Dr. Peter D'Adamo: Personalized Healing

You are a collection of cells, literally trillions of them, each with a specific design and function. With a few exceptions, cells have a basic architectural design, most of the time being depicted as looking like a fried egg cooked sunny side up. However, in reality they are three dimensional beings, so it might be better to think of the average cell as a golf ball that you’ve cut across its midline. The “white” of our cell model is the body of the cell, and here are found many specialized areas called organelles that do particular jobs, much like our own internal organs have specific jobs as well. The “yolk” of our cell model is called the nucleus, and in this compartment there lies the object of our affections, the chromosomes.

Chromosomes were first discovered at the end of the 19th century by a German biologist named Walther Flemming. Flemming was looking at cells under a microscope and got the idea to use colors to dye the cell to make it easier to see things. The idea must have worked better than anticipated since he at once began to see spaghetti looking things in the nucleus that dyed a very deep color. As is the fashion, he named these entities chromosomes which is Greek for “colored bodies”.

Chromosomes are one of the more dynamic faces of Nature; they have to be, since they are responsible for the passing on of the Baton of Life that we call reproduction. The number of chromosome in the cell nucleus differs somewhat from species to species. We human have 46 chromosomes; dogs have 78; alligators 32; cabbage plants 18.

Your chromosomes are both the governess and chauffeur of the most important molecules in your body; DNA. Like any blueprint, DNA needs to read in order for the work order to be constructed. Now, DNA is a long, long molecule. If it were completely unraveled it would be about six feet long, yet so thin that it would be invisible. If the entire DNA, in every cell of your body, was stretched out and laid end-to-end in a straight line, it would reach to the sun and back over one thousand times.

I think an effective way of describing the dynamic qualities of the chromosome is to use a few metaphors. My older daughter likes to knit, so we often visit the knitting supply shop in town for fresh yarn. Yarn usually comes wrapped in skeins, a length of yarn wound around a reel. Most yarn comes in lengths of 80-150 yards. One of the nice things about buying yarn this way, rather than just as one long unwound string, is that you can put it under your arm and walk to the car. This is certainly better than tying a knot to the rear bumper and pulled the unwound string all the way home. Thus, the first important lesion of chromosome dynamics; if you’re going to reproduce you’ve got to stuff that entire DNA into a very small, tight package. Chromosomes are just that: tight packages of DNA.

On the other hand, it is very difficult, if not downright impossible to knit anything if the skein of yarn still has the paper label wrapped around it. In order to use the yarn, you have to unwind it. That’s the formula: when the cell needs to use DNA to get information about how to make a protein, it has to unwind it. When it needs to reproduce, or turn off the DNA information flow, it needs to concentrate and condense it.

DNA is packaged and concentrated by special proteins termed histones. This concentrated DNA is called chromatin, which is the DNA plus the histones that package DNA within the cell nucleus. Chromatin structure is also relevant to DNA replication and DNA repair.

Histones are very cool bead-like proteins that spool the DNA in a way that makes it either tighter or looser, sort of like the cardboard around which our skein of yarn is wrapped. Histones respond to changes in their structure by tightening the DNA wrap or loosening it. Whenever a cell needs to access the genetic information encoded in its DNA, the histones on the section of the DNA that is needed undergo a chemical reaction called acetylation by which a molecule called an acetyl group is stuck on the histones, causing them to relax and unravel. When business is concluded for the day, special enzymes come along and chomp off the acetyl group cause the histones to become de-acetylated, which makes them tighten up again, sending the DNA in the region back to its resting state. Think of it like this; when your DNA needs to work its histones chow down on acetyl groups for breakfast and they do yoga; when it needs to reproduce or shut down, the histones lift weights --the strain of which causes the acetyl group to pop out of their mouths.

Only until recent times have we understood this mechanism, and of its supremely paramount importance: That it is used by the environment to influence gene function and that influence, for either good or bad, can be passed on as inheritance. Amazingly, we not only inherit the genes from our parents, but state of histone acetylation of the genes as well. Thus, the histone acetylation patterns of the genome are a prime mechanism of epigenetic inheritance, along with DNA methylation.

Scientists have given each human chromosome a number, according to its size; thus chromosome number 1 is the largest, then number 2, etc. Chromosomes come in pairs, one from each parent. So there are 23 pairs, for a total of 46 in us humans. Numbers 1-22 are non-sex chromosomes called autosomes, and pair 23 contains the X and Y sex chromosomes.

In the few minutes it has taken to read up to here, this, around 400 million of your red blood cells were depleted and replaced, consistent with the set of genetic instructions contained in your DNA. This is where the genetic code comes in.

More 'damned data' (Charles Fort's words, not mine): studies from the scientific literature which could pass for some of the more outlandish statements in The GenoType Diet:

The phenotype of an individual is the result of complex interactions between genotype, epigenome and current, past and ancestral environment, leading to lifelong remodelling of our epigenomes. Various replication-dependent and -independent epigenetic mechanisms are involved in developmental programming, lifelong stochastic and environmental deteriorations, circadian deteriorations, and transgenerational effects. Several types of sequences can be targets of a host of environmental factors and can be associated with specific epigenetic signatures and patterns of gene expression. Depending on the nature and intensity of the insult, the critical spatiotemporal windows and developmental or lifelong processes involved, these epigenetic alterations can lead to permanent changes in tissue and organ structure and function, or to reversible changes using appropriate epigenetic tools. Given several encouraging trials, prevention and therapy of age- and lifestyle-related diseases by individualised tailoring of optimal epigenetic diets or drugs are conceivable. However, these interventions will require intense efforts to unravel the complexity of these epigenetic, genetic and environment interactions and to evaluate their potential reversibility with minimal side effects.

Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond. Clin Chem Lab Med. 2007;45(3):321-7

Epigenomics or epigenetics refers to the modification of DNA that can influence the phenotype through changing gene expression without altering the nucleotide sequence of the DNA. Two examples are methylation of DNA and acetylation of the histone DNA-binding proteins. Dietary components - both nutrients and nonnutrients - can influence these epigenetic events, altering genetic expression and potentially modifying disease risk. Some of these epigenetic changes appear to be heritable. Understanding the role that diet and nutrition play in modifying genetic expression is complex given the range of food choices, the diversity of nutrient intakes, the individual differences in genetic backgrounds and intestinal physiological environments where food is metabolized, as well as the impact on and acceptance of new technologies by consumers.

Epigenomics and nutrition. Forum Nutr. 2007;60:31-41.

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. This anticarcinogen was first identified as a potent inducer of Phase 2 detoxification enzymes, but evidence is mounting that SFN also acts through epigenetic mechanisms. SFN has been shown to inhibit histone deacetylase (HDAC) activity in human colon and prostate cancer lines, with an increase in global and local histone acetylation status, such as on the promoter regions of P21 and bax genes. SFN also inhibited the growth of prostate cancer xenografts and spontaneous intestinal polyps in mouse models, with evidence for altered histone acetylation and HDAC activities in vivo. In human subjects, a single ingestion of 68 g broccoli sprouts inhibited HDAC activity in circulating peripheral blood mononuclear cells 3-6 h after consumption, with concomitant induction of histone H3 and H4 acetylation. These findings provide evidence that one mechanism of cancer chemoprevention by SFN is via epigenetic changes associated with inhibition of HDAC activity. Other dietary agents such as butyrate, biotin, lipoic acid, garlic organosulfur compounds, and metabolites of vitamin E have structural features compatible with HDAC inhibition. The ability of dietary compounds to de-repress epigenetically silenced genes in cancer cells, and to activate these genes in normal cells, has important implications for cancer prevention and therapy. In a broader context, there is growing interest in dietary HDAC inhibitors and their impact on epigenetic mechanisms affecting other chronic conditions, such as cardiovascular disease, neurodegeneration and aging.

Dietary histone deacetylase inhibitors: from cells to mice to man. Semin Cancer Biol. 2007 Oct;17(5):363-9. Epub 2007 May 5

The purpose of this paper was to selectively review the literature on the role of epigenetics in mental illnesses. Aberrant epigenetic regulation has been clearly implicated in the aetiology of some human illnesses. In recent years a growing body of evidence has highlighted the possibility that epigenetics may also play a key role in the origins and expression of mental disorders. Epigenetic phenomena may help explain some of the complexity of mental illnesses and provide a basis for discovering novel pharmacological targets to treat these disorders.

Role of epigenetics in mental disorders. Aust N Z J Psychiatry. 2008 Feb;42(2):97-107.

A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B(12) and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.

DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19351-6. Epub 2007 Nov

Major efforts have been directed towards the identification of genetic mutations, their use as biomarkers, and the understanding of their consequences on human health and well-being. There is an emerging interest, however, in the possibility that environmentally-induced changes at levels other than the genetic information could have long-lasting consequences as well. This review summarises our current knowledge of how the environment, nutrition, and ageing affect the way mammalian genes are organised and transcribed, without changes in the underlying DNA sequence. Admittedly, the link between environment and epigenetics remains largely to be explored. However, recent studies indicate that environmental factors and diet can perturb the way genes are controlled by DNA methylation and covalent histone modifications. Unexpectedly, and not unlike genetic mutations, aberrant epigenetic alterations and their phenotypic effects can sometimes be passed on to the next generation.

Environmental and nutritional effects on the epigenetic regulation of genes. Mutat Res. 2006 Aug 30;600(1-2):46-57. Epub 2006 Jul 18

The British biologist Conrad Hal Waddington conceived of genotype (your genetic plan) passing through environment into phenotype (the physical you) as a walk through an 'Epigenetic Landscape'. He conceived a mode of visualizing this process, in which phenotype development is seen as marbles rolling downhill. In the beginning development is plastic, and a cell can become many fates. However, as development proceeds, certain decisions cannot be reversed. This Landscape has hills, valleys, and basins and marbles compete for the grooves on the slope, and eventually coming to rest at the lowest points, which represent the eventual types of tissues they become.

The Epigenetic Landscape. (After Waddington, C. H., 1956, Principles of Embryology)

Waddington was a big thinker. Not only did he visualize development as passing through the peaks, slopes and valleys of the Epigenetic Landscape, he considered this process one of increasing constraint, or as being "canalized� as he referred to it: That the early choices influence the later options. If we think of the canals of Venice, the analogy works even better; our little gondola floats from one canal into another and then another. Each choice leaves it fewer options than before, and since gondolas need water, so we can't just pick it up and put plunk it into another canal.

Now just for a moment visualize a newly fertilized egg. It already contains all the wisdom and information needed to eventually go on to produce a completely formed human being in its DNA, but over time it must develop various cell lines (called germ layers) that can then go off and further distinguish themselves as arteries, nerves and organs. Its unfolding is stochastic (a process that is non-deterministic in the sense that the current state state does not fully determine its next state.).

"Stochastic" is one of those great words that is more often misunderstood than understood. It is often quoted as being synonymous with random, but the actual Greek seems to imply something closer to "unknowable." It's often used in the arts (very often in music composition.)

In short: We know it's going to happen; we just don't know what is going to happen.

Your journey from genetic imprinting (the genes that were determined at conception) to full phenotype (the physical you) is to a great degree a stochastic process. which is why Waddington's metaphor is so great. Any architect will tell you that a house almost never winds up like that original plans. Environmental variables (cost of materials, availability) alter reality as the construction project moves from one stage to the other. We cannot always predict the eventual outcome, but we can describe and learn about the landscape in which it takes place and that, to a degree allows us to understand things.

Hindsight is always 20/20, because the outcome almost always describes the process.

That journey started long before your conception, since epigenetic gene control is hereditable.

You are in essence, not what you eat, but rather what your parents, grand parents and even great grandparents ate. Unlike defective genes, which are damaged for life, epigenetically controlled genes can be repaired. And, activation and silencing tags that are knocked off can be regained via nutrients, drugs, and enriching experiences. (1)

Conceivably the cancer you may get today may have been caused by your grandmother's exposure to an industrial poison 50 years ago, even though your grandmother's genes were not changed by the exposure… or the mercury you're eating today in fish may not harm you directly, but may harm your grandchildren (2)

These inherited traits can continue to influence the onset of diseases like diabetes, obesity, mental illness and heart disease, from generation to generation.

All in all, the next few years should prove most interesting...

The post-genomic era, which is fueled by automation and other technologies, provokes a change in our grossly naive view of genetic determinism (that single genes govern complex traits) to the obvious reality that most human diseases are complex entities. Gene(s), although necessary, contribute only partially to disease, while environmental factors, lifestyles, epigenetics and epistasis significantly influence pathophysiology and, eventually, the expression of transient biomarkers that can be utilized for diagnosis and prognosis. Human osteoarthritis and rheumatoid arthritis are multifactorial, complex diseases. The genetic inheritance of these diseases remains elusive, although they tend to run in families wherein some siblings have a two- to tenfold increased risk of developing the diseases.

From: Future of genomics in diagnosis of human arthritis: the hype, hope and metamorphosis for tomorrow
Ashok R Amin?, Seth D Thompson? & Shailey A Amin
Future Rheumatology
August 2007, Vol. 2, No. 4, Pages 385-389

Epigenetic alterations have been known to be of importance in cancer for ~2 decades. This has made it possible to decipher epigenetic codes and machinery and has led to the development of a new generation of drugs now in clinical trials. Although less conspicuous, epigenetic alterations have also been progressively shown to be relevant to common diseases such as atherosclerosis and type 2 diabetes. Imprinted genes, with their key roles in controlling feto-placental nutrient supply and demand and their epigenetic lability in response to nutrients, may play an important role in adaptation/evolution. The combination of these various lines of research on epigenetic programming processes has highlighted new possibilities for the prevention and treatment of metabolic syndrome.

From: Nutritional Epigenomics of Metabolic Syndrome
Catherine Gallou-Kabani, and Claudine Junien
Diabetes 54:1899-1906, 2005

Full Article

1. Asim K. Duttaroy Evolution, Epigenetics, and Maternal Nutrition 2006 Darwin Day Celebration.

2. Montague T. A New Way to Inherit Environmental Harm. Synthesis/Regeneration 39 (Winter 2006)

This Transfusion: Parachutes and death from gravitational challenge | Hawthorn and heart disease | Blood group A and ovarian hyperstimulation syndrome | Rh blood group and hearing loss | Epigenetics, diet and super oxide dismutase (SOD)

Welcome to The Weekly Transfusion, 1.5 for the week of April 13, 2009.

Insufficient evidence for parachute use to prevent death and major trauma related to gravitational challenge

As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.

Article Link

Comment:

Evidence based medicine is the buzz-phrase of the moment, the idea being that you scour the medical literature on a particular association,for example using the herb Hawthorn to treat chronic heart failure. You set the selection criteria, such as the type of study (placebo controlled, etc.) and the amalgamate the data. Evidence Basis has some very important advantages, namely that it gives the most accurate current assessment of a treatment or strategy since you are pooling all the available data.

One problem with evidence based medicine is the simple reality that evidence and benefit are not always the same thing. As shown by this slightly tongue in cheek study, there is still an insufficient evidence basis to conclude that parachutes are effective in preventing major trauma related to gravitational challenge. The researchers failed to find suitable studies showing the effects of using a parachute during free fall, despite setting logical criteria (death or major trauma, defined as an injury severity score > 15) and scouring he available literature.

Setting artificial standards can also impeded the workings of common sense: Edward Murphy put it best in his classic The Logic of Medicine: 'Only a fool would require a double-blind study to see if it was raining outside.'

Lack of evidence is not evidence of lack.

Evidence based medicine has potential to revolutionize day to day health care. However I think an even bigger revolution lurks under the surface: The reinterpretation and reorganization of medical facts derived under the older 'disease-care paradigm' by evolving paradigms that better fit new real-world circumstances.

A common argument against the need for heterodoxy in medicine is that 'when facts are proven, they stop being alternative.' This may well be true, but it neglects that facts themselves are forever open to reevaluation, deconstruction and recycling. Much of my work with the ABO polymorphisms was the simple reappraisal and restructuring of the conventional biomedical literature on the subject --but done with an eye to its ulterior benefits in naturopathic circumstances. Had they not been subjected to the 'naturopathic lens' these facts may well still be floating in their own splendid isolation.

Hawthorn extract for treating chronic heart failure

For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo... Exercise tolerance were significantly increased by hawthorn extract... The pressure-heart rate product, an index of cardiac oxygen consumption, also showed a beneficial decrease with hawthorn treatment... Symptoms such as shortness of breath and fatigue improved significantly with hawthorn treatment as compared with placebo...These results suggest that there is a significant benefit in symptom control and physiologic outcomes from hawthorn extract as an adjunctive treatment for chronic heart failure.

Article Link

Comment:
I first wrote about Hawthorn (Crataegus spp.) in my book Eat Right For Your Type over thirteen years ago, making specific reference to its benefit for blood group A individuals with cardiovascular problems. In general the plant has a good track record, especially, if used in quite low doses for extended periods of time. The herb seems to allow cardiac patients to derive extra benefit from exercise (link), has some very nice effects on the artery lining (link) and has been shown to lower blood pressure in patients taking diabetic medication. (link)

Hawthorn was shown to be well tolerated and safe. However, it should not be used as a substitute medication in circumstances of active heart disease or concurrently with other cardiac medicines unless under the supervision of a physician trained in its use. In one study, it actually seemed that the hawthorn group had a worse outcome than the placebo group. (link) Hawthorn also does produce occasional side-effects, though they appear uncommon and rather mild.(link) Perhaps this is the darker side of the biochemical individuality revolution; it's no longer acceptable to claim that all natural products are safe in every person. Anything that can add to the personalization of herbal recommendations can only help to increase their safety profile.

Blood type A women get more complications from fertility treatment

Ovarian hyperstimulation syndrome is a potentially life-threatening complication during controlled ovarian stimulation for fertility treatment. Since no association of this condition with ABO blood groups was known, we compared ABO antigens with severity and onset of symptoms in a case-control study...The odds ratio for patients undergoing controlled ovarian stimulation with blood group A versus O to develop the early-onset form of this condition was 2.171 (p-value 0.002). Blood group A may be associated with early-onset ovarian hyper-stimulation syndrome in Caucasians...This possible association may be considered for an individualized hormone dosing in controlled ovarian stimulation.

Article Link | Article Link

Comment:
Ovarian hyperstimulation syndrome (OHSS) is a complication from some forms of fertility medication. Most cases are mild, but a small proportion is severe. Symptoms can range from a more mild form that includes abdominal bloating and feeling of fullness, nausea, diarrhea, and slight weight gain to a more severe form that includes and fullness/bloating above the waist, shortness of breath, urination significantly darker or cessation of urination altogether, calf and chest pains, marked abdominal bloating or distention, and lower abdominal pains. This study looked at 127 Caucasian patients hospitalized because of ovarian hyperstimulation syndrome after receiving in vitro fertilization, in the period from January 2000 to February 2007 and found that blood group A was markedly more frequent and blood group O less frequent in patients with ovarian hyperstimulation syndrome.

Other studies have found a slightly greater incidence of ovarian cancer in women who are blood group A (link) and blood group antigens (as mucins or 'blood group substances') are known to be richly deposited on ovarian tissue. (link) Hopefully fertility specialists will consider individualizing hormonal treatment by blood group when working with fertility patients.

Four patients developed thrombosis (clots) in the jugular or subclavian vein, none of whom had blood group O; this correlates with earlier studies linking blood groups other that type O with an increased risk of thrombosis (link) at some of this clotting may in fact be due to enhanced sensitivity to estrogen, at least in women who are not blood group O.(link)

What was that? Being Rh positive may increase your risk of hearing loss

Noise-induced hearing loss (NIHL) is one of the most common occupational problems and is one of the main causes of deafness. Many factors cause NIHL. Individual susceptibility is one of them. Rhesus (Rh) antigens and ABO blood groups can be factors in determining individual susceptibility. In conclusion, we suggest that the people with Rh-positive blood group are more prone to develop NIHL.

Article Link

Comment:

The researchers looked at factory workers who had been exposed to a noise level more than 85 dB for 8 hours a day for a period of over 15 years. Two hundred and nineteen (55.4%) of Rh-positive workers and seventeen (39.5%) of Rh-negative workers have noise-induced hearing loss, and the difference between the two groups was statistically significant (P < 0.05). There was no link between hearing loss and ABO blood type.

If you are a rabid reader of this blog, you'd immediately notice that these results are just ever-so-slightly statistically significant (and not be much of a discovery) since given enough noise, virtually anyone will develop hearing loss. However we could speculate that something in being Rh positive influences the structure of the ear anatomy to make these people more likely to get hearing damage. Or on the other hand, what is it about being Rh negative that makes these people less likely to get hearing loss?

An earlier study with infants and adults also showed a higher incidence of hearing loss in Rh positive people, with a slightly better level of significance (0.01) if the mother was Rh negative blood type (which might support the idea that the problem would then be seen in the incompatible Rh-positive children). Another maternal influence via blood group!

Diet influences epigenetic regulation of super oxide dismutase (SOD) gene

The impact of nutrition on the epigenetic machinery has increasingly attracted interest. The aim of the present study was to demonstrate the effects of various diets on methylation and gene expression. The antioxidative enzyme mitochondrial superoxide dismutase (MnSOD) was chosen as the model system because epigenetic regulation has been previously shown in cell lines for this gene. A 3-fold increase in the expression of the MnSOD gene was associated with decreased CpG methylation of the analyzed promoter region in the vegetarian group compared with the age-matched omnivores group. These results indicate that diet affects the epigenetic regulation of human MnSOD.

Article Link

Comment:

The super oxide dismutases are a class of enzymes that catalyze the conversion of free radical superoxide molecules into oxygen and hydrogen peroxide. They are an important antioxidant defense in nearly all cells exposed to oxygen. SODs 'outcompete' healthy tissue for the damaging free radical molecules. They protect the cell in a way reminiscent of a common scene in the the old Laurel and Hardy movies where two soldiers in a trench hoist a helmet on a stick above their heads and then retrieve it having been shot full of bullet holes. Although SOD supplements are a common item on health food store shelves, oral SOD products are completely destroyed in the gut, so methods to increase the native (endogenous) production in our own cells would be optimal.

Epigenetics is best explained as the 'non-genomic' or 'post-genomic' control of gene expression, mechanisms such as DNA methylation, or histone acetylation, which act a 'volume controls' on the ability of the cell to read the section of DNA that contains that gene. In the case of this study, the vegetarian group has less methylation on the CpG section of promoter region of the SOD gene.

In English, what they are saying is that diet removed some of the restrictions (methyl groups) on the part of the gene that activates it (the promoter region). Removing methyl groups usually takes the brakes off a gene, especially when they are in the gene's cystine-rich 'front.'

Exciting stuff. Now we'll need to see exactly which specific foods have the maximum epigenetic effects on SOD.

Until next week.

Note to readers: By mistake I had uploaded an earlier, non-spell-checked version of this entry on Monday. I beg your indulgence on this matter. Although I am a reasonably good speller, if truth be told I am a terrible typist.

Welcome to The Weekly Transfusion, 1.4 for the week of April 6, 2009.

Editorial: Medical journal statistics for autodidacts

You can become a better consumer of health information if you take the time to read the research source material (i.e the scientific publication in which the original claim was made). Of course if the study is technical you can see quite a bit of jargon that you may or may not understand. However many medical terms are widely understood and where you bump up against the odd phrase or name that you don't comprehend, there are usually places on the Internet where you can find simple, easy to understand explanations. Wikipedia is actually pretty good for this type of look-up, as long as the subject at hand is not controversial.

However, methodology and monikers aside, most scientific studies distill down to a simple testable premise which is easily understand by almost anyone. Did the medicine work? Was the association between this gene and that disease valid? Past asking the question, what is needed next is to look at and gauge the value of the answer. Surprisingly, even though this is usually some sort of statistical type of answer (and most laypeople are not well versed in statistics) once you know what to look for, you'd be amazed just how easy it is to evaluate most studies.

Most research studies feature a subsection entitled Results or Conclusions. It is here that the results are most often given. There are many way of calculating statistical significance, but the premise is quite simple: What is the chance that the thing we just observed/ hypothesized was random versus the odds of it being due to the relationship we are studying. This is known as probability and in statistics is usually called the P value. To find out just how significant the results of any study are, just look for the P value. The smaller this number is, the less likely the results occurred by chance. Put another way, the lower the P value the more likely you'll want to view the results as significant or important.

The great Ronald Fisher viewed P values as measures of the evidence against a hypotheses, sort of like how a prosecutor presents a case based on exceeding the jury's sense of 'reasonable doubt.'

Now for the secret (OK, not so secret) key to taking control of the medical facts in your life: The standard level of significance used to justify a claim of a statistically significant effect is when P is equal to or less than 0.05; in essence, a one-in-twenty chance that the result had nothing to do with your hypothesis.

For better or worse, the term 'statistically significant' has become synonymous with P<=0.05.

So when looking at any published results, always look for the P value and if it is greater than five cents on the dollar (0.05) you'd probably want to ignore that results (unless the premise of the article was that the researchers failed to show a relationship, which is of course just another type of observation; however, these types of studies usually don't make it out of the researcher's file cabinet) or take a look at the methodology behind the study (scientists are human; studies can be poorly designed and the conclusions derived may not have been the best test of the hypothesis).

So, P<0.05 means the results are significant, but just barely. Good enough to convict, but also likely to send a few innocent people to jail as well, since there are still strong indications that the hypothesis fails to account for the whole of the facts. Personally I like to see P values of at most 0.01-0.02 before I get excited about anything I'm reading. However I do make exceptions for studies with small numbers of participants, or if the we're dealing with an herb or vitamin where the effects studies may be slight or slow to surface.

Oftentimes you'll see P values with lots of zeros. That means they've found a more statistically reliable result. For example, the P value in the following article is P<0.001. This actually means that there 1 in a 1000 chance of the result being a random occurrence and a 999 in 1000 chance that the result was related to the premise of the study.

Just remember, look for at least a P<0.05. That means the results were statistically significant. Beyond that the more zeros you see in the P value, the better. Try your new-found statistical powers on the articles below. Look for the P values in the studies. What do they signify?

Now that you can evaluate scientific material at its source, you'll be less likely to fall for the 'man bites dog' con-jobs that are all too commonly reported in the news or as what passes for scientific discussion these days.

Resting heart rate as a low tech predictor of heart problems in women

In a large, diverse group of postmenopausal women, resting heart rate was an independent predictor of coronary events, with higher heart rate associated with greater risk. The relation between resting heart rate and risk of coronary events was stronger in younger postmenopausal women than in older ones. Resting heart rate did not independently predict stroke.

In general, age, body mass index, and saturated fat consumption were higher and cardiovascular risk factors such as hypertension, diabetes, smoking, hypercholesterolaemia, and depressive symptoms more prevalent in women with higher resting heart rate, as was self reported nervousness. Physical activity and alcohol use were inversely related to heart rate (both P<0.001), and heart rate was lower in women who used postmenopausal hormone therapy than in those who did not (P<0.001).

Article Link

Comment:

One can't argue that this is about as low tech a predictor of future health problems as one is likely to find. It has already been shown that resting heart rate predicts coronary events in men. For women however, the relation between heart rate and coronary events or stroke has been uncertain. The study broke the participants into groups including a 'high heart rate group' whose heart rate was greater that 76 beats per minute and 'low heart rate group' whose heart rate was greater than 61 beats per minute. The association with 'coronary events' (aka heart attacks and death). This association appears stronger in women aged 50-64 than in those aged 65 or older

Being overweight makes you age faster

Obesity and weight gain in adulthood are associated with an increased risk of several cancers. Telomeres play a critical role in maintaining genomic integrity and may be involved in carcinogenesis. Using data from 647 women ages 35 to 74 years in the United States and Puerto Rico (2003-2004), we examined the association between current and past anthropometric characteristics and telomere length in blood. These findings support the hypothesis that obesity may accelerate aging, and highlight the importance of maintaining a desirable weight in adulthood.

Article Link

Comment:

A telomere is a region of repetitive DNA at the end of chromosomes, which protects the end of the chromosome from destruction. When DNA needs to be read (to replicate itself, or generate RNA so as to begin coding proteins) a problem arises in that the enzymes that duplicate the chromosome and its DNA cannot continue their duplication all the way to the end of the chromosome. They need a blank area to 'park' much like the cassette tapes of days past had white 'leader tape' at their front and the back so that the tape head did not start in the song itself. Unlike cassette tape, every time DNA reproduces, a bit of the white leader tape, the 'telomere' at the end, is frittered off and has to be replaced. Telomeres and replenished by an enzyme, the telomerase reverse transcriptase. Telomeres protect a cell's chromosomes from fusing with each other or rearranging - abnormalities which can lead to cancer - and so cells are normally destroyed when their telomeres are consumed. In the women studies for this article, those having a higher body mass index (BMI) in their 30s were associated with shorter telomere length in their 40s (P < 0.01).

I suspect some of this association is epigenetic, and points again to the fact that the GT5 Warrior epigenotype may well need to get their weight profile optimized early in life and be increasingly calorie conscious as they age.

Vitamin D, adult-onset diabetes and metabolic syndrome

Vitamin D is a potent immunomodulator that also enhances the production and secretion of several hormones, including insulin. Vitamin D deficiency has been associated with increased risk of type 1 diabetes. Glycemic control and insulin resistance are improved when vitamin D deficiency is corrected and calcium supplementation is adequate.

Article Link

Comment:

More and more information is surfacing about vitamin D (actually more of a hormone than a vitamin) and insulin resistance. Studies consistently show that vitamin D levels in both North America and the Pacific are typically lower than optimal. In the USA , most vitamin D intake from foods is provided by fortification. Canada and New Zealand have fewer fortified choices, and intakes are correspondingly lower. The mechanism of action of vitamin D in adult onset (type 2) diabetes is thought to be to its role in the control of plasma calcium levels, which help regulate insulin synthesis, but may also be the result of vitamin D stimulating the insulin secreting (beta) cells of the pancreas directly. If you have a history of metabolic syndrome or adult onset diabetes in close family members you may want to consider adding vitamin D to your supplement regimen. However, make sure that you do it in partnership with a nutrition professional.

One from the vaults: Mom's blood type can influence child's risk of Strep (1978)

In a prospective study of maternal genital colonization with streptococci at the time of delivery, epidemiological data, including blood type (ABO group), were recorded for the 1,062 patients studied. Blood type B was found in a statistically significant (P <.005) higher proportion of patients colonized with streptococci (28%) compared with the total population (16.4%)

Article Link

Comment:

Evidence suggests that probiotic supplementation does change the vagina flora of women. Since it appears that the route of transmission of Streptococcus is from the birth canal, physicians should recommend probiotic supplementation for pregnant women beginning 3-4 weeks prior to expected date of delivery as a way to prevent streptococcus infection in neonates. This should be especially emphasized if the mother is either blood group B or AB.

This study again illustrates the fact that some of the best ABO correlation studies are outside the purview to today's physicians, most of whom would tell you that any research from 1978 is better suited to a history class than to any thing taught in medical school.

Since Mother's Day is fast approaching, also remember that recurring otitis media (ear infections) is strongly associated with the child's mother being blood type A. In fact the correlation here is quite startling. Children of mothers who are blood type A are twenty seven times more likely to get a second ear infection within one year of contracting the first. To give you an idea of just how strong this association is, look at the chart below to compare the RR (relative risks) of a few other disease/ lifestyle links.

Update: IfHI 2009

Just a quick word to the wise about the IfHI Conference, Norwalk Connecticut, June 5-7. We had run out of available rooms at the Dolce Center Campus. However 10 additional rooms have just been made available. Unlike previous conferences, where attendees could book almost to the day of the event, IfHI 2009 looks like it will be completely booked by the middle of May, a full month before the event. If you are planning on attending, either for certification or just personal enrichment, please make your reservations ASAP, especially if you want to stay overnight on campus.

Until next week.