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What I’d Really Love to Tell You About the Methylation Cycle

Dr. Hank Liers, PhD geneticsI previously published “Homocysteine Genetics – Coenzyme B Vitamins” in which I considered in-depth how homocysteine (an intermediate chemical in the Methylation Cycle) is formed from methionine, how genetics affects the metabolic pathways, and how B vitamins are used in metabolic pathways. I also wrote “Folate Ingredients – Folinic Acid & 5-MTHF” which discussed how coenzyme folate vitamins are far superior to the synthetic folic acid form. In today’s article, I take a broader view of the topic that encompasses the Methylation Cycle, genetics, and B vitamins.

THE METHYLATION CYCLE

The Methylation Cycle is considered to be one of the most important metabolic pathways in the human body. Its most important function is to provide methyl groups via SAM (S-adenosyl methionine) to hundreds of different body substrates. Methylation is continually occurring in the body, transforming many millions of molecules throughout the body every second. Molecules receive methyl groups, then separate and recombine continuously, transforming and reforming constantly in the ongoing process of life!

As a reminder of the pathways involved in the Methylation Cycle, the following figure provides a flow chart showing the details.

 

Methylation Cycle

Figure 1. Metabolic Pathways in Methylation Cycle

A key purpose of this cycle is to provide methyl groups (CH3) needed by a broad range of of body functions (over 200 different functions). Examples include:

  1. Influences the genetic expression that parents give their children and helps guide the development of the embryo.
  2. Is needed by the nervous system to produce neurotransmitters and maintain the nerves.
  3. Mobilizes fats and cholesterol so they do not accumulate where they are harmful, such as the arteries and liver.
  4. Regulates hormones, including, estrogen, adrenaline, and melatonin.
  5. Detoxifies harmful chemicals and histamine a prime substance involved in inflammation.
  6. Helps repair damaged proteins in the cells so they can function properly.
  7. Protects the DNA in the genome (genetic code) to reduce the chances of mutation.
  8. Creates antioxidants used in the antioxidant defense system.

DESCRIPTION OF PATHWAYS WITHIN THE METHYLATION CYCLE

The overall flow of the Methylation Cycle begins with dietary methionine (an essential amino acid) which combines with ATP (adenosine triphosphate – body energy) to form SAM (S-adenosyl methionine) – the common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. When SAM transfers a methyl group to a body chemical the residue from this reaction leads to the production of homocysteine.

Homocysteine can be converted in the transsulfuration pathway that requires coenzyme vitamin B6 to produce cysteine, glutathione, taurine, and sulfates. These sulfur containing substances provide important antioxidant protection and detoxification functions in the body.

Homocysteine can be converted back to methionine through the betaine (trimethyl glycine) pathway which requires zinc and magnesium. This pathway also requires dietary betaine or choline which the body can convert into betaine.

Also, homocysteine can be converted back to methionine via the remethylation pathway which requires 5-MTHF, coenzyme vitamin B2 and methylcobalamin (B12).

GENETICS

It is important to understand that each of the pathways described above are able to be executed only in the presence of enzymes (shown in blue boxes in the diagram) created by specific genes in your genetic code. For example, Betaine-Homocysteine S-Methyltransferase (BHMT) is the enzyme required in the betaine pathway, Cystathione Beta Synthase (CBS) is the enzyme required in the transsulfuration pathway, and Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase (MS) are enzymes required in the remethylation pathway.

Assuming that you have perfect genetics (no mutations, SNPs, free radical damage, insertions/deletions, etc.), the proper functioning of these pathways are still subjected to the fact that the required vitamins and minerals (vitamin B6, vitamin B2, Folate, vitamin B12, zinc, magnesium, and betaine) need to be provided by your diet or from supplements for the body to function correctly.

In addition, exposure to high levels of toxins from your environment and high levels of stress require that the nutritional needs will be even higher for the pathways to work properly. For example, exposure to high levels of toxins requires that the transsulfuration pathway be more active possibly reducing the amount of available methionine to support necessary methyl transfer reactions.

For these reasons alone the consensus of knowledgeable practitioners is that you should be eating an organic whole foods diet, taking appropriate nutritional supplements, avoiding and eliminating toxins from food, water, and air (living in a clean environment), and avoiding an unduly stressful life. All of these actions fall into the category of Epigenetics which you generally have control over!! Doing these things alone could significantly balance the functioning of your Methylation Cycle and improve your health.

Unfortunately, few people have perfect genetics which often causes the various pathways in the Methylation Cycle to become imbalanced and unable to correct the dysregulation imposed upon the body. For example, the enzyme MTHFR can have heterozygous (single chromosome) genetic variations in up to 50% of certain populations and homozygous genetic variations (both chromosomes) in 10% or more of certain populations.

Some disorders that researchers have associated with MTHFR genetic variations include:

  • Alzheimer’s disease
  • Asthma
  • Atherosclerosis
  • Autism
  • Bipolar disorder
  • Bladder issues
  • Blood clots
  • Breast problems
  • Chemical sensitivity
  • Chronic fatigue syndrome
  • Down syndrome
  • Epilepsy
  • Fibromyalgia
  • Gastric problems
  • Glaucoma
  • Heart murmurs
  • High blood pressure
  • Irritable bowel syndrome
  • Leukemia
  • Male infertility
  • Methotrexate toxicity
  • Migraines with aura
  • Multiple sclerosis
  • Myocardial infarction
  • Nitrous oxide toxicity
  • Parkinson’s disease
  • Pulmonary embolisms
  • Schizophrenia
  • Stroke
  • Thyroid issues
  • Unexplained neurologic disease
  • Vascular dementia

This extensive list is highly significant and tells us that it is very important to have genetic testing done for the genes/enzymes in the Methylation Cycle pathway. I prefer the BodySync genetic test which evaluates the key Methylation Cycle genes plus many other important genes in a single test.

B VITAMINS AND MINERALS

We are strong believers that everyone should start their nutritional program by eating a balanced, organic, whole foods diet. We have been doing this ourselves for the past 30 years. Unfortunately, only a small percentage of people follow this advice and in most cases this leads to poor nutritional status that does not adequately support the body’s needs. This is especially true with respect to obtaining the nutrients needed to support the Methylation Cycle.

Nine of our family members and associates have taken the BodySync genetic test which evaluates the condition of 45 different enzymes including CBS, MTHFR (2 variations), MTR (related to B12 and 5-MTHF as they relate to methionine synthase – MS), and MTRR (related to maintaining B12 levels needed by the MTR enzyme). In every case the results showed at least 2 and up to 4 enzymes had genetic variations. These results indicate that the nutritional requirements for folate as 5-MTHF, vitamin B12 as methylcobalamin, vitamin B6, vitamin B2, magnesium and zinc will likely be significantly greater than normal.

Given the above information, it seems essential for good health to take nutritional supplements that provide the important nutrients. Below I will discuss various formulas that I have developed and refined over many years that are useful especially for the Methylation Cycle.

Please note that Health Products Distributors, Inc. (HPDI) is the preferred supplier of nutritional supplements by the BodySync genetic testing company.

MULTIVITAMINS

When looking at the total needs the body has for nutrients that the body does not produce, including fat soluble vitamins (A, D (some), E, K1 and K2), vitamin C, B vitamins (B1, B2, B3, B5, B6, folate, B12, biotin, choline, and inositol), minerals (Ca, Mg, Zn, Se, Cu, Mn, Cr, Mo, K, boron, and vanadium), and betaine it only seems wise to include as a top priority a Multivitamin that includes all of these in what I term therapeutic amounts (carefully selected after evaluating thousands of research studies carried out over many years.)

In this context, it is important to recognize that every enzymatic reaction in the body requires mineral cofactors in order to carry out its function. A good multivitamin provides many of these required minerals.

Additionally, the multivitamin should contain ingredient forms that research has confirmed to be the most absorbable and usable by the body. These include coenzyme B vitamins, Krebs cycle (citrate, alpha-ketoglutarate, succinate, fumarate, & malate) minerals, and amino acid chelates.

In the context of supporting the Methylation Cycle we are looking for specific forms and amounts of B vitamins that can adequately provide the body’s needs. The means that there should be coenzyme folate as 5-MTHF of at least 400 mcg, coenzyme vitamin B-12 as methylcobalamin of at least 200 mcg, Vitamin B6 (including significant amounts of pyridoxal 5′ phosphate) of at least 40 mg, and Vitamin B2 (including significant amounts of riboflavin 5′ phosphate) of at least 25 mg. In addition, magnesium (100 mg) and zinc (at least 20 mg) should be provided.

Please note that the body’s requirements for magnesium is generally accepted by nutritional experts to be higher than 400 mg daily (and as high as 1,000 mg daily). For this reason we generally recommend that a person take supplemental magnesium (such as HPDI’s MYO-MAG) at levels over 400 mg daily.

The two multivitamin formulas Health Products Distributors provides for adults that meet these requirements (and more) are the Hank & Brian’s Mighty Multi-Vite and Multi Two (in both capsule and tablet forms). Click on the bottles below for technical details.

Hank & Brian's Mighty Multi-Vite multivitamin methylation cycle

Multi Two Caps or Tablets methylation cycle

B COMPLEX

In situations where significant genetic variations are present it may be wise to add a B COMPLEX supplement to the MULTIVITAMIN to provide even larger amounts of the needed B vitamins. HPDI provides a B-Complex-50 product that includes significant amounts of coenzyme forms and contains 50 mg of Vitamin B1, 50 mg of Vitamin B2, 100 mg of Vitamin B3, 50 mg of Vitamin B6, 500 mcg of coenzyme folate (both folinic acid and 5-MTHF), 100 mcg of B12 (both methylcobalamin and hydroxocobalmin), 50 mg of Vitamin B5 (pantothenic acid), 500 mg of Biotin, 50 mg of choline, and 50 mg of inositol. Click on the bottle below for technical details.

B-Complex-50 full spectrum B vitamins with coenzyme forms methylation cycle

FOLATE AS 5-MTHF

In situations where an inadequate diet is present and genetic testing indicates an MTHFR variation (especially a homozygous variation) Health Products Distributors provides a 5-MTHF folate supplement that easily absorbs into the body and can be directly used in combination with Vitamin B12 to convert homocysteine to methionine. Click on the bottle below for technical details.

5-MTHF 1 mg in veggie cap methylation cycle

5-MTHF 1 mg in veggie cap

B-12 as METHYLCOBALAMIN

It is often the case for older patients and vegetarians that Vitamin B12 is deficient. In these cases it is wise to supplement with a significant amount of methylcobalamin to ensure that the Methylation Cycle has sufficient to effectively convert homocysteine into methionine. Health Products Distributors Vitamin B12 contains 5 mg of methylcobalamin in sublingual lozenge form that supports excellent absorption even if swallowed and absorbed by diffusion. Click on the bottle below for technical details.

Vitamin B-12 5 mg methylcobalamin sublingual lozenge methylation cycle

Vitamin B-12 – 5 mg Methylcobalamin sublingual lozenge.

MINERALS

Magnesium and zinc are two important minerals used in the betaine pathway of the Methylation Cycle in which homocysteine is converted back to methionine.

In the body magnesium is involved in more than 400 essential metabolic reactions and is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP). Therefore, it also is involved in converting methionine to SAM.

Over 300 different enzymes depend on zinc for their ability to catalyze vital chemical reactions. Zinc-dependent enzymes can be found in all known classes of enzymes.

Health Products Distributors provides 100 mg magnesium/vcap in its MYO-MAG supplement which is especially important in increasing ATP in the Krebs Cycle. This product also contains vitamin B1, vitamin B2, and vitamin B6 with substantial amounts of coenzyme forms and manganese. Click on the bottle below for technical details.

MYO-MAG with 100 mg magnesium per serving key B vitamins methylation cycle

MYO-MAG with 100 mg magnesium per serving and key B vitamins.

Health Products Distributors provides 25 mg zinc/serving in its Double Zinc Plus supplement. This formula provides zinc in the picolinate and citrate forms as well as 3 mg of P5P (coenzyme B6). Click on the bottle below for technical details.

Double Zinc Plus supplement with P5P and 25 mg zinc methylation cycle

Double Zinc Plus supplement with P5P and 25 mg zinc

SUMMARY

The Methylation Cycle is recognized as one of the most important metabolic pathways in the human body. When not properly supported by key B vitamins and minerals, the Methylation Cycle can become severely imbalanced which can lead to a very wide range of poor health conditions. Furthermore, genetic variations in the genes that produce important enzymes allowing the Methylation Cycle to function correctly lead to even further imbalances and greater possibility for conditions of poor health.

In this article, I have provided insight into how the Methylation Cycle works and how it can be significantly supported by lifestyle changes regarding diet and environment (Epigenetics) and by specific B vitamins and mineral supplements that I have developed over many years. In addition, we have shown that knowledge gained from genetic testing can further provide a critical understanding of your specific needs so that your health can be optimized.

RELATED HPDI BLOG ARTICLES

Homocysteine Genetics – Coenzyme B Vitamins

 

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OMEGA-3 ESSENTIAL FATS REMAIN “ESSENTIAL” – A REBUTTAL FROM OMNS

Fred Liers PhD omega-3 essential fats plus e EFA formulaOmega-3 essential fatty acids (EFA) are critically important for health. That is the reason we at HPDI include them in our foundational supplements system in the form of our Essential Fats Plus E formula. Essential Fats Plus E provides a balanced ratio of 4:1 omega-3 EPA to omega-6 GLA fatty acids proven to optimally support health.

As important as Omega-3 fats are in good health, various studies conclude they are of little value. In order to help clarity the fallacies found in such studies, this month we re-print the recent article “Omega 3 Fatty Acids and Cardiovascular Disease” from the Orthomolecular News Service (OMNS).

BACKGROUND

Essential fats including Omega-3 and Omega-6 are so important to health that we consider them as foundational or “core” to basic nutrition as multivitamins, antioxidants/vitamin C formulas, and high-RNA superfoods, like Rejuvenate! Plus.

Many of today’s health problems relate to deficiencies in Omega-3 essential fatty acids rather than overabundance of it. It makes sense for everyone to supplement their diets with at least a minimum amount of essential fats. This is addition to consuming foods high in Omega-3 (and Omega-6) essential fats, including leafy greens, nuts, seeds, and seed oils. Also, small amounts of wild-caught fish from clean waters. Preferably these fish would come from low on the food chain, such as sardines, herring, or young mackerel, for example.

In December 2107, my father Hank Liers, PhD, wrote “The Truth about Essential Fatty Acids.” In his article, he delves into detail about why essential fatty acids are critical for health.

The diagram below from Dr. Hank’s article shows in detail the pathways for the production and use of fatty acids in the body. In the figure the metabolic pathways (running left to right) for four fatty acids types are shown (top – Omega-3, second – Omega-6, third – Omega-9, bottom – Omega-7). Notice that only the omega-3 and omega-6 oils are considered to be essential fatty acids because they cannot be made in the body. This means they must come from food.

omega-3 fats omega-6 fats

Furthermore, an additional diagram from Dr. Hank’s article shown below provides details of the omega-6 and omega-3 pathways. Pathway specifics indicate key eicosanoids (series 1 prostaglandins [anti-inflammatory], series 2 prostaglandins [pro-inflammatory], and series 3 prostaglandins [anti-inflammatory]), oil sources, and important nutrient cofactors that are needed for the reactions to take place.

omega-3 fats omega-6 fats

In particular, Dr. Hank discusses how superior benefits to health result from a balanced 4:1 ratio between Omega-3 eicosapentanoic acid (EPA) fatty acids and Omega-6 gamma linoleic acid (GLA).

Below we list some of the functions and benefits obtained when by diet or supplementation the correct ratios and amounts of essential fatty acids are consumed.

• Regulate steroid production and hormone synthesis
• Regulate pressure in the eyes, joints, and blood vessels
• Regulate response to pain, inflammation, and swelling
• Mediate Immune Response
• Regulate bodily secretions and their viscosity
• Dilate or constrict blood vessels
• Regulate smooth muscle and autonomic reflexes
• Are primary constituents of cellular membranes
• Regulate the rate at which cells divide
• Necessary for the transport of oxygen from the red blood cells to tissues
• Necessary for proper kidney function and fluid balance
• Prevent red blood cells from clumping together
• Regulate nerve transmission

Dr. Hank also discusses the fallacy of thinking that supplemental Omega-3 fats alone are sufficient to produce health. That is, despite the relative lack of Omega-3 essential fats and the prevalence of Omega-6 fats in modern diets, it is nevertheless the forms (EPA and GLA)—and the critical 4:1 ratio between them—that makes the difference in how they act synergistically for health. The result of Hank’s scientific understanding of essential fatty acids has resulted in his formulation of a balanced EFA product, Essential Fats Plus E.

Orthomolecular Medicine News Service Article “Omega 3 Fatty Acids and Cardiovascular Disease”

Regarding the Orthomolecular Medicine News Service article “Omega 3 Fatty Acids and Cardiovascular Disease” (republished below) rebutting the “Cochrane Database of Systematic Reviews” which relies on so-called “Evidence Based Medicine” (EBM) to distort truth on Omega-3 essential fatty acids, the fact that Omega-3 fats are under such false attack represents a huge disservice to the public.

While essential fatty acids may not generate profits for corporations—and in fact may lead to improved health outcomes that threaten the use of chemicals and drugs—essential fats nevertheless remain foundational for health.

Above we have shown the important reasons Omega-3 fats and other essential fatty acids are scientifically termed “essential.” And why people continue taking essential fats, and giving them to their families and children, for supporting health and well-being. Primary among these reasons is that you cannot be healthy without them. Hence, they are essential. Why believe anyone who says otherwise?

The bottom line: Omega-3 essential fatty acids are critical for health. Supplementing the diet with them is a good idea for nearly everyone. This is especially true because typical diets are proven to be most deficient in Omega-3 among essential fats.

Below we re-print in full the recent article “Omega 3 Fatty Acids and Cardiovascular Disease” from the Orthomolecular News Service (OMNS) for the benefit of our HPDI blog readers. ~

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FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, Aug 6, 2018

Omega-3 Fatty Acids and Cardiovascular Disease

Commentary by Damien Downing, MBBS, MSB and Robert G. Smith, PhD

The Cochrane Database of Systematic Reviews has just updated its own review: Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease [1]. Here’s our take on it.

Michael Pollan, the brilliant food writer, reckoned you could sum up what to do about nutrition and diets in 7 words; “Eat food, not too much, mostly plants.” That sums up both what’s best for humans and what’s best for the planet.

We reckon you can sum up what’s wrong with evidence-based medicine (EBM) in 10 words; “Evidence is a waste of data; systematic reviews are palimpsests.” You can use that as a knife to quickly dissect this study.

There are many things wrong with this review. Somebody’s PR department has spun the review’s “no clear evidence of benefit” into “evidence of no benefit” – absence of evidence becoming evidence of absence. And clearly the media were entirely happy to take that one and run with it.

Systematic reviews are palimpsests

What’s a palimpsest? Back when things got written on vellum, an animal skin, not on paper, you didn’t throw it away; you recycled it and wrote over the original. It was called a palimpsest.

A systematic review gives an opportunity to write over the conclusions of a whole list of papers with your new version of the truth. You do that by the way that you select and exclude them.

For instance there was a meta-analysis (that’s a systematic review with more numbers) in 2005 that concluded that vitamin E supplements significantly increased the risk of death [2]. The way they did that was to rule out any study with less than 10 deaths – when fewer deaths was exactly the outcome they were supposed to be looking for.

The reason they gave for doing that was “because we anticipated that many small trials did not collect mortality data.” We’re not buying it; they used it as a trick to enable them to get the negative result they wanted – to over-write the findings of a long list of original studies.

And here we have authors doing the very same thing in this omega-3 study – and upping the ante slightly. Now the threshold is 50 deaths. Fewer than that and your study is ruled out of the final, supposedly least biased, analysis . . on the grounds that it’s more biased.

We don’t know how they could keep a straight face while saying (our interpretation); “The studies with fewer deaths showed more benefit from omega-3s, so we excluded them.” At least that’s what happened back in 2004 when the first version of this came out.[3]

But this is the 8th update (we think) and they no longer bother to tell you about what they included or excluded in detail, so we can only assume that if they had changed that exclusion they would have told us.

The weird thing is that they are allowed to do it. Nutrition researcher Dr. Steve Hickey has shown that in systematic reviews there is generally control for bias in the included studies, but none for bias in the actual review and its authors.[4,5]

They found not one example of adequate blinding among 100 Cochrane reviews (like this one); they could all be palimpsests. Do we know that they are fake? No, but it doesn’t matter: what we do know is that we can’t trust them. Nor can we trust this Cochrane review. Things haven’t changed since 2004.

Evidence is a waste of data

Evidence is what lawyers and courts use to find someone Guilty or Not Guilty, and we all know how that can go wrong. It’s a binary system: you’re either one or the other. But at least if you’re on trial all the evidence should be about you and whether you did the crime.

In EBM the evidence is all about populations, not about individuals. When a doctor tells you “There’s a 1 in 3 chance this treatment will work” he is required to base that on big studies, or even systematic reviews. You don’t, and you can’t, know what that means for you because very likely you don’t fit the population profile.

As Steve Hickey (again) said, the statistical fallacy underlying all this states that you have one testicle and one ovary – because that’s the population average! The authors of this study update started off with about 2100 papers that looked relevant. They then excluded 90 per cent of them for various reasons – some of them good reasons, some not.

A smarter way to work would be to data-mine them and look for useful information about sub-groups and sub-effects in all the papers. Is there a particular reason omega-3s might work for you and not for others? Perhaps you can’t stand fish, or are allergic to them, and so are deficient in omega-3s.

But the review system doesn’t allow it, it insists on overall conclusions (about populations), and that’s a colossal waste of data. It also confounds the overall finding of the review – it biases it in fact.

Here’s an example: while most subgroups that made it to the final analysis showed a small reduction in risk from taking omega-3s in one form or another (pills, food, whatever), those who got it from supplemented foods, which we understand means stuff like margarine with added omega-3, showed a 4.3-fold death risk increase!

The problem here is that the effects of omega-3 fatty acids cannot be studied alone as if they were a drug. What counts are all the other components of the diet that affect a person’s health.

Processed foods and drinks that contain many unhealthy ingredients can’t be made healthy by adding small doses of vitamins, minerals, and omega-3 fatty acids. In fact, many processed foods that contain small doses of vitamins and other essential nutrients are unhealthy because they contain large doses of sugar, salt, and harmful ingredients such as preservatives, dyes, and other non-food items.

Why lipids are so important

Part of the problem is that lipids are truly complicated, and not many people, patients, doctors or even scientists, understand them well. You need a good understanding of lipid metabolism to appreciate the difference in metabolism and impact between alpha-linolenic acid (ALA, in food such as oily fish) and extracted oils such as EPA and DHA that are only found at high levels in omega-3 supplements.

At these levels they are effectively new to nature; nobody, indeed no mammal, was exposed to really high doses of DHA until we invented fish oil supplements [6]. Miss that fact and you miss the difference between having people eat fresh oily fish or just using omega-3 margarine!

We know from a variety of studies that a diet containing generous portions of green leafy and colorful vegetables and fruits, moderate portions of eggs, fish, and meat, and supplements of adequate doses of essential nutrients (vitamins and minerals) is effective at lowering the risk for cardiovascular disease.

Adequate doses of both omega-3 (in flax oil, walnuts, fish) and omega-6 (in seed oils such as canola, soybean, peanut) fatty acids are essential for health. Although essential, omega-6 fatty acids are thought to contribute to inflammation throughout the body whereas omega-3 fatty acids are anti-inflammatory.

Omega-3 fatty acids are essential for most body organs including the brain but are found in lower levels than omega-6 fatty acids in most vegetables. Risk for cardiovascular disease can be lowered by adequate doses of vitamins C (3,000-10,000mg/d), D (2,000-10,000 IU/d), E (400-1,200 IU/d), and magnesium (300-600 mg/d) in addition to an excellent diet that includes an adequate dose of omega-3 fatty acids.[7]

(Dr. Damien Downing is a specialist physician practicing in London, and President of the British Society for Ecological Medicine. Robert G. Smith is a physiologist and Research Associate Professor at the University of Pennsylvania Perelman School Of Medicine.)

 

References:

1. Abdelhamid, A, Brown TJ, Brainard JS, et al., (2018) Omega 3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Syst Rev. 7:CD003177. https://www.ncbi.nlm.nih.gov/pubmed/30019766
http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD003177.pub3/abstract

2. Miller ER, Pastor-Barriuso R, Dalal D, et al., (2005) Review Meta-Analysis?: High-Dosage Vitamin E Supplementation May Increase. Annals of Internal Medicine, 142(1), pp.37-46. Available at: http://annals.org/article.aspx?articleid=718049.

3. Hooper L, Thompson RL, Harrison RA, et al.. (2004) Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev. (4):CD003177. http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD003177.pub2/abstract

4. Hickey S, Noriega LA. Implications and insights for human adaptive mechatronics from developments in algebraic probability theory, IEEE, UK Workshop on Human Adaptive Mechatronics (HAM), Staffs, 15-16 Jan 2009.

5. Hickey S, Hickey A, Noriega LA, (2013) The failure of evidence-based medicine? Eur J Pers Centered Healthcare 1: 69-79. http://ubplj.org/index.php/ejpch/article/view/636

6. Cortie CH, Else, PL, (2012) Dietary docosahexaenoic acid (22:6) incorporates into cardiolipin at the expense of linoleic acid (18:2): Analysis and potential implications. International Journal of Molecular Sciences, 13(11): 15447-15463. http://www.mdpi.com/1422-0067/13/11/15447

7. Case HS (2017) Orthomolecular Nutrition for Everyone. Turner Publication Co., Nashville, TN. ISBN-13: 978-1681626574

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