diets" Kjeldsen-Krage (1999). Some patients with RA, but not all, benefited from fasting followed by a vegetarian diet. Responders, patients who had less symptoms on the vegetarian die,t had changes in their fecal microbiome.
     • Diet therapy for the patient with rheumatoid arthritis? Hagen et al. (1999) A review of dietary studies on RA patients: 1. Sköldstam et al (1979) Fasting improves symptoms, but a return to regular diet or lactovegetarian diet, increased symptoms. 2. (Sköldstam et al,1983) of 20 RA patients, a fast followed by a vegan diet (no animal products) led to improvement of symptoms. 3. Panush et al, (1983) On an elimination diet (no dairy, red meat, citrus, tomatoes, alcohol or coffee), 2 patients improved. One patient worsened on dairy, and one on red meat, spices and alcohol. 4. Darlinton et al, (1986) Patients on a low reactive foods diet (list of foods not available) then added back foods one at a time. The foods causing symptoms were excluded. Out of 53 patients, 33 improved on their individual low-reactive diet. 5. Haugen et al. (1991) 57 RA patients, half in the vegetarian+elimination diet group and half in the control group, were followed for 13 months. 44% of the diet group improved. After 2 years, those patients who remained on their symptom-reducing diet were still improved. Over half of the diet group had increase in symptoms after adding meat, almost half after adding sugar and coffee. 6. By questionnaire 37 – 43% of rheumatic disease patients, not just rheumatoid arthritis patients, had an increase in disease symptoms with intake of certain foods, suggesting "that diet may influence the inflammatory process in general and is not a specific feature of RA."
     •  "Whole-Foods, Plant-Based Diet Alleviates the Symptoms of Osteoarthritis" Clinton et al (2015) A whole-foods, plant-based diet improves self-assessed symptoms of osteoarthritis patients.

Note that in most of these small studies, many, but not all, rheumatoid arthritis patients responded to dietary intervention, and each patient's least symptom-provoking diet was different. However, there appeared to be some general principles, such as drastically less red meat, sugar and oxidized fats (including frying with low smoke point oils, like coconut oil and butter) and a more plant-based diet. And each patient went through a trail–and–error process to discover which foods to eliminate. There are no one-size-fits-all diet plans for optimizing an individual's health.

Other chronic illnesses are improved by higher diet quality:
     •  "Diet quality is associated with disability and symptom severity in multiple sclerosis" Fitzerald et al. (2017) "Our large cross-sectional survey suggests a healthy diet and a composite healthy lifestyle are associated with lesser disability and symptom burden in MS"

What is optimized health? A lot of evidence supports reducing inflammation. Inflammation increases with age and contributes to most chronic lifestyle illnesses such as cardiovascular disease, diabetes, degenerative brain diseases (Alzheimer's, Parkinson's, Multiple Sclerosis etc).

What does increased inflammation feel like? What follows are many of the rules I use to reduce inflammation in my life. For me, reducing inflammation is crucial because I have a chronic inflammatory illness called Systemic Mast Cell Activation Syndrome that causes mast cells, a part of my innate immune system to be highly reactive. Mast cells are the major cell in body tissues and organs that release inflammatory mediators (including histamine, prostaglandins, leukotrienes, cytokines, over a hundred varieties) in response to physical injuries such as burns, wounds, insect or snake bites, toxic substances, invading bacteria, fungi and viruses. Unfortunately, my mast cells react to substances that normal people might have a small, local reaction to but not an extreme or systemic reaction (the worst being anaphylactic shock and/or death). A substance such as vinegar, a dilute acid that may be mildly irritating to mouth tissues, and nasal passages, doesn't bother many people. But for me, a whiff of the fumes that sets off a mast cell reaction in my nose, is not a limited local reaction, but starts a cascade of reactions that results in my face flushing, blood shot eyes, blood pressure that initially falls and then spikes up as adrenaline is released, stomach upset and heartburn, itching of the soles of the feet, etc. This same over-reaction can occur with many foods, medications, supplements, cleaning products, sun exposure, exercise, emotionally charged thoughts etc. etc.. Strangely, these reactions are in some way normal; the substances and other conditions I react to will cause mast cells in a petri dish to release inflammatory mediators, for example. But the abnormal part is the spreading of these reactions to other parts of the body.

Limit or Avoid Certain Foods Depending on Severity of Reaction: If specific foods cause heartburn, abdominal distress or other reactions such as fatigue, headaches, redness of the eyes and/or swelling around the eyes, leg spasms/cramps at night, heart palpitations, rise in blood pressure or heart rate etc., gastrointestinal mast cells may be irritated and releasing inflammatory mediators like histamine, which causes the heartburn. (Histamine type 2 receptors are blocked by anti-acid meds like Zyrtec and Pepsid.) Don't just medicate the reaction, eliminate the food, at least temporarily. If the reaction is a mild one and the food very nutritious, 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 a doctor. For multiple food intolerances, an elimination diet* may help.

"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 bioavailability of other nutrients and supplements. Check out what interferes with what on my Anti-Nutrients page.

Problem Foods: Not everyone has the same ones, but these may include:

   — Foods that test positive for classical IgE allergy by skin prick or RAST testing; the most common food allergies are to eggs, peanuts, tree nuts, shellfish, milk and wheat.
   — Milk products may cause intolerance reactions in adults who do not make lactase, the enzyme that splits lactose milk sugar into glucose and galactose. Lactase deficiency may cause some cases of IBS (Irritable Bowel Syndrome) (ref ref) See next entry on FODMAPS
   — FODMAPS: fermentable carbohydrates that are poorly absorbed and pass into the large intestine where gut bacteria ferment and produce gas from them. Bacterial fermentation causes bloating, farting, diarrhea, cramping, and other typical symptoms of IBS in sensitive people.

FODMAP diet and FODMAP FOOD LISTS:
— "Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach" by Gibson and Shepherd of Monash University in Victoria, Australia.
— Stanford Low Fodmap diet with high, moderate and low fodmap foods.
FODMAP Diet Beats General Dietary Advice for IBS-D Practice Update (2017)
— IBS Diets.org food list 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) (A recent study finds association of spicy food with reduced incidence of "total and certain cause specific mortality (cancer, ischemic heart diseases, and respiratory diseases), independent of other risk factors" - Consumption of spicy foods and total and cause specific mortality: population based cohort study Lv et al, 2015)

   — Foods containing histamine and other bio-active amines, which are heat-stable breakdown products of amino acids found in fermented/cultured with microbes or aged foods such as many cheeses; processed, smoked and fermented meats such as sausages, luncheon meats, salami; shell fish, fin fish (if not gutted immediately, cooked and eaten quickly), canned fish, pickled and marinated foods, fermented foods such as soy sauce. sauerkraut. and may include yogurt, cottage cheese and sour cream (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 may be a problem for those sensitive to potential for intestinal gas production from high fiber and for those with thyroid problems—such as low thyroid or goiter. Consult a physician before eating raw cruciferous vegetables. See Glucosinolate section.
[I have extreme sulfite/sulfate intolerance but have recently been able to eat cauliflower and broccoli with no reaction at all. ]

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. See pdf of Anne Swain et al. article, Salicylates in foods – contains salicylate content of 333 foods);
   — vegetables such as spinach and rhubarb (very high in oxalates that have formed irritating, needle-like crystals of calcium oxalate 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
   — Salicylates act like aspirin, which is a very potent salicylate. Aspirin and other NSAD's are actually misnamed. They are not anti-inflammatory but anti-prostaglandin. Some prostaglandins mediate inflammation but others are critical for the healthy functioning of organs such as stomach, kidneys and brain. Though NSAIDs shut off prostaglandins, the precursor, arachidonic acid, is simply used to make inflammatory leukotrienes. NSAIDS also degranulate mast cells causing the release of dozens of different inflammatory mediators including histamine, which causes overproduction of stomach acid.

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 fresh fruit. The sugar in high sugar fruits such as apples that are processed into smoothies is released as quickly into the blood stream as table sugar. So sip fruit smoothies slowly, especially as a stand-alone snack. A meal with fat eaten beforehand will slow down absorption also.
   — 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 the epidemiology 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."
   — Does too much sugar cause Alzheimer's Disease? At the least, higher blood sugar will cause dysregulation of the innate immune system in Alzheimer's disease through glycation and inhibition of an immune regulator called Macrophage Migration Inhibitor Factor or MIF. See Macrophage Migration Inhibitory Factor is subjected to glucose modification and oxidation in Alzheimer’s Disease. (Kassaar et al, 2017)
   — 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 high in Soluble Oxalates, especially for those who tend to form calcium-oxalate 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 soluble oxalates, which are easily absorbed such as spinach, chocolate and most nuts (almonds are almost twice as high in oxalates as the next highest nut (cashews), ref.  (insoluble oxalates are only slightly or not absorbed and are excreted in feces, unless oxalate metabolizing bacteria are present in the large intestine)
   — foods high in salt
   — foods high in refined carbohydrates (see comprehensive Medscape article on Hyperoxaluria)

Food high in refined vegetable oils: Most of these contain large amounts of polyunsaturated fatty acids (PUFA), which oxidize (turn rancid) in the presence of oxygen. PUFA oxidation speeds up at high higher temperature and slows at lower temperatures e.g. refrigeration. In the body, PUFA undergo lipid peroxidation to form 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. Glyoxal also 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.
   — Canola oil is 28% polyunsaturated faty acids (PUFA), which predisposes it to more oxidative degradation during the refining process and high heat cooking, than olive oil, which is 10.5 PUFA. See Effect of canola oil consumption on memory, synapse and neuropathology in the triple transgenic mouse model of Alzheimer’s disease, Lauretti and Pratico (2017) "...we found that chronic exposure to the canola-rich diet resulted in a significant increase in body weight and impairments in their working memory..." synaptic impairment and increase in ratio of insoluble amyloid 42 to soluble amyloic 40. (Olive oil had a beneficial effect on these mice.)

Cooking Method:
   — Fried, baked, grilled and roasted foods—all forms of dry heat at high temperature cooking—cause oxidation of refined PUFA vegetable oils producing reactive exigent species and releasing of toxic fumes such as aldehydes, acrolein etc. (Emissions of volatile aldehydes from heated cooking oils, Katragadda et. al, 2010) Toxic emissions from coconut, safflower, canola, and extra virgin olive oils increased with the oil temperature. Above the oil's smoke point, emissions drastically increased. Thus the oils with low smoke point, such as coconut, were not useful for deep-frying. Canola oil generated the lowest amount of toxic volatiles: an indoor air pollution problem. Acrolein formation was found even at low temperatures. (see a list of smoke points for common cooking oils)
(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), which bind to AGE receptors (RAGE) on mast cells causing the release of inflammatory mediators. "Oral advanced glycation end products (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses, AGE receptor-1 and sirtuin 1" ref.
   — Grilling of meat produces Harmane, a heterocyclic amines (HCAs) and also a potent neurotoxin. "... harmane was detectable in nanograms per gram quantities in cooked meat (especially chicken) and... was more abundant than other HCAs." Quantification of the neurotoxic beta-carboline harmane in barbecued/grilled meat samples and correlation with level of doneness. Louis et al (2007) and Higher blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations correlate with lower olfactory scores in essential tremor. Louis et al (2008).

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, full article: Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity by Hollon et al (2015) "Increased intestinal permeability after gliadin [gluten protein] exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission."
Foods and ingredients that negatively effect the gut microbiome
   — Maltodextrin "Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin" by Nickerson et al (2025)
   — Crohn's Disease-Associated Adherent-Invasive Escherichia coli Adhesion Is Enhanced by Exposure to the Ubiquitous Dietary Polysaccharide Maltodextrin Nickerson and McDonald (2012)
   — and other emulsifiers such as carboxymethyl cellulose (CMC), carrageenan, xanthan gum and polysorbate-80. "Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome" by Chassaing et al. (2015) "Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential."
   — Beal et al (2012) Late onset necrotizing enterocolitis in infants following use of a xanthan gum-containing thickening agent.

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 or desensitization 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 eaten into extinction by animals. What I did, by 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 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. (On the other hand, a shorter time period of elimination, on the order of weeks, rather than many months or years, helps calm the over-reacting cells until medication stabilizes the cells.)
   — "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)

1.1 Reduce 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)
   — High Sodium Intake Linked to Increased MS Exacerbations, Medscape (2014) In a small observational study, Farez et al (2014), reported that "We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium [2 to 4.8 g per day] or high [> 4.8 g per day] sodium intakes compared with the low-intake group [< 2 g per day]. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI."
   — High sodium diets may increase risk 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 clinical studies are contradictory. Dietary and Holistic Treatment of Recurrent Calcium Oxalate Kidney Stones by Laura Flagg (Medscape but originally published in Urol Nurs. 2007)
   — The alternate view: low sodium diets are reported to increase cardiovascular and all-cause deaths. Salt and Battery: Debate on Sodium Targets Gets Feisty, in Medscape by M. O'Riordan (2014). This article concerns the Prospective Urban Rural Epidemiology or PURE study, a large international study of over 100,000 participants that concluded that individuals who consumed between 3000 mg and 6000 mg of sodium per day had the lowest risk of death and cardiovascular mortality but that there is a U- or J-shaped association between sodium intake and adverse clinical outcomes at higher and lower levels of sodium intake, where mortality and cardiovascular events are increased." But as usual observational studies cannot prove cause and effect, only association. "The evidence isn't perfect, because of concerns about reverse causality--people who are eating less salt might be eating less food, and they might be eating less food because they are sick to start." [Bruce Neal - University of Sydney, Australia] Of 101,945 individuals 10% consumed <3000 mg of sodium/day and another 10% consumed 7000 mg/day or more. About half consumed between 4000 and 5990 mg of sodium daily. Very few consumed less than 2300 mg of sodium daily. [A person eating a minimally processed, whole foods diet of plain, boiled meat, steamed vegetables, raw fruits, boiled grains, boiled sweet potatoes, raw nuts, some olive oil, a bit of added salt and no spices, would barely consume 700 mg of sodium a day. Is this not healthy? Am I making myself sick?]

1.2 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. (Though sometimes, such as recent reports about table sugar (half fructose) and high fructose corn syrup being major causes of non-alcoholic fatty liver disease and metabolic syndrome, I tend to believe it because the biochemistry makes total sense (fructose is only processed in the liver) and the research literature, including epidemiology supports it.) 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."

1.3 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. I've since read that thirst activates the same brain area as hunger. After a full meal drink a glass of water if still feeling hungry. Also I've realized that hunger after a full meal is a deceptive message that does not need to be followed. This is the kind of craving that will leave quickly.

1.35 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)"

1.4 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.

1.5 Drink Adequate Amounts of Fluids: It's important to drink enough non-dehydrating fluids during the day—but only enough so that 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.

To gauge hydration: hold one's hand horizontal or place on a level surface with palm down. Pinch a bit of skin across the back of the hand (around the knuckles). If the ridge remains, hydration is needed. If the ridge flattens quickly, hydration is adequate.

1.6 Avoid constipation, which can be a source of inflammation and also a trigger for mast cell degranulation. (This is from my own experience, and was a surprise to me.) A small amount of magnesium citrate may help. Calcium supplements can be a cause of constipation, but I have found that calcium carbonate, eaten with meals to maximize absorption, tends not to be constipating. Lots of greens, vegetables and fruits, moderate amounts of nuts and whole grains, help decrease colon transit time, in my experience.

1.7 What to eat:
   i. Lots of greens and other vegetables and a smaller but significant amount of whole fruit ("smaller" to avoid too many simple sugars, especially fructose) —"... fruit and vegetable intake may play a potential role as a driver, not just of physical, but also of mental well being in the general population." in Major health-related behaviours and mental well-being in the general population: the Health Survey for England
  ii. Moderate, not a high amount of whole grains, to minimize the high glycemic load of overall diet that is contributed by most grains. Whole grains have phytate that is both a positive but also a negative in that it binds zinc and other minerals, so don't eat whole grains at more than one meal per day.
  iii. Moderate amounts of raw whole tree nuts (an ounce or two) and eat them with a calcium source to avoid absorbing too much oxalate. Remove the dark skins from nuts like hazelnuts (but not pecans or walnuts because the skin is thinner and quite impractical to remove) or soak in hot water and drain, to avoid large amounts of tannins that bind copper and proteins and lower their bioavailability.

2. Physical Activity:

Higher levels of physical activity, especially aerobic and strength training, strengthens skeletal and heart muscle, improves immunity, decreases inflammation, helps resist stress, improves sleep quality, improves brain function, decreases cardiovascular risk factors and 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 (150 minutes of sustained exercise at 40-60% of maximal aerobic capacity) helps strengthen the body, the immune system and decreases inflammatory C-reactive protein and interleukin-6. 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) reported that brisk walking speed reduced the risk of Metabolic Syndrome more effectively than longer, slower walks.

    • Reduces risk of cardiovascular disease. See recent article (Nov, 2017) Association of Physical Activity With Risk of Major Cardiovascular Diseases in Chinese Men and Women. Bennett et al (2017) "..higher occupational or nonoccupational physical activity was associated with significantly lower risks of major CVD. ...The associations of higher physical activity levels and CVD events may be mediated partly through established CVD risk factors, including improved profiles of inflammation, adiposity, blood lipids, and blood pressure. See this reference: Physical Activity and Reduced Risk of Cardiovascular Events: Potential Mediating Mechanisms, Mora et al. (2007) Lowering of cardiovascular risk by higher physical activity levels is a consistent finding across all people.

    • Helps fight depression: See Exercise as a treatment for depression: A meta-analysis adjusting for publication bias. Schuch et al (2015). The authors suggest that publication bias accounts for large differences, non-significant to large effects, for exercise efficacy in studies and other reviews. They conclude that "In MDD [Major Depressive Disorder], larger effects were found for moderate intensity, aerobic exercise, and interventions supervised by exercise professionals. ... Exercise has a large and significant antidepressant effect in people with depression (including MDD ). "Previous meta-analyses may have underestimated the benefits of exercise due to publication bias. Our data strongly support the claim that exercise is an evidence-based treatment for depression."
Depression is increasingly looked upon as an inflammatory illness, and thus the anti-inflammatory effects of frequent exercise may be the link to improvement seen. See this reference: Inflammation in Depression and the Potential for Anti-Inflammatory Treatment, Kohler et. al. (2016). "Thus, in light of the low remission and response rates among patients with depression, a better understanding of personalized antidepressant treatment regimens is needed. Anti-inflammatory intervention may represent one new line of treatment options that can be used in personalized treatment of individuals with depression and an inflammatory component."
In particular, endurance exercise appears to shift neurotoxic kynurenine production in the brain towards the production of non-toxic kynurenic acid within an hour of exercise (ref).

    • 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)

    • Avoid high doses of antioxidant supplements on exercise days: Large amounts of Vit C and Vit E before and after exercise prevents the "good oxidative stress" that prompts the body to respond to physical exercise with increase in muscle size (Vitamin C and E supplementation blunts increases in total lean body mass in elderly men after strength training Bjornsen et al. 2015 - Vit C 500 mg before and after exercise, and Vit E 117.5 mg before and after exercise) and prevents positive metabolic changes such as increase in insulin sensitivity and increase in endogenous ROS (reactive oxygen species) defense capability. (Antioxidants prevent health-promoting effects of physical exercise in humans Ristow et al, 2009 - Vit C-500 mg/twice a day and Vit E - 400 IU per day)

    • Negative effects of too much exercise: Repeated bouts of very strenuous exercise negatively effects the immune system. [see Exercise and the Immune System by Brolinson et al., Is it Time to Skip the Gym? by Robert Mocharla, MD (2014), Overtraining Syndrome by R. Budgett, and Dose of Jogging and Long-Term Mortality : The Copenhagen City Heart Study (Schnohr et al, 2015) – "...findings suggest a U-shaped association between all-cause mortality and dose of jogging ... Light and moderate joggers have lower mortality than sedentary nonjoggers, whereas strenuous joggers have a mortality rate not statistically different from that of the sedentary group."]
   Dealing with chronic physical stress requires more energy to support increased metabolism and tissue repair. Optimal maintenance of the immune system also requires energy. Immune cells have a high turnover rate and high metabolic activity, and depending on the type of cell, may include synthesizing and storing large quantities of inflammatory mediators, pumping out immunoglobulins (e.g. antibodies), surrounding, engulfing and destroying invaders. Energy and resources being limited, during periods of high stress, the body must choose to address the immediate danger of physical stress, or the relatively long term need for an optimal immune system. Often the immune system loses, so the adrenals pump out cortisol, which inhibits the immune system.

    • Avoid frequent swimming in chlorinated water: Asthma Very Common Among Olympic-Level Swimmers (K. Doyle, 2015) "Each year, between 12 and 25% of swimmers had asthma. In 2008, almost 25% of swimmers, 26% of open water swimmers and 22% of synchronized swimmers had asthma. In general, more athletes in endurance events like triathlon, pentathlon or cycling had asthma than those in nonendurance sports like fencing, volleyball or table tennis, the authors note. Asthma was more common in aquatic endurance sports, which included swimming, open water swimming and synchronized swimming, than in nonendurance events like diving... ." "It is exposure to the chlorine and chlorinated compounds that is responsible for the changes in airway hyper responsiveness," said Dr. Don McKenzie, who studies respiratory exercise physiology at the University of British Columbia in Vancouver. The more swimming you do, the more the risk increases, and elite {endurance swimming] athletes spend the most time with the chemicals...."If you swim in non-chlorinated pools, lakes, ocean etc. then the risk disappears," he said. Original abstract: Prevalence and characteristics of asthma in the aquatic disciplines by Mountjoy et al.

    • Exercise-induced anaphylaxis: For those with hypersensitive mast cells, exercise may induce release of inflammatory mediators. 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 muscle and perhaps also the 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.) But even so, regular exercise in most people is consistently associated with lower levels of inflammatory mediators and reduced fatty tissue inflammation. In the article, "Exercise Induced Anaphylaxis: A Clinical View" by Dascola and Caffarelli (2012). "The development of anaphylaxis during exertion often requires the concomitant exposure to triggering factors such as intake of foods (food dependent exercise-induced anaphylaxis) or drugs prior to exercise, extreme environmental conditions." The reaction to exercise may be in the form of bronchoconstriction characterized by asthma symptoms or cough. A doctor's advice is necessary but when food is a trigger, exercise should be done before eating in the morning or several hours after eating. Like exercise, the act of eating transiently releases inflammatory mediators, particularly after a high fat meal with resulting serum lipidemia. Fasting between meals limits postprandial inflammation to fewer hours during the day, while between meal snacking exposes the body to low grade inflammation throughout the day. See The Potential Ways for Preventing Postprandial Inflammation - A Review, Chiu et al (2013)

3. Stress Management

                                Be imaginative, turn stressful situations into challenges

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 anti inflammatory 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 the cholinergic 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
  iii) Acupuncture
  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.
   — Walk in Nature: Taking group walks in nature is associated with improved well-being, and lower stress and depression. See full article: Examining Group Walks in Nature and Multiple Aspects of Well-Being: A Large-Scale Study. An older study found that forest environments helped calm acute emotions, especially among those experiencing chronic stress. See the abstract: Psychological effects of forest environments on healthy adults: Shinrin-yoku (forest-air bathing, walking) as a possible method of stress reduction (Morita et al, 2006)


   — 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. Sleep

Since childhood and up until my early 50's, I never had problems getting to sleep or staying asleep. But then came a paralyzed stomach from a stomach virus that caused 24-7 nausea and heartburn, and my worsening neck, shoulder and back pain, so it was pretty hard to sleep and I did resort to sleep medication. About the time my stomach healed two years later, I developed a chronic inflammatory illness called Mast Cell Activation Syndrome (MCAS) that caused middle–of–the–night episode of heart palpitations, ear buzzing and intense anxiety, which made it difficult to stay asleep. Amazingly when the MCAS had calmed down and I'd recovered from my my posture-related pains plus weaned off anti-depressants, sleep meds and pain medication, I went back to sleeping fine. It wasn't until my first bout of insomnia when I lay awake in my bed until morning. It was like my brain had forgotten how to sleep, and my thoughts went to my father, who had died from Alzheimer's dementia. Insomnia is one of the early signs of Alzheimer's. But that morbid thought didn't stop me from searching the internet to find the reason I'd gotten insomnia. Since then, I've had insomnia more than a dozen times. My main problem is always initiating sleep. Once I get over that hurdle, I can stay asleep and return to sleep, even after waking to use the bathroom. The following are the reasons, as far as I can tell, that I got insomnia and what helped to get me out of it:

1. Milk—both a sleep promoter and a hidden cause of insomnia? — Being unable to tolerate calcium supplements, I drank around three cups of milk per day for over two years. When I began tolerating calcium supplements, I reduced milk consumption, mainly because I was eating way too much animal protein (3 cups of milk, 3 chicken drumsticks and 3 large bowls of plain oatmeal a day and luckily 1 1/2 Centrum Silver a day—the only 3 foods and the multivitamin (the old formula that had extra copper) that I didn't react to). Around this time I also began having severe insomnia; I'd lie awake all night long in some kind of semi-stupor—not able to rise but not able to sleep either. Occasionally I'd turn my head and check the clock, but that was anxiety-provoking. Also my mast cell reactions were increasing—my eyes became red-rimmed, ears buzzed, skin itched, and I had more ankle swelling—from lack of sleep. I didn't connect the insomnia and increased reactions to reducing my milk intake, which I had continued cutting by a half cup a week. I though it was from stomach upset from eating too much oatmeal. So I'd lower the oatmeal and be able to sleep a few days later. But then another bout of insomnia arrived, so I'd reduce the oatmeal more and again, a few days later I could sleep again. But with the next bout of insomnia, there was nothing more to reduce. I was pretty worried because the insomnia was torture. By this time, I had eliminated milk completely. And then I thought, why eliminate milk when I felt so much better with it? I added back a cup of milk and voila, slept like a "baby." Looking over my food journal, I realized that every time I reduced the milk, I couldn't sleep. Why was that? It wasn't the tryptophan content (melatonin is made from tryptophan—an amino acid from protein). My diet with and without milk had about the same amount of tryptophan (Thank you, NutritionSelfData). But milk has something else that could effect sleep. Digestion of casein milk protein produces casomorphin peptides that have opiate effects, at least in lab tests. A side effect of withdrawing from opiates is severe insomnia. So I concluded. at least for a sensitive person, that milk promotes sleep through the digestion product, casomorphin. But erratic consumption may cause insomnia from withdrawal effects – just like opiates, benzodiazepines or sleeping pills. As I result of all this back and forth with insomnia, and other reported negative effects including that the breakdown product of lactose milk sugar, galactose, is inflammatory and used to mimic aging in mice, and that the growth hormone in milk intended for young animals, not older adults, in which excess growth hormone could encourage cancer growth, and finally, that milk seems not to increase bone density in older women even though high in absorbable calcium. So I currently do not include milk in my diet. I react to all other dairy products, I've tried. Most are either high in histamine, because they are fermentation products such as hard cheeses like parmesan and swiss, or were processed with vinegar, which is also a fermentation product also as well as a mast cell irritant.

2. Flaxseed, a sleep killer? — After the milk debacle, I slept well for quite a while, but then began experimenting with adding back foods to my diet. One of the first I didn't react to was ground flaxseed. I enthusiastically added it to at least 2 of my 3 meals. Then a while later, total insomnia for days. At first I didn't connect my insomnia to ground flaxseed, but come to find that flaxseed is the only food that contains a natural inhibitor of vitamin B6 called linotene, a substance that binds to and prevents B6 from being absorbed. The B6 depleting property of flaxseed was discovered when chicks fed flaxseed got sick and didn't grow. Supplementing the flax with B6 allowed the chicks to develop normally. So I'd made myself B6-deficient and had insomnia as an early symptom, which is understandable since B6 is needed to make melatonin, a hormone that signals time for sleep when light (particularly blue light) is low and it's the usual time for sleep. B6 is also a cofactor in at least a hundred other enzyme reactions in the body. This was an easy fix—just eat the ground flax at one meal a day, and take the multi-vitamin with B6 at another meal. Problem solved.
A precaution: Do not supplement with the inactive pyridoxine form of B6, which needs to be converted to the active pyridoxal form in the body; a little pyridoxine in a multi-vitamin is fine, but at higher doses, unchanged pyridoxine can cause permanent neuropathy by inhibiting binding of the active form—pyridoxal-5-phosphate. (The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Vrolijk et al., 2017)

3. Too much zinc, too little copper, a sleep killer! Again, I couldn't sleep. Part of the problem was the darn buzzing in my ears from increased mast cell reactions, but that wasn't the entire problem. I could lessen the buzzing with a dose of histamine-blockers, but my mind was wide awake, like my brain had forgotten how to sleep.

I'd been adding back foods and could tolerate a surprising number, including sweet potatoes, carrots, broccoli, cauliflower, kale, endive, leaf lettuce. several kinds of berries and high protein garbanzo beans. Now I could cut back on the chicken and oatmeal. The oatmeal in particular, which I'd always worried about how much I was eating because of the high amount of phytates that bind to minerals, especially zinc and prevent absorption; so I'd always added a little zinc gluconate to my oatmeal in addition to the zinc oxide in the Centrum Silver multivitamin. It was after I cut back on oatmeal that insomnia struck again, along with increased mast cell episodes at night. I already knew that taking too much zinc inhibited copper uptake, but as far as I knew it took a lot more zinc than I supplemented to interfere with copper levels. But a web-search revealed that it might take a lot less zinc to reduce copper absorption. So why would I be so sensitive to low but normal copper? Well, as it turned out, DAO, one of two enzymes that breaks down histamine, is dependent on copper as a co-factor. And my illness causes high histamine, so I'm very sensitive to increased levels. Too much histamine, depending on how much, can cause itching, bloodshot eyes, diarrhea, increased asthma symptoms, and at really high levels, cardiovascular collapse and death (ref.) Surprisingly, histamine in the brain also acts as a neurotransmitter that increases wakefulness. No wonder I couldn't sleep. So to raise my copper levels, what if I stopped the zinc gluconate, relied on the zinc oxide (less bioavailable form) in Centrum Silver, and supplemented with copper gluconate. (By coincidence, Pfizer had just reformulated Centrum Silver, lowering copper.) You might wonder, why this reticent approach. Why not take lots of copper and be done with it. But I was hesitant because of the association of excess copper with Alzheimer's disease. But insomnia also increases the risk of Alzheimer's, and besides, I felt miserable from lack of sleep. So I began taking copper, about one mg/day: and voila, a couple of days later, sweet sleep returned! (I lowered the amount of supplemental copper to about 1/4 mg a day. I'm still not comfortable with it, but my sleep is still good as long as everything else is taken care of too.)

So why am I so sensitive to low blood levels of copper (a lab test showed I was low normal)? The reason might be found in my 23andMe raw data; both copies of my DAO histamine-degrading enzyme are low activity variants associated with histamine intolerance. My theory is that a higher than minimal copper level is needed to stabilize low activity DAO structure. A similar mechanism exists for heat-sensitive, unstable MTHFR variant, 677T, where supplementing folate stabilizes and improves the variant enzyme"s function. (Guenther et al, 1999) and (de Bree et al., 2003)

4. Sleeping too long to make up for a acute insomnia or frequent sleep interruptions can cause chronic insomnia; who would have thought!! Okay, I was having another bout of insomnia. And none of my previous fixes helped. I knew I had been staying up late on the computer, not sleeping well or not being able to get too sleep until 3 or 4 in the morning, and then sleeping more than 9 hours into the late morning or early afternoon to make up for it. And even at that, I still have a hard time getting up. I thought, because of how late I fell asleep or how poor my sleep was, that my brain just needed the extra sleep. One particular night I didn't get to sleep at all, and had to get up anyway by 4 am to drive my husband to the airport. I decided not to sleep at all that day, but went to bed earlier and for the first time in weeks, got right to sleep and slept well. So not sleeping allowed me to sleep well the next night. Interesting. I consulted the internet again and found an article on Sleep Restriction and Behavioral Therapy for Insomnia: Too Much Time in Bed May Diminish Sleep Efficiency. So what I needed to do was go to sleep earlier and get up earlier. And that did it: the end of another adventure in insomnia. However, another factor was probably involved in this episode and that was blue light from my computer screen.....

5. Too much screen time and any other source of blue light, another sleep killer! A common problem. Surfing the internet and seeing how friends are doing on Facebook are addictive. It's so easy to put off going to sleep and keep clicking away. I knew that light from computer screens, TVs and mobile phones is reputed to interfere with sleep because bright light and especially the blue wavelengths at night reduce melatonin levels. But somehow I thought I was immune. But I couldn't think of another reason why I had insomnia again! So I put f.lux on my desk-top computer, got amber lenses for a pair of glasses, lowered house lights and turned on the night screen option on my cell phone. It worked, I slept well again. Another insomnia mystery solved.

6. Creatine: spares methylation, is a miracle muscle builder, and improves brain performance, just not for me! I had total insomnia again and the only thing I'd changed was to supplement creatine monohydrate. I began creatine to:
   i.) Spare methylation – I have the low activity variant of the MTHFR gene and creatine synthesis required over 40% of body's methylation capacity. Consuming creatine ready-made in animal meat helps lower the need for methylation, but I don't eat much meat.(Listen to Chris Masterjohn's podcast, Living with MTHFR).
  ii.) Build muscle and increase endurance
 iii.) As a plus, to increase brain power in those who eat low animal meat diets or are sleep-deprived. Oral creatine monohydrate supplementation improves brain performance, Rae et al. (2003), and
I began slow, taking a quarter gram in the morning and had no problems, and then half a gram twice a day, which is when the insomnia began. Being the only thing I'd changed lately, I stopped the creatine and the insomnia stopped. Then I added back one quarter gram and had insomnia again. Then an eight of a gram, again insomnia. Somehow my brain had become sensitized to creatine, so I had to stop altogether. Why would I get insomnia from creatine? I'd never read about insomnia being a side effect. But another internet search turned up anecdotal reports of insomnia by body builders, but no controlled studies. I searched PubMed and found a study showing that rats supplemented with creatine needed less sleep. No use continuing, so I stopped the creatine and no more insomnia...of that type...at least. (Recently I restarted with 1/8 gram in the morning. So far no insomnia.)

6. Other measures that improve sleep quality:
     • Lowering bedroom temperature signals the brain that it is time to sleep.

     • Ventilation: I sleep better with my bedroom window open a bit. Maybe this article explains why: The effects of bedroom air quality on sleep and next-day performance, Strom-Tejsen et al. (2015) Sleep quality, next-day sleepiness and test performance "...improved significantly when the CO2 level was lower...." Of course, poor outdoor air quality and high noise levels would worsen sleep if a window was left open.

     • White Noise Machine: Nightly use effectively reduces my episodes of mast cell releases, and if I miss one night, the night-time episodes come right back. (Sometimes white noise reminds me of sounds I've heard underwater. Perhaps white noise triggers a primal memory of being a fetus and sloshing around in amniotic fluid? I wonder, do babies sleep better with white noise machines?)

     • Nutrient deficiencies: If you think your diet doesn't contain enough vitamins and minerals to meet daily needs, consider a multivitamin that provides 100% or less of Daily Values of vitamins and minerals such as zinc, copper, and selenium. Vitamins such as B6 are necessary as co-factors in the synthesis of melatonin. Supplement with magnesium sepparate from calcium, which interferes with uptake of several other minerals. Use magnesium citrate or similar magnesium compounds (but not magnesium oxide, which is poorly absorbed). Magnesium citrate (200mg/day) stopped my nightly leg cramps, which helped me sleep better.

     • Avoid Supplementing with too much Vitamin D. High blood levels of Vitamin D may decrease natural production of melatonin. See The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis. Golan et al. (2013) After 3 months supplementation, 25-OH-D levels increased and nighttime melatonin secretion decreased significantly in the high dose group, but not in the low dose group. Repletion of vitamin D associated with deterioration of sleep quality among postmenopausal women. Mason et al. (2016) Postmenopausal women whose serum Vit D rose above 32 ng/ml in response to supplementing 2000 IU vit D3 per day during a weight loss and exercise program had worse sleep quality than women whose serum Vit D stayed below 32 ng/m despite supplementation or did not have supplementation.

     • Eating Late at Night interferes with sleep and confuses the body's sleep-wake cycle.

     • Sleep Medications 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 more sleepless nights. Benzodiazepines (Xanax, Atavan, Valium) are particularly difficult to stop and must be tapered over many weeks to months to avoid 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, but only by 15 minutes. 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. The Sleep-Diabetes Connection. Long term use can cause worsening of depression. see the article "10 things the sleep-aid industry won't tell you"

     • Avoid NSAIDS (such as aspirin and ibuprofen) — Nonsteroidal Anti-Inflammatory Drugs affect normal sleep patterns in humans.(Murphy et al, 1994) NSAIDs probably interfere with deep sleep via inhibition of protaglandin D production in the brain. See Prostaglandin D synthase gene is involved in the regulation of non-rapid eye movement sleep (Pinzar et al, 2000).

[For those who tolerate Nsaids; they can reduce night-time polyuria.]

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. Maybe it's both; whatever the cause, my dreams are more vivid and troubling when I've been exposed to a mast cell triggering situation during the day. (Histamine is a neurotransmitter, and directly increases arousal in the brain.)

Tips to 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.
      • 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.

See Imagery Rehearsal Therapy for Chronic Nightmares in Sexual Assault Survivors With Posttraumatic Stress Disorder: A Randomized Controlled Trial, Krakow et al.

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.

Interesting Sleep Articles

On making 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. ref

Schmid 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..."

See the article Bedtime procrastination: introducing a new area of procrastination by Kroese et al. (2014) "...procrastination may also lead to harmful outcomes in the area of health behavior, introducing bedtime procrastination as an important factor related to getting insufficient sleep and consequently affecting individual well-being. Bedtime procrastination is defined as failing to go to bed at the intended time, while no external circumstances prevent a person from doing so. ...people who scored lower on self-regulation variables reported more bedtime procrastination."

    — 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.

5. Others

Don't Overuse Over The Counter (OTC) Medications That Degranulate Mast Cells and Inflame the Gut – and especially NSAIDS, which stands for non-steroidal anti-inflammatories. These include such as aspirin, Ibuprofen and Naproxin. Nsaids are not multi-purpose anti-inflammatories but anti-prostaglandins [some prostaglandins are inflammatory and some are needed for health such as in kidney and stomach lining], because they block the COX enzyme that makes prostaglandins from arachidonic acid, a polyunsaturated omega-6 fatty acid. but blocking the cox enzyme then allows the excess arachidonic acid to be shunted to the inflammatory leukotrienes by way of the LOX enzyme, which is probably why mast cells degranulate (release inflammatory mediators) when Nsaids are taken. Thus, the increased risk of heartburn, stomach upset or other reactions (e.g. tinnitis, facial flushing, heart palpitations, poor sleep).
  — 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.)

Since beginning my efforts to reduce body wide inflammation, I have had less overall musculo-skeletal pain, and after exercise (30 mins of step aerobics, another 30 minutes of stretching and strengthening with light weights) any soreness tends to resolve by the next day. Some of this pain improvement, especially the upper back/shoulder muscular pain, the spinal and perhaps the big toe joint pain, is probably due to postural improvement, but I believe that avoiding my inflammation triggers (especially dietary) has also played a role. [Of course this is not proof, but I feel much better, so I will keep doing what I'm doing.]

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.

— neopterin

— 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.

See 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.

 

 

© 2017 Rochelle Cocco