Female Athlete Triad

When I was in high school, one of my best friends was a long-distance runner and a dancer. After only a few months of training, I knew something was wrong. She changed her diet to one of protein and almost no other calories. She was obsessed with exercise leading to a loss of many of her friends. Later on she lost a lot of weight and, to me, instead of becoming healthier she appeared to look pretty unhealthy.

What I didn't know then was that my friend may have suffered from the "female athlete triad". It is a three-part syndrome that affects the health and performance of female athletes and includes osteoporosis, disordered eating and menstrual disorders. Each of these are inter-related and inter-play. Together they can cause serious illness or death.

Writing in a review in British Medical Journal, Dr. Karen Birch explains that the syndrome can be caused by pressures psychological and physiological associated with a sports requirements to perform optimally, which can lead to a perception of needing a "low body mass, result of high-volume training" (1).

Being somewhat controversial, at least one medical researcher has called for abandonment of the syndrome. Dr. Michael Cullen of the British Association of Sport and Exercise Medicine points out that the term "blurs the concepts of a true eating disorder with that of a driven athlete who is simply ignorant of nutritional demands" and that osteoporosis in atheletes is rare (2).

Despite whether a syndrome should be recognized or not, clinicians should continue to recognize which women are most at risk, which are teen girls and female athletes of many kinds, especially where body image counts: gymnasts, figure skaters, ballerinas, swimmers, endurance runners, and so on (3).

The first signs of the female athlete triad may be low-calorie dieting or exercising to excess or obsession (3). The low-calcium diet contributes to low bone density. If amenorrhea results, it may be linked to decreased estrogen levels (3). It has also been my experience that smoking usually is another sign of an eating disorder among teens. The reasons why is because the teens see it as an effective method to control appetite and weight (4). Unfortunately, for a teen suffering already from female athlete triad, smoking can cause an exacerbated loss of bone (5 & 6). The impact of female athlete triad can lead to infertility and stress fractures in the future (1).


References

1. Birch K. Female athlete triad. ABC of sports and exercise medicine. British Medical Journal. Available at: http://www.bmj.com/cgi/content/extract/330/7485/244.

2. Cullen M. et al. 10 Feb 2005. The Female Athlete Triad. Available at: al.http://www.bmj.com/cgi/content/extract/330/7485/244.

3. WebMD. The Female Athlete Triad. Available at: http://www.webmd.com/a-to-z-guides/female-athlete-triad.

4. http://www.ncbi.nlm.nih.gov/pubmed/17056404

5. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

6. http://www.ausport.gov.au/participating/women/issues/osteo

Growth hormone: The fountain of youth

Growth hormone, also known as human growth hormone, seems to be implicated in a number of metabolic conditions associated with aging, and, more generally, poor health.

In adults, growth hormone deficiency is associated with: decreased calcium retention and osteoporosis, loss of muscle mass, increased fat deposition, decreased protein synthesis, and immunodeficiency. In children, growth hormone deficiency is associated with stunted growth.

Levels of growth hormones decline with age, and their decrease is believed to contribute to the aging process. Abdominal obesity is associated with low levels of growth hormone, and is also associated with the onset of the metabolic syndrome, a precursor of diabetes and cardiovascular disease.

While there are many treatments in the market that include exogenous administration of growth hormones (e.g., through injection), there are several natural ways in which growth hormone levels can be increased. These natural ways can often lead to more effective and sustainable results than prescription drugs.

For example, fasting stimulates the natural production of growth hormone. So does vigorous exercise, particularly resistance exercise with a strong anaerobic component (not cardio though). And, to the surprise of many people, deep sleep stimulates the natural production of growth hormone, perhaps more than anything else. (Although only once every 24 hours; sleeping all day does not seem to work.)

In fact, during a 24-hour period, growth hormone typically varies in pulses, or cycles. The pulses are somewhat uniformly distributed during the day, with a peak occurring at night. The graph below (source: Fleck & Kraemer, 2004) plots the typical variation of growth hormone during a 12-hour period, including the deep sleep period.

As you can see, growth hormone peaks during deep sleep; which is achieved a few hours after one goes to bed, and not too long before one wakes up.

By the way, if you want to know more about human physiology and metabolism, forget about popular diet and exercise books. Next to peer-reviewed academic articles (which are often hard to read), the best sources are college textbooks used in courses on physical education, nutrition, endocrinology, and related topics. The book from which the graph above was taken (Fleck & Kraemer, 2004), is a superb example of that.

Reference:

Fleck, S.J., & Kraemer, W.J. (2004). Designing resistance training programs. Champaign, IL: Human Kinetics.

Half-hearted Atkins diet and cardiovascular disease

I would like to comment on a recent article comparing the Atkins, Ornish and South Beach diets (Miller et al., 2009; full reference at the end of this posting), which has been causing quite a lot of commotion among bloggers recently. Especially low carb. bloggers.

An excellent post by Michael Eades clarifies a number of issues with the study, including what one could argue is the study's main flaw. Apparently the study compared a half-hearted Atkins diet, with probably equally half-hearted Ornish and South Beach diets.

I refer to the study's Atkins diet as half-hearted because it seems to rely on a daily consumption of between 120 and 180 grams of carbohydrates. This is unlikely to lead to ketosis, the cornerstone of the Atkins diet, where the body uses ketone bodies (made from dietary as well as body fat) as a source of energy.

As I see it, the main findings of the study were that the participants in the half-hearted Atkins diet, after a period of 4 weeks on the diet, and when compared with the participants in the other diets, had: (a) greater levels of total cholesterol and LDL cholesterol, with only a small improvement in their HDL cholesterol and triglycerides levels; and (b) greater levels of markers for inflammation (e.g., C-reactive protein).

The participants were young and healthy. Their average age was 30.6 years, and their average body mass index was 22.6. On average, their total cholesterol was 184.9 mg/dL, triglycerides were 78.1 mg/dL, LDL cholesterol was 107.2 mg/dL, and HDL cholesterol was 62.2 mg/dL. These are arguably fairly healthy numbers; although quite a few doctors might want to put most of these folks preventively on statins because of their LDL being greater than 100.

What I find interesting about this study, and consistent with both my own experience and also a theory that I have, is that it suggests that a low carb. diet has to really be low carb. in order to bring about the benefits that one normally sees as a result of a diet that induces ketosis. A diet with, say, > 150 g of refined grains per day, is not really a low carb. diet.

Again, in my experience, and that of many other people, a truly low carb. diet (very low in, if not devoid of, refined carbs and sugars), will lead to an impressive increase in HDL cholesterol (especially for those who have low HDL to start with), an equally impressive decrease in triglycerides, increased insulin sensitivity, and possibly a decrease in LDL.

However, a half-hearted Atkins diet may actually lead to elevated LDL (of the small-dense type), and more inflammation, just like this study suggests it does, without the benefits regarding HDL and trigs. The reason is that the still relatively high level of carbohydrate intake, especially if it comes in the form of refined carbs. and sugars, will lead to higher levels of insulin being secreted into the bloodstream. This will promote increased body fat deposition. The extra saturated fat being consumed will be turned into body fat, and not used as energy, starving the cells and leading to increased hunger.

A diet rich in saturated fat may indeed be bad when it is also a diet even moderately rich in insulin-boosting, easily digestible carbs. This may be one of the main reasons why there have been so many studies in the past showing a correlation between saturated fat consumption and heart disease; studies that typically did not control for carbohydrate consumption.

In a recent interview on the Livin' La Vida Low-Carb Blog, Dr. John Salerno goes into more detail regarding this issue, recommending a much more rigid adoption of the Atkins diet than many think is okay. (In fact, I often talk to people who think that if they cut a very high carb. intake in half - e.g., from 400 to 200 grams per day - replacing the carbs with fat, they will be halfway into a full blown Atkins diet.) Dr. Salerno has worked in the past with Dr. Atkins. He calls his diet the Silver Cloud Diet. I am not sure I agree with all that Dr. Salerno had to say, but his argument in favor of a diet very low in carbs. does make sense to me.

Finally, I think that it is dangerous to extrapolate the results of any study, no matter how comprehensive, to the population in general. Each individual is unique in terms of his or her genetic makeup and life history; the latter also influences metabolic patterns. (Even identical twins raised together may display different metabolic patterns, because of their different life histories.)  So, while a low carb. diet may work well for a lot of people, it may have very negative effects on a few. Increases in inflammation markers and adverse effects on LDL cholesterol (especially when LDL is measured directly, accounting for particle numbers and sizes) are warning signs that any low carb. dieter should pay attention to.

Reference:

Miller, M. et al. (2009). Comparative effects of three popular diets on lipids, endothelial function, and c-reactive protein during weight maintenance. Journal of the American Dietetic Association, 109, 713-717.

Family influence on meals

My thoughts after reading "A Review of Family Meal Influence on Adolescents' Dietary Intake" by Sarah Woodruff and Rhona Hanning:

It's pretty easy to imagine why having dinner with one's family would instill positive nutritional habits. Even the word family exudes in its meaning what goes further to credit an environment of caring and, above all, nurturing.

When mother and father are at the table, they are naturally given to see to it that their children are eating well. At the same time, they must also set the right example. Thus, it's clear why the authors of the article found that the studies reviewed found that those adolescents who ate with their families had a higher intake dairy, fruits and vegetables.

I would further suggest that family influence comes with wisdom as to healthy eating pattens. For example, when grandma or grandpa or mom or dad make a meal, they themselves are passing on food traidtions that may have well sustained generations with better health. When family is not available and adolescents are left to choose their own eating patterns, one could imagine they're much more inclined to make poorer choices as they have to "reinvent the wheel" so to say.

One element I would have liked to have seen the article address with more detail was actual preapartion of food. It's my own experience that a personal relationship with food can go a long way in how nutritious it is to a person. You might call it a greater food consciousness--more understanding of what's about to be eaten. Food consciousness is often lost on teens when going out to eat or when leaning on the microwave meals. When a teen prepares his or her own food, just the creativity itself involved by choice and cooking is likely to play a factor in actual nutrition.

Total cholesterol and cardiovascular disease: A U-curve relationship

The hypothesis that blood cholesterol levels are positively correlated with heart disease (the lipid hypothesis) dates back to Rudolph Virchow in the mid-1800s.

One famous study that supported this hypothesis was Ancel Keys's Seven Countries Study, conducted between the 1950s and 1970s. This study eventually served as the foundation on which much of the advice that we receive today from doctors is based, even though several other studies have been published since that provide little support for the lipid hypothesis.

The graph below (source: canibaisereis.com, with many thanks to O Primitivo) shows the results of one study, involving many more countries than Key's Seven Countries Study, that actually suggests a NEGATIVE linear correlation between total cholesterol and cardiovascular disease.

Now, most relationships in nature are nonlinear, with quite a few following a pattern that looks like a U-curve (plain or inverted); sometimes called a J-curve pattern. The graph below (source also: canibaisereis.com) shows the U-curve relationship between total cholesterol and mortality, with cardiovascular disease mortality indicated through a dotted red line at the bottom.

This graph has been obtained through a nonlinear analysis, and I think it provides a better picture of the relationship between total cholesterol (TC) and mortality. Based on this graph, the best range of TC that one can be at is somewhere between 210, where cardiovascular disease mortality is minimized; and 220, where total mortality is minimized.

The total mortality curve is the one indicated through the full blue line at the top. In fact, it suggests that mortality increases sharply as TC decreases below 200.

Now, these graphs relate TC with disease and mortality, and say nothing about LDL cholesterol (LDL). In my own experience, and that of many people I know, a TC of about 200 will typically be associated with a slightly elevated LDL (e.g., 110 to 150), even if one has a high HDL cholesterol (i.e., greater than 60).

Yet, most people who have a LDL greater than 100 will be told by their doctors, usually with the best of the intentions, to take statins, so that they can "keep their LDL under control". (LDL levels are usually calculated, not measured directly, which itself creates a whole new set of problems.)

Alas, reducing LDL to 100 or less will typically reduce TC below 200. If we go by the graphs above, especially the one showing the U-curves, these folks' risk for cardiovascular disease and mortality will go up - exactly the opposite effect that they and their doctors expected. And that will cost them financially as well, as statin drugs are expensive, in part to pay for all those TV ads.

Stop Measuring and Start Thinking

Stop Measuring and Start Thinking

I recently wrote a paper suggesting that the arts might just offer us the most potent means of questioning the grotesque market-driven society that we live in, a society that insists on measuring everything in terms of cost-benefit-analysis.

In this paper that will be published shortly, I suggested that the arts not only offer us a means of questioning the world, and imposing some sort of order on the chaos that surrounds us; but that popular culture too, offers a potent part to play in the arts/health agenda. For those of you interested in popular culture and public health I’d like to recommend the writing of Mark Burns and his Sex and Drugs and Rock and Health, which can be found at www.sexanddrugsandrockandhealth.com

Since the global downturn, lots of economists have been talking of creative approaches to their work; whatever that might mean. To be honest; it makes me slightly nervous. Consumerism, to which we’re all in some way addicted, has infected all aspects of society. In the art world itself, the hyper-inflated egos and prices associated particularly with ‘Brit Art’ reflects elitism, consumerism and our obsession with celebrity culture.

Over the past thirty years, market forces have been the governing philosophy of how we live our lives, and over the last 12 months we’ve seen how imposing market values on all elements of human life has terrible consequences. The impact of mental illness in dominant, unequal societies offer some stark financial facts, with doctors in England in 2005 writing 29 million prescriptions for anti-depressant drugs, costing over £400 million to the NHS ¹ and in 2003, the USA spent more than $100 billion on mental health treatments. ²

Across the North West I’ve experienced some amazing practice in the arts and seen the impact participating can have on people and yet I’m constantly asked for hard unequivocal evidence as to its value. In his Reith Lectures for the BBC this year Michael Sandel, Harvard Professor of Government, invites us to think of ourselves, less as consumers and more as citizens, and argues for politics of the common good where commodities of community, solidarity and trust are not commodities that deplete with use, like our finite environmental or economic resources, but are more like muscles, that grow stronger with exercise. These wonderful and relevant lectures can be listened to at www.bbc.co.uk/programmes/b00kt7sh

So, do we really need to weigh, measure and count everything we do to justify the arts?

After recently giving the paper in which I expanded on these themes, there followed a discussion that turned to the work I’m supporting around a National Forum for Arts and Health. This was about ‘strategy’ and ‘manifestos’ and I could feel the delegates’ eyes beginning to glaze.

Whatever statements and strategies we develop around the arts in relation to society and well-being, they’re going to date and stagnate on a thousand groaning shelves.

As a student, I always loved the pompous and extreme nature of artists’ manifestos (think Marinetti)… ‘we have been discussing right up to the limits of logic and scrawling the paper with demented writing.’³

Perhaps when we look to manifestos and pamphleteering, we should take a slightly more provocative stance. I’d like to recommend two pieces of art that I put forward as manifestos in their own right.

The first is Jonathon Swift and his Modest Proposal,⁴ written in 1729. This was a stinging satire in the form of a pamphlet. In the guise of a well-intentioned economist, Swift proposed a solution to the poverty and inequity of the time, by suggesting the rich purchase and eat the children of the poor. Monstrous and politically loaded, this is as biting and as powerful as the written word gets. A manifesto? Perhaps not, but an artist at the height of his powers exploiting popular culture (pamphleteering) to attack and question the norms.

As a counter-blast to Swift’s, Modest Proposal, I’d like to offer Sam Taylor-Wood’s, Still Life⁵ , a 3 minute 44 second film. This film of a bowl of fruit slowly decomposing is very much in the lines of an elegant still life typical of 16^th and 17^th century painting of the Netherlands. As the fruit slowly transforms to a mass, a cheap and throwaway, plastic ballpoint pen in the foreground, remains static and unchanged

I urge you to try and see this work. There are 6 of them out there including one at Tate Modern. Of course youtube have a few, but they don’t do it justice. I shall leave you to form your own opinion of what the work’s about and what relevance it might have to our practice and the issues facing society. For me, this work speaks far more loudly than any strategy or conscious manifesto.

1. Hansard. Written answers to questions, (2005) 439:22 Nov. 2005: Column 1798w

2. Mark, T.L et al. Mental Health Treatment Expenditure Trends, 1986 – 2003, Psychiatric Services (2007) 58 (8): 1041 – 8.

3. F.T. Marinetti, The Futurist Manifesto, 1909

www.cscs.umich.edu/~crshalizi/T4PM/futurist-manifesto.html

4. A Modest Proposal: For Preventing the Children of Poor People in Ireland from Being a Burden to Their Parents or Country, and for Making Them Beneficial to the Publick.

http://en.wikisource.org/wiki/A_Modest_Proposal

5. Sam Taylor-Wood, Still Life, 2001, Edition of 6, 35 mm Film/DVD

www.whitecube.com/artists/taylorwood/misc/

What's an ALT test?

Alanine aminotransferase (ALT) is an enzyme that is concentrated in the hepatocytes. When the liver is injured or affected by disease, the enzyme is released into the bloodstream. When jaundice occurs, for example, elevated ALT levels can distinguish a liver injury or disease instead of red blood cell hemolysis.

The test is performed on a patient by collecting 7-10 mL of blood in a red-top tube, then sending it to a lab for analysis. If a patient does have liver dysfunction, then the clinician should note that bleeding times may be longer.

Significantly elevated ALT levels may indicate hepatits, hepatitis necrosis or hepatits ischemia. Moderately increased levels may indicate cirrhosis, cholestatis, a hepatic tumor, a hepatotoxic drug, obstructive jaundice, severe burns or trauma to striated muscle. Drugs that may elevate ALT levels include acetaminophens, clofibrate, codeine, salicylates, tetracyclines among many others.

ALT levels may also increase to a lesser extent due to myositis, acute pancreatitis, myocardial infarction, mononucleosis or shock.

Summarized from the following:

Pagana, K.D., Pagana, T.J. Mostby's Manual of Diagnostic and Laboratory Tests, 3rd ed. Mosby Elsvier, 2006, pp. 40-42.

Lee RD, Nieman DC. Nutritional Assessment. New York: McGraw-Hill, 2007.

When You Have an Abnormal Lipid Profile

An abnormal lipid profile is a consistent indicator of atherosclerosis and cardiovascular disease (CHD). Blood lipids include total cholesterol, LDL-C, HDL-C and triglycerides. Because each of these factors are ultimately affected by diet, it serves to reason to recommend dietary strategies to help lower total cholesterol and LDL-C, increase HDL-C and reduce triglyceride levels.

ATP III uses the term therapeutic lifestyle changes (TLC) for recommendations that can help to improve abnormal lipid profiles and reduce risk of CHD. TLC makes recommendations for saturated fat (less than 7% of total calories), polyunsaturated fat (up to 10% of total calories), monounsaturated fat (up to 20% of total calories), total fat (25-35% of total calories, fiber (20-30g/d), protein (approx. 15% of total calories), and cholesterol (less than 200 mg/d). The total calories recommendation, in addition, is based on a balance of energy intake and expenditure to maintain a healthy weight (1).

Because it is often difficult for patients to adhere to specific percentages, a nutritionist can help patients by summarizing recommendations as eating less to lose weight as appropriate, exercising regularly as appropriate, avoiding animal fats in keeping to a low-cholesterol diet, replacing saturated fats with polyunsaturated fats whenever possible, and eating more fruits and vegetables.

A nutritionist could also approach patients with a Mediterranean-style diet. Recent research is showing that this diet is appropriate because it represents many of the same diet recommendations included in TLC. This diet may also have lipid-lowering effects and cardio-protective benefits from the regular intake of red wine, olive oil and fish (2).

Reference List

1. Lee RD, Nieman DC. Nutritional Assessment. New York: McGraw-Hill, 2007.
2. Cheskin LJ, Kahan S. Low-carbohydrate and Mediterranean diets led to greater weight loss than a low-fat diet in moderately obese adults. Evid Based Med 2008;13:176.

When should prevention of atherosclerosis start?

I have three children, one boy, 13 and two girls, 10 and 11. As far as I’m concerned prevention of atherosclerosis should begin as early as possible. That means yesterday. However, I understand that there exists some uncertainty of exactly what age to begin prevention. It has to do partly with juvenile fatty streaks. What may appear unimaginable is that the occurrence of juvenile fatty streaks somehow may have an importance in child development.

Most North American children develop fatty streaks in their aortas by age 3 and in coronary arteries along with macrophage foam cells by age 10 (1); by the time children are reaching puberty, they may already have developed fatty streak lesions. Fatty streaks are nothing new. As offered by McGill et al, our hominin forebears likely developed them as do current non-human Old and New World primates even when living in natural habitats. Studies of other mammals reveal that many of them also develop fatty streaks.

From an evolutionary perspective, then, fatty streaks may have provided a selective advantage to pre-human or human ancestors. Or, as in most cases, there are “trade-offs” in evolution. What may have been a cause of poor health in the long run for human ancestors may have been important part of early development. Fats and calories, for example, may have helped a child's brain or muscle development (3). It also stands to reason that while fatty streaks are normal, they may not necessarily lead to atherosclerosis. Wild mice develop fatty streaks, for example, but won’t develop lesions. Caged mice on a high-fat/cholesterol diet, however, will develop lesions and atherosclerosis as they age (2). When comparisons are given of mice and men (or women), our modern “caged” sedentary lifestyles and high-fat/cholesterol diets suggest humans are a burden to their own health.

Long-range prevention, then, should be focused on encouraging an improved diet early. How early? The American Heart Association’s guidelines suggest starting children on a widely varied diet low in fat and calories by age 2 (4). The amounts of fats and calories, however, must take child development into consideration. Even once children reach puberty this should be the case. As with my own children, who I have on a Mediterranean-style DASH diet rich in fats from olive oil and fish, it is important to give the body a holistic approach.

Reference List

1. McGill HC, Jr., McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr 2000;72:1307S-15S.
2. Li Y, Gilbert TR, Matsumoto AH, Shi W. Effect of aging on fatty streak formation in a diet-induced mouse model of atherosclerosis. J Vasc Res 2008;45:205-10.
3. Mitchell MK. Nutrition Across the Life Span. "Chapter 9: Nutrition During Growth: Preschool through Preadolescence". Second Edition. Waveland Press: Long Grove, Illinois, 2003, pp. 271-300.
4. Lee RD, Nieman DC. Nutritional Assessment. New York: McGraw-Hill, 2007.

Refined carbs, sugar, and cholesterol: My own experience

A few years ago I went to the doctor for a routine appointment, and I was told that my LDL cholesterol was elevated. I was in my early 40s. My lipid profile was the following - LDL: 156, HDL: 38, triglycerides: 188. The LDL was calculated. I was weighing about 210 lbs, which was too high for my height (5 ft 8 in). My blood pressure was low, as it has always been - systolic: 109, diastolic: 68.

My doctor gave me the standard advice in these cases: exercise, lose weight, and, most importantly, reduce your intake of saturated fat. I was also told that I would probably have to take statins, as my high LDL likely had something to do with my genetic makeup. Again, this is quite standard, and we see it all over the place, particularly in commercials for statins.

I told my doctor that I would do some research on the topic, which I am going to save for other posts. Let me get to the point, by telling you what my lipid profile is today - LDL: 123, HDL: 66, triglycerides: 46. Again, the LDL value is calculated. I am weighing about 152 lbs now, with about 13 percent of body fat.

The HDL and triglycerides numbers above are shown in bold font because my research convinced me that these two numbers are the ones most people should really worry about when trying to address what is known as dyslipidemia. Here I am assuming that only standard lipid profiles are available; there are better alternatives, such as particle type analyses, which are not yet standard.

Many people who suffer from cardiovascular disease have low LDL cholesterol, but very few of those have high HDL cholesterol, which is one of the best predictors of cardiovascular disease among lipids. More specifically, if you have an HDL higher than 60, you have a very small chance of developing cardiovascular disease. (It can happen, but it is very unlikely, with a percentage chance in the single digits.)

Interestingly, low HDL cholesterol is also associated with the metabolic syndrome. This syndrome is characterized by the following:

- High fasting serum glucose (hyperglycemia), which is one of many signs of insulin resistance, a precursor to diabetes type 2;
- High blood pressure;
- Abdominal obesity (also known as pot or beer belly);
- Low HDL cholesterol; and
- Elevated triglycerides.

Now, you may ask, how did you increase your HDL? Well, I tried a number of things - diet and lifestyle changes - and had a blood test every 3 months. After a while I was able to put all of the measures in a spreadsheet table, and correlate them using a statistical software that I developed, to give me an idea of what was going on.

Weight was a big factor on LDL, and I was able to bring my weight down to 150 lbs and my LDL to below 100 at some point. For me, and many other people, body weight and LDL cholesterol are strongly and positively correlated (the higher the weight, the higher the LDL cholesterol - actually body fat seems to be the real culprit). Moreover, my LDL seemed to decrease more markedly when my weight was on the way down, and not as much when it was stable, even if low.

But the HDL would only increase if I increased my saturated fat intake. The problem is that every time I increased my saturated fat intake my LDL would go up; it reached 162 at one point, when my HDL went up to a modest but encouraging 47. That was my highest HDL until I eliminated refined carbs and sugars (e.g., bread, pasta, cereals, doughnuts, bagels, regular sodas) from my diet.

When I brought my intake of refined carbs and sugars down to zero, my intake of protein and saturated fat went up. Either that would happen, or I would starve, because you have to eat something. (I figured that I would not die by doing a low carb/high fat-protein experiment for 3 months to see what happened.) Also, I dramatically increased my dietary cholesterol - two to four eggs per day, organ meats, and seafood.

That is when my HDL shot up, to 66, and my LDL went down. Yes, my LDL levels seem to be negatively correlated with dietary saturated fat and cholesterol amounts, as long as I do not consume refined carbs and sugars. Moreover, it is very likely that my LDL particle size increased, and large LDL particles DO NOT cause atherosclerosis because they cannot penetrate the artery walls.

So, the bottom line is that, at least for me, an INCREASE in saturated fat and a DECREASE in refined carbs and sugars, happening together, seem to have taken me out of my previous path toward the metabolic syndrome.

Moreover, I feel a lot more energetic than before, my immune system seems to have gotten better at fighting disease, and even my pollen allergies are not as bad as they were before. Admittedly, these benefits may be strongly associated with the weight loss and the related reduction in body fat percentage.

I hope this post is helpful to others. The standard advice that people with high LDL cholesterol receive, which usually focuses on reducing saturated fat intake, has a big problem. When you reduce your intake of a type of food, you usually increase your intake of other types of food. Most people who try to reduce their saturated fat intake invariably increase their carb intake, usually with the wrong types of carb-rich foods (the man-made ones), simply because they go hungry.

When to use a C-peptide test

Normally, measuring insulin directly is more accurate with diabetics. But C-peptide levels more accurately reflect islet cell function in situations of insulinomas as well as cases of diabetics taking exogenous insulin (for treatment or secretly).

C-peptide, short for "connecting peptide" is the protein connecting beta/alpha chains of proinsulin. The chains are separated when proinsulin becomes insulin and C-peptide. C-peptide ends up in equal amounts to insulin in the portal vein, lasts longer than insulin so can be found more readily in peripheral circulation, and correlates with insulin levels.

Summarized from

Pagana, K.D., Pagana, T.J. Mostby's Manual of Diagnostic and Laboratory Tests, 3rd ed. Mosby Elsvier, 2006, p. 197.

Why get a glycosylated hemoglobin test?

Measuring blood glucose periodically is critical for staying off the blood sugar rollercoaster. But how can a clinician be sure a patient hasn't gotten on board the rollercoaster? This is when glyosylated hemoglobin comes into the picture.

What happens is that when a person is diabetic and doesn't adequately control blood glucose, her or his blood glucose becomes elevated. The hyperglycemia that results begins to affect certain proteins in the blood as well as hemoglobin. Blood glucose bonds to the hemoglobin and it becomes "glycosylated". The glycosylation mainly happens to hemoglobin A (HbA, the major form of hemoglobin, and it's pretty much irreversible.

After a few weeks, the amount of glycosylated hemoglobin will decline, but only if blood sugar is controlled. If it's not controlled, then a physician can order a glycosylated HbAIC test, or AIC test. A person without diabetes should have about 4-8% HbAIC and the American Diabetes recommends diabetics to stay below at least 7%. The glycosylated hemoglobin test is meant to evaluate how well treatment is going and how well a patient is following recommendations. It also serves as a method to individualize programs, compare therapys, differentiate short-term hyperglycemia in nondiabetics and diabetics, and also to offer as a reward for patients who do well in their control.

Summarized from

Lee, R.D. & Nieman, D.C. Nutritional Assessment, 4th ed. McGraw Hill Higher Education. Boston, 2007, p. 307.

Pagana, K.D., Pagana, T.J. Mostby's Manual of Diagnostic and Laboratory Tests, 3rd ed. Mosby Elsvier, 2006, p. 282.

Baby Steven

John and Susan are both prone to being overweight. They are concerned that their infant son, Steven will also have weight problems. They are referred to you when Steven is 5 months old. Steven's growth data are as follows

Age Weight Length
Birth 8lb 20inches
1 week 8lb 1oz 20 inches
1 month ll lb. 21.5 inches
2 month 12lb 8oz 23 inches
3 month 14lb 8oz 23.5 inches
4 month 16lb 25.5 inches
5 month 18lb 26.5 inches

Steven breast feeds six times daily for about 20-25 minutes at each feeding. He is not presently receiving any other sources of nourishment. Answer the following questions for John and Susan:

Their pediatrician told them that Steven's weight is above average. Is he gaining too much weight?

When charted, Steven’s birth weight and weight gain for the next two months is at about the 50th percentile (1 p. 566). His weight gain afterward appears to be higher than average and he is at the 90th percentile by 5 months (1 p. 566). Steven’s birth length for four months is at about the 50th percentile and then flows upward slightly closer to the 75th percentile (1 p. 567).

Because Steven’s length is slightly higher than average, I would judge that it is the extra growth that may also explain the extra weight gain. The weight gain, then, is probably not at a level that should be worried about. I will agree with others who have replied that at this moment the primary concern should be making sure Steven’s fed well to best support his physical and neurodevelopment that occur in the first year of life (1 p. 216).

Should they delay adding solid foods or add something now? If they should add something, what would recommend?

At Steven’s age of 5 months, the appropriate foods to be supplying him are breast milk or formula, infant cereal and strained fruits and vegetables. He’ll be teething soon, so within two or three months, he’ll be able to enjoy strained meats and breads (1 . Within five to seven months, he’ll be chomping on chopped fruits, vegetables and meats. Steven ca be weaned around 2 to 3 years (1 p. 200).

Should they give Steven juice in a bottle?

No, they should not. According to the American Academy of Pediatrics, there is no reason why juice should be given to Steven at all based on nutritional considerations (2). This is the case even as he grows older. From my own experience with my children, I can tell you that juice, while sure to be fascinating to a baby’s taste buds, would simply turn into a habit whereby breast milk and formula are avoided.

In fact, my own mother tells me all the time that she wishes she never would have given me juice because, as a baby, I immediately stopped breastfeeding when I tried it. The fruit juice also displaced nutrition I could have received otherwise (1 p. 242). Eventually baby bottle tooth decay would also be my fate (1 p. 242).

A neighbor has suggested that Steven could be given skim milk instead of breast milk, Do you recommend this?

Steven’s breastfeeding of six times daily is normal for babies of 2-3 months (1 p. 239). Once reaching 3-6 months, the level normally should drop to 4-5 and he should be introduced to other foods as mentioned above (1 p. 239). Steven should not be given milk at all, be it raw, whole, 2% or skim. Breast milk is best because of its unique properties such as lactoferrin, immunoglobulins and the bifidus factor (1 p. 231-232). These are able to prevent allergies, asthma and infections over time (1 p. 231-232). Infant formula is acceptable, however, and, unlike cow’s milk, can also provide a commonly deficient nutrient in infants: iron (1 p.236). Infant formula is carefully formulated and fortified with vitamins, minerals and essential fats to best support child development (1 p. 235).

References
1. Mitchell MK. Nutrition Across the Life Span. "Chapter 9: Nutrition During Growth: Preschool through Preadolescence". Second Edition. Waveland Press: Long Grove, Illinois, 2003.
2. http://pediatrics.about.com/od/weeklyquestion/a/0806_baby_juice.htm

Gut inflammation and stool tests overview

The gut’s immune system is ultimately responsible for maintaining a healthy gut free of infection or infestation. It must accomplish this task while at the same time being unresponsive to food and helpful bacteria (1).

Gastrointestinal inflammation etiology is largely infection such as via parasite. However, modern lifestyles have increasingly been harassed by new chronic inflammatory diseases such as Crohn’s or ulcerative colitis (1). These are associated mainly with genetic mutations or adaptive immunity affecting immune system recognition as well as by epithelial permeability (1).

Stool tests indicating gastrointestinal inflammation include those for fecal proteins such as eosinophil protein-X (EPX), fecal calprotectin (FC) and fecal myeloperoxidase (MPO):

• FC is a calcium-binding protein found in large amounts in neutrophils and macrophages, which rush into the lumen at onset of inflammation (2-4). FC is considered more sensitive than endoscopy, for example, for evaluating inflammatory bowel disease such as ulcerative colitis and Crohn’s disease. Calprotectin can also be used to determine post-infectious irritable bowel syndrome, NSAID enteropathy or cancer.
  
• MPO is a derivative of neutrophil granulocytes (2). It’s useful diagnostically because it’s found in intestinal mucosa and in feces. Levels of MPO are elevated in active inflammatory bowel disease and mark mucosal inflammation. MPO and FC appear to be better markers in comparison to EPX during the treatment of inflammatory diseases ulcerative colitis or Crohn’s disease (2).
  
• EPX is a glycoprotein that is released when eosinophil granulocytes (white blood cells responsible for battling infectious parasites and bacteria) (2). Its increased levels in feces reflect infection, inflammation and tissue damage relating to food allergies, celiac disease, helminthic infection, inflammatory bowel disease, and cancer (5).

Reference List

1. MacDonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005;307:1920-5.
2. Wagner M, Peterson CG, Ridefelt P, Sangfelt P, Carlson M. Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease. World J Gastroenterol 2008;14:5584-9.
3. Savino F, Castagno E, Calabrese R, Viola S, Oggero R, Miniero R. High Faecal Calprotectin Levels in Healthy, Exclusively Breast-Fed Infants. Neonatology 2009;97:299-304.
4. Gaya DR, Mackenzie JF. Faecal calprotectin: a bright future for assessing disease activity in Crohn's disease. QJM 2002;95:557-8.
5. Genova Diagnostics. 2009. "Comprehensive Digestive Stool Analysis 2.0" Gastrointestinal Assessments. Available at: http://blackboard.bridgeport.edu/@@651E45893EFF586CEA74E9CF68D701AA/courses/1/NUTR-560E-DLB-2009NF/content/_22116_1/Comprehensive%20Digestive%20Stool%20Analysis-%20Genova.pdf. Accessed 28 Nov 2009.

Kid Nutrition

Nutritional and energy needs for a child differs profoundly from that of an adult because of a child's continual growth and development. A child is in greater need of nutrient-dense foods--although not to the extent as infants--and requires more energy for basal metabolic rate, physical activity and thermic effect of food. Energy needs are highest during rapid growth and expansion of lean mass.

Each individual child is best understood by first dividing stages of child growth and development into two periods: a preschool period and a school-age period:

• During the pre-school period, from 2-6 years of age, the child grows more slowly in comparison to infancy. A toddler will quadruple birth weight in a full year or so. The brain of the toddler also grows more slowly than as was expected as an infant so head circumference will only increase by a couple of centimeters. A toddler's weight increase can range from 2.5 kg per year for ages 2 and 3 to 2 kg per year for ages 4 and 5. She or he will also grow about 12 cm from age 2 and 3. During that time, body composition will also change as total body water content settles to a comfortable 60-65% and growth of new cells and skeletal muscle causing a decrease in extracellular fluid and increase in intracellular fluid.
  
• The school-age period, or latent growth period, beigns from 6 until puberty of which girls can reach a little earlier at 10 and boys normally at 12. As "baby fat" is lost, the child becomes leaner and mor muscular. The pattern of growth is highly individual. On average, weight increase will be about 3-3.5 kg per year during this period. The child will move beyond the limited vocabulary of three-word-sentences and begin adapting to an environnment of greater language skills, motor skills, as well as personal-social skills. This, of course, will also mean more control over diet through self-feeding.

As both periods represent critical times for growth and development, the focus of recommendations for energy and nutrient intake are based on supporting optimal outcomes. The recommendations are, again, more critical than for adults because of dire long-term consequences. A child, for example, will need special attention to be sure that they receive proteins of high biologic value for growth requirements. Fat and carbohydrate needs will be greater during rapid growth periods as will numerous vitamins and minerals, especially vitamin D and calcium of which are largely deficient in children. Fiber too, which helps normalize bowel movements, is critical for ensuring a child lives free of future risk of disease. All in all the goal is to provide the best support to provide children with bright futures.

Summarized from

Mitchell MK. Nutrition Across the Life Span. "Chapter 9: Nutrition During Growth: Preschool through Preadolescence". Second Edition. Waveland Press: Long Grove, Illinois, 2003, pp. 271-300.

Somatic Protein Status

Protein status is assessed by evaluating both somatic and visceral protein status. Somatic protein status is a measure of the protein in skeletal muscle while visceral protein status is a measure of all other proteins (organs, viscera, serum, blood cells, white blood cells).

Evaluation of somatic protein status can generally be performed using muscle circumference or mid-arm muscle area. However, because no single indicator is completely accurate biochemical measures can help better provide perspective for somatic protein status.

Creatinine serves as a useful measure because creatinine is produced in the skeletal muscle. The more skeletal muscle a person has, the more creatinine will be excreted. A 24-hour urinary creatinine excretion test is easily tested in the laboratory. The measure can then be compared to standards based on stature and body weight. The 24-hour urinary creatinine excretion can also be compared to reference values from the creatinine-height index (CHI). The CHI is a ratio of 24-hour urinary creatinine excretion and an expected amount depending on sex and stature. Creatinine measures have their limits samples have to be collected in exactly 24 hours and diet can compromise creatinine measurements and, thus, measures of excretion and CHI.

The amino acid, 3-methylhistidine, is another useful measure of muscle mass because it is found in the contractile proteins of muscle, actin and myosin. It is releasaed when the contractile proteins are catabolized and excreted in the urine. As long as protein synthesis and degradation is steady, the amount of 3-methylhistidine should paint a picture of muscle mass. However, just as 24-hour urinary creatinine excretion, the measure of 3-methylhistine is limited. The value can be affected by diet, age, sex, maturity, hormonal status, physical shape, any recent intense exercise, injury or disease. A significant pool of 3-mehtylhistidine also lies outside of skeletal muscle that also creates complication as an index of skeletal protein breakdown.

Energy needs of healthy term and high-risk infant

The infant, despite whether healthy term or high-risk, will require energy for BMR, thermic effect of food, physical activity, maintenance, growth and for energy lost in feces and urine. There is also energy needed just to maintain body temperature until the early extrauterine period passes. The newborn requires approximately 108 kcal/kg for about six months followed by 98 kcal/kg for the next six.

The high-risk newborn will have the same energy requirements, but Calorie needs will differ in whether or not the infant is enterally fed or parenterally fed. The enterally fed infant needs a greater amount of Calories, at 120/kg, than the healthy infant due to specific dynamic action and cold stress. The parentally fed will need fewer amount of Calories, at about 80-90 kcal/kg, than the healthy infant because of the infant won't use as many calories for activity, cold stress, specific dynamic action or stool losses. Caloric needs for both enterally and parenterally fed high-risk infants will aslo need to depend on medical problems and growth needs.

Assessment methods by which energy needs are determined include anthropometry, biochemical assessment and dietary assessment. Anthropometry assesses weight, length and head circumference. Because weight is most important for the high-risk infant, it will need to be weighed one or more times daily. Biochemcial lab measurements will need to be performed over several days in the high-risk infant to determine development.

The high-risk infant will also need a clinical assessment and a nutrient intake assessment. The clincal assessment will evaluate condition including state of hydration relative to urine and weight gain as well as feeding tolerance including vomiting records. Nutrient intake will evaluate nutrient sources in a qualitative fashion as well as nutrients in terms of quantity. Nutrient sources will need to depend on the condition of the high-risk infant such as state of digestive abilities. Nutrient amounts depends on absorption capacities, whether parenterally or enterally fed and weight.

Reference

Mitchell MK. Nutrition Across the Life Span. Second Edition. Waveland Press: Long Grove, Illinois, 2003.

Protein-deficient diet and teratogenicity

One interesting detail I came across while researching teratogens is that a protein-deficient diet may enhance the effects of xenobiotics in general.

For example, dietary protein deficiency along with exposure to inorganic arsenic through injection in mice was found to increase risk of birth defects, possibly because of lack of methyl donors for arsenic methylation (1). Also, high-dose caffeine teratogenicity is increased when in combination with protein deficiency (2).

Other xenobiotics such as tobacco carcinogens, anticonvulsants and sedatives appear to be teratogenic depending on the status of the cytochrome P450 system of the fetus (1). The effect may or may not be related to protein deficiency. The toxicity is thought to occur due to lack of anitoxidative enzymes such as GSH peroxidase and GSH reductase, which would increased endogenous oxidative stress and cumulative damage (3).

Reference List

1. Lammon CA, Hood RD. Effects of protein deficient diets on the developmental toxicity of inorganic arsenic in mice. Birth Defects Res B Dev Reprod Toxicol 2004;71:124-34.
2. Nehlig A, Debry G. Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data. Neurotoxicol Teratol 1994;16:531-43.
3. Wells PG, Kim PM, Laposa RR, Nicol CJ, Parman T, Winn LM. Oxidative damage in chemical teratogenesis. Mutat Res 1997;396:65-78.

Caffeine and pregnancy

I was shocked to learn that FDA in 1980 had determined that caffeine in amounts exceeding 300 mg could potentially be teratogenic (1). Teratogens are agents that cause fetal malformations or birth defects. Good thing caffeine does not harm the fetus when taken in smaller amounts, despite evidence in rats to the contrary (1-2).

However, after digging deeper, I found that the researchers did find that caffeine potentiated teratogenic effect of smoking and alcohol (2). The mechanism appears to be through inducing materno-fetal vasoconstrictions that lead to ischemia (2).

If caffeine potentiates effects of other teratogens in amounts less than 300 mg, I imagine it's still wise of pregnant women to avoid caffeine altogether during pregnancy just in case they are exposed to teratogens of some kind and are unaware of it.

Reference List

1. Mitchell MK. Nutrition Across The Life Span. Long Grove, IL: Waveland Press, 2003.
2. Nehlig A, Debry G. Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data. Neurotoxicol Teratol 1994;16:531-43.

Cannabis Teratogenicity

Cannabis sativa’s psychoactive tetrahydrocannabinol (THC) has not been established as a human teratogen (1), but there is a history of teratogenic effects linked to use by expectant mothers (2). The perinatal exposure is thought to interfere with neurodevelopment and affect neurobehavorial outcomes (1-2).

Although the teratogenicity of marijuana is not as catastrophic as other illicit drugs such as cocaine, it’s harm can still lead to problems such as disturbed sleep and attention deficit disorder (2-3). Worth noting is that when cocaine exposure is accompanied by marijuana, the neurological effects can be pronounced (3).

There is also indication that maternal marijuana use may increase risk of acute myeloid leukemia, however, more recent research has not been able to confirm this relationship (4).

Reference List

1. Kozer E, Koren G. Effects of prenatal exposure to marijuana. Can Fam Physician 2001;47:263-4.
2. Reece AS. Chronic toxicology of cannabis. Clin Toxicol (Phila) 2009;47:517-24.
3. Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B. Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA 2001;285:1613-25.
4. Trivers KF, Mertens AC, Ross JA, Steinbuch M, Olshan AF, Robison LL. Parental marijuana use and risk of childhood acute myeloid leukaemia: a report from the Children's Cancer Group (United States and Canada). Paediatr Perinat Epidemiol 2006;20:110-8.

When you’re eating for twins or more

Nutritional needs soar when you have a multiple pregnancy. According to Barbara Luke from University of Miami, the mother has a “greater nutritional drain” on her body. Because of quicker glycogen depletion that might slow fetal growth rate, Luke suggests a diabetic regimen with caloric ratio of 40% carbs, 20% protein, and 40% fat. In addition, she suggests supplementation with iron, calcium, magnesium and selenium for preventing “complications and improvement of postnatal health”.

Reference List

Luke B. Nutrition and multiple gestation. Semin Perinatol 2005;29:349-54.

Eggs for Pregnancy

Eggs, considered a nutritional powerhouse, is an excellent food to recommend to these women during pregnancy. According to Niva Shapira of Tel-Aviv University in Israel, eggs can provide various nutrients, vitamins and minerals that are also found in human milk and that support peak brain development (1).

If those eggs are also produced in such a way as to contain high levels of DHA, then they become even more supportive to the young one’s brain (2).

Reference List

1. Shapira N. Modified egg as a nutritional supplement during peak brain development: a new target for fortification. Nutr Health 2009;20:107-18.

2. Carlson SE. Docosahexaenoic acid supplementation in pregnancy and lactation. Am J Clin Nutr 2009;89:678S-84S.

Low-fat vs low-carb and Med-diet

On July 17, 2008, a study was published (1) that I believe should change how nutritionists and dietitians would look at the current Dietary Guide for Americans, the Food Guide Pyramid and the whole concept of a “heart-healthy” low-fat diet as recommended by the American Heart Association.

The paradigm-shift study was a 2-year intervention trial in The New England Journal of Medicine in which weight loss was compared among moderately obese subjects who were assigned to either a restricted-calorie Mediterranean diet, a non-restricted calorie low-carbohydrate, or a typical restricted-calorie low-fat diet (1). What did they find? Surprising results.

All the subjects lost weight, but were greater in both the low-carbohydrate group (despite nonrestricted calories) and the Mediterranean-diet group (1). The lipid profiles, more surprisingly, improved in the Mediterranean-diet group and most in the low-carbohydrate group (1). Best LDL cholesterol levels were found among the Mediterranean-diet group (1). The level of high-sensitivity C-reactive protein, most surprisingly, improved only in the Mediterranean-diet and low-carbohydrate groups (1).

The study, going further, took into consideration those with diabetes by measuring their fasting plasma glucose, insulin and glycated hemoglobin levels. There were no significant changes in fasting plasma glucose levels, but drastic decreasaes in insulin levels across the board (1). But the glycated hemoglobin decreased the most in the low-carb group (1).

Given the results of this study, my inclination is to adopt the Harvard School of Public Health’s Healthy Eating Pyramid because it appears to more resemble the Mediterranean-style of eating. And I would add recommendation for lower-carb eating in general along with inclusion of monounsaturated fat from olive oil and higher intake of fish versus red meat, etc.

Reference List

1. Cheskin LJ, Kahan S. Low-carbohydrate and Mediterranean diets led to greater weight loss than a low-fat diet in moderately obese adults. Evid Based Med 2008;13:176.

Fighting a Losing War That Must Be Won

Once the “war on cancer” was declared in 1971 by Congress, researchers have sought to defeat it (1), but after losses of many knights in shining armor, a newfound respect has come around for this dragon of a disease (1). In the 1990s and 2000s, however, a new sense of hope had come about.

“End cancer by the year 2015” was the message shared in 2003 by Andrew C. von Eschenbach, MD, director of the National Cancer Institute (NCI). And although he’s had many critics saying it couldn’t be done, others joined him in saying it could. Just two years afterward, in 2005, NCI modified it’s lofty goal to a softer “alleviate pain, suffering and death associated with cancer” (2). The change meant a new direction of “controlling” but not “curing” the disease .

The same year, 2005, one Eschenbach supporter put forward a plan for a victory (3). His name was Mikhail V Blagosklonny, MD, PhD, and his approach was by combining strategies that target cancerous cells directly while protecting normal cells in targeted tissues (3). Blagosklonny’s three-pronged attack (as suggested cures tend to be) may appear relatively simple, but so far scientists are finding the goal nothing more than elusive.

At cancer’s core there is a only one etiology, which strikes like sabotage at the core of the human body’s own blueprint: mutation. Genetic instability is why cancer has proved to be a more formidable enemy than diabetes or heart disease. The disease is completely unpredictable, arising any number of tissues, with more than 100 possible etiologies (1), and by the time you know its there, it’s an army of cancerous cells reproducing faster than rabbits, using healthy cells to shield itself from attacks, and ultimately making its final blow in a battle of attrition.

Can the 2015 goal be sustained? And, more curiously, will there ever be a cure? As always judgment will be left up to science leaving all with a need for patience, but over the years since the ‘70s much has been learned thanks to thousands of studies on cancer. Marching onward it is progressive understanding and creativeness in treatments that present hope that researchers will eventually prevail.

Reference List

1. Hesse BW. Harnessing the power of an intelligent health environment in cancer control. Stud Health Technol Inform 2005;118:159-76.
2. Conrads TP, Hood BL, Petricoin EF, III, Liotta LA, Veenstra TD. Cancer proteomics: many technologies, one goal. Expert Rev Proteomics 2005;2:693-703.
3. Blagosklonny MV. How cancer could be cured by 2015. Cell Cycle 2005;4:269-78.

Anti-Soy Fiction

I just read a citizen's petition to FDA by Gail Elbek calling for the removal of soy because of antinutrients (trypsin inhibitors and phytates) and endocrine disruptors. Gave me a bit of a laugh, but I expect it will scare a lot of unwitting people.

The outrageous claims Ms. Elbek makes are not grounded in any science. Soy phytotoxicity is going to “kill our children”? Please. I’m not about to throw out my soy milk, tofu and soy sauce. What’s next? Spinach. Spinach contains a lot of phytates. Many raw foods like raw soybeans contain all sorts of anti-nutrients, but that’s why we dehull, cook, or ferment these raw foods. Most anti-nutrients are eliminated just by the processing.

There is a point to be made about high amounts of concentrated phytoestrogens (soy isoflavones) in a few dietary supplements, which are often marketed to women as natural hormonal therapy. These are basically drugs of which we don’t know enough about. The research is still out on whether or not they’re beneficial or if they can do harm.

But, again, there’s really not really anything raise eyebrows regarding levels of isoflavones in tofu or other soy products. The low levels of isoflavones that are in them are probably even good for you. So even if we ever did offer a soy protein shake, I don’t think I’d be too worried. We mustn’t forget that there have been more than 40 human clinical studies on soy protein’s health benefits. Not to mention that an entire, but relatively insignificant, country called China pretty much subsists on soy.

Boron and Disease

Boron's ability to induce sex hormone levels give it a role preventing chronic disease. For example, adequate dietary boron may potentially reduce risk of lung cancer (1). The effects also explain why boron supplementation may support bone density guarding against osteoporosis (2).

However, caution should be exercised before supplementation with boron. Greater estrogen levels due to boron supplementation may potentially increase risk of breast cancer (1;2). Thus, boron should not be taken by women with high risk of breast cancer or who've had breast cancer.

Reference List

1. http://www.pccnaturalmarkets.com/health/2813008/
2. http://www.osteopenia3.com/Boron-Osteoporosis.html

Nickel toxicity

Nickel is a known carcinogen. When in the diet in toxic amounts it contributes to oxidative stress, just as mercury and cadmium do, by reducing glutathione thereby interfering with cell membrane integrity and increasing lipid peroxidation (1). The oxidative damage, like from free iron or copper, can cause DNA damage (2).

Reference List

1. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12:1161-208.

2. Tkeshelashvili LK, Reid TM, McBride TJ, Loeb LA. Nickel induces a signature mutation for oxygen free radical damage. Cancer Research; 53, 4172-4174, September 15, 1993.

Flouride and the World

As one travels around the world, especially in developing countries, the state of oral health stands out as an issue that needs attention. Fluoride treatment of drinking water can be an important step in improving oral health (1), but some populations may find it's not necessary because they may already be consuming adequate or even too much fluoride daily.
Careful review of fluoride exposure must be evaluated region by region before deciding to treat local water with fluoride (2). According to the World Health Organization (WHO), flouride intake can vary depending fluoride already in water, on diet and other variables such as local pollution (2).

Areas of greater volcanic activity, for example, tend have highest concentrations of fluoride in groundwater (2). The act of tea drinking can provide significant amounts of fluoride (1). In parts of China where high-fluoride coal is burned, the ash that pollutes crops may be providing fluoride (2). And in Tanzania, the use of contaminated trona to tenderize vegetables contributes fluoride can easily result in excess amounts of fluoride ingested daily (2).

Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.3.
2. World Health Organization. Fluoride in Drinking Water. Available at http://www.who.int/water_sanitation_health/publications/fluoride_drinking_water_full.pdf

Molybdenum and Gout

A young electrician with a painful gouty arthritis in 2005 became the first case observed of occupational exposure of toxic amounts of molybdenum (1). Molybdenum is an activator of xanthine oxidase, which oxidizes xanthine producing uric acid (2). Too much produced hyperuricemia (1). The electrician can be thankful that his doctors found the cause of the gout because of previous men afflicted with gout by having consumed 10 to 15 mg of molybdenum daily (3;4). Tolerable uptake limits are set at 2 mg (2).

Reference List
1. Selden AI, Berg NP, Soderbergh A, Bergstrom BE. Occupational molybdenum exposure and a gouty electrician. Occup Med (Lond) 2005;55:145-8.2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.3. http://lpi.oregonstate.edu/infocenter/minerals/molybdenum/4. http://www.crnusa.org/safetypdfs/027CRNSafetyMolybdenum.pdf

Manganese as a Neurotoxin

Toxicity of manganese is more common than its deficiency (1), which unfortunately cause damage to the brain. Manganese appears to cause neurogeneration by activating microglia and causing them to release neurotoxins such as reactive oxygen and nitrogen species, which produce oxidative damage (2). The neurotoxins are also thought to possibly alter influence of neurotransmitters such as dopamine or gamma-aminobutyric acid (GABA) (1). According to a studies on non-human primates exposed to high doses of manganese, the mineral can lead to deficits in working memory performance and even induce an increase of beta-amyloid production linking manganese to Alzheimer's disease (3;4).

Reference List
1. Anderson JG, Fordahl SC, Cooney PT, Weaver TL, Colyer CL, Erikson KM. Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain. Neurotoxicology 2008;29:1044-53.
2. Zhang P, Wong TA, Lokuta KM, Turner DE, Vujisic K, Liu B. Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: role of free radical generation. Exp Neurol 2009;217:219-30.
3. Schneider JS, Decamp E, Clark K, Bouquio C, Syversen T, Guilarte TR. Effects of chronic manganese exposure on working memory in non-human primates. Brain Res 2009;1258:86-95.
4. Burton NC, Guilarte TR. Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates. Environ Health Perspect 2009;117:325-32.

Mutagenic Metals

The biochemical mechanism by which metals are mutagenic is by their effects on DNA. The main pathway shared by iron, copper, chromium, vanadium and cobalt is by redox-cycling reactions and mercury, cadmium and nickel by depleting glutathione and bonding to sulfihydryl groups (1). Free iron, in particular, can cause oxidative damage on DNA that can cause cancer in the spleen (2). Arsenic, in particular binds directly to critical thiols producing DNA damage (1). Cadmium interferes with and inhibits DNA repair (3;4).

Reference List
1. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12:1161-208.
2. Wu X, Kannan S, Ramanujam VM, Khan MF. Iron release and oxidative DNA damage in splenic toxicity of aniline. J Toxicol Environ Health A 2005;68:657-66.
3. Slebos RJ, Li M, Evjen AN, Coffa J, Shyr Y, Yarbrough WG. Mutagenic effect of cadmium on tetranucleotide repeats in human cells. Mutat Res 2006;602:92-9.
4. Giaginis C, Gatzidou E, Theocharis S. DNA repair systems as targets of cadmium toxicity. Toxicol Appl Pharmacol 2006;213:282-90.

Ca and Mg balance

Calcium (Ca) and magnesium (Mg) are non-heavy metals with the same valence charge that are both critical for physiologic function, yet overlap each other in their mechanisms. For example, they both use the same transport systems in kidney competing with each other for absorption. They also oppose one another in blood coagulation, smooth muscle contraction and PTH release.

The relationship between Ca and Mg is important as it promotes a balance in given biological systems for proper function of the body. Deficiency either mineral could result in an improper balance leading to problems.

Vanadium treatment of type 2 diabetes enhanced by organic ligands

Vanadyl ions can act in an insulin-like manner in the body. Thus, when taken orally they may potentiate insulin’s effects, which can potentially improve situations of type 2 diabetes (1).

Bioavailability of vanadyl compounds, however, can depend on whether of organic or inorganic nature (2). The organic bis-ligand oxovanadium appear to be far more bioavailable and efficacious than inorganic vanadyl sulfate (2).

According to a couple of trials performed earlier this year in Canada, the organic version taken in doses of 10-90mg has no adverse effects (2). Further, it was found to help reduce fasting blood glucose levels and improves glucose tolerance (2).

Reference List
1. Conconi MT, DeCarlo E, Vigolo S et al. Effects of some vanadyl coordination compounds on the in vitro insulin release from rat pancreatic islets. Horm Metab Res 2003;35:402-6. 2. Thompson KH, Lichter J, LeBel C, Scaife MC, McNeill JH, Orvig C. Vanadium treatment of type 2 diabetes: a view to the future. J Inorg Biochem 2009;103:554-8.

Life Depends on Arsenic?

As Gropper, Smitth and Groff tell it, arsenic "conjures an image of toxicity" unlike any other ultratrace mineral (1), but there are good things that come of arsenic and its story is worth discussion.

Without arsenic, DNA synthesis couldn't happen. This is because arsenic is needed for normal metabolism. Specifically, the mineral is required for forming and using methyl groups to S-adenosylmethionine (SAM) (1). SAM is used for methylation to form DNA compounds (1).

Arsenic, in fact, may have once been part of DNA itself. The mineral is very similar to phosphorus, which is currently the backbone of nucleic acids. Because this is is so it has been suggested that arsenic may have served as an alternate element early on, although not possible in modern biochemistry (3).

According to scientists Felisa Wolfe-Simon, Paul Davies and Ariel Anbar, there may even be possibility that organisms may still be using arsenic in their DNA today, but simply not yet found (3).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

2. Emsley J. Nature's Building Blocks: An A-Z Guide to the Elements. Oxford University Press, 2003.

3. Wolfe-Simon F, Davies PCW, Anbar A. Did nature also choose arsenic? Nature Precedings, Jan 2008.

Estrogen & Osteoporosis

Estrogen appears to directly influence bone turnover. Its mechanism is byacting on estrogen receptors in bone cells (1). The hormone influencesvitamin D metabolism by increasing conversion of 25-hydroxyvitamin D(25OHD) to 1,25-(0H)2D as it does in birds (2).

The increase of 1,25-(0H)2D then enhances calcium absorption in the bones(2). Estrogen, thereby, contributes to bone density by slowing down boneloss and its absence can lead to lower bone density and predispose forosteoporosis (1;2).

This biochemistry supports evidence that already exists that estrogenreplacement therapy (ERT) combined with adequate calcium and vitamin Dintake as well as exercise may help prevent osteoporosis (3;4).

Despite the effects, however, I have the same opinion about using long-term estrogen replacement therapy (ERT) in postmenopausal women for osteoporosis as I do about estrogen for reducing risk of cardiovascular disease in postmenopausal women.

While there are benefits outlined suggesting that future research on long-term estrogen therapy is merited, the side risks involved may be too serious for estrogen for prescription at this time. Side risks, which include higher risk of breast cancer and other cancers, generally outweigh benefits of ERT.

Short-term ERT, however, may have its place. According to WebMD and Women's Health Initiative authors and those of WebMD, short-term ERT in low doses may reduce or eliminate risks associated with long-term ERT (5;6). More research is needed to explore use of short-term ERT.

Reference List

1. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ. Modern Nutritionin Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins, 2009.

2. Gallagher JC, Riggs BL, DeLuca HF. Effect of estrogen on calciumabsorption and serum vitamin D metabolites in postmenopausal osteoporosis.J Clin Endocrinol Metab 1980;51:1359-64.

3. Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatmentwith estrogen and calcitriol in the prevention of age-related bone loss. JClin Endocrinol Metab 2001;86:3618-28.

4. Gallagher JC. Role of estrogens in the management of postmenopausalbone loss. Rheum Dis Clin North Am 2001;27:143-62.

5. Banks E, Canfell K. Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009;170:24-8.

6. WebMD. Women's Health Initiative (WHI): Risks and benefits of hormone replacement therapy (HRT) and estrogen replacement therapy (ERT). Available at: http://www.webmd.com/hw-popup/womens-health-initiative-whi-risks-and-benefits-of-hormone-replacement-therapy-hrt-and-estrogen.

Chromium and Glucose Tolerance

Because of chromium’s known ability to potentiate action of insulin, an adequate chromium status is important especially for people with diabetes, insulin resistance and hypoglycemia to maintain glycemic control (1;2).

According to an evaluation of 15 randomized clinical trials, amounts of about 200 mcg per day appear to improve use of glucose (3). In addition, a placebo-controlled trial of 180 Chinese patients found that doses at 200 mcg and as high as 1,000 mcg of chromium taken per day lowered blood glucose levels by 15-19% (3).

Dose may depend on form of chromium since one form may be more bioavailable than another. Chromium picolinate appears to be the most bioavailable and, thus, the most potent (3).

The amount of chromium taken, however, should not exceed 1,000 mcg per day due to potential toxicity (1). Chromium picolinate, in addition, should not be taken in amounts over 600 mcg because of association with renal failure and hepatic dysfunction (1).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Pohl M, Mayr P, Mertl-Roetzer M et al. Glycemic control in patients with type 2 diabetes mellitus with a disease-specific enteral formula: stage II of a randomized, controlled multicenter trial. JPEN J Parenter Enteral Nutr 2009;33:37-49.
3. Linus Pauling Institute. Chromium. Micronutrient Information Center. Available at: http://lpi.oregonstate.edu/infocenter/minerals/chromium/.

Chromium nicotinate, but not picolinate may improve body composition

Advertisements that suggest chromium picolinate may help consumers lose fat or gain muscle mass are largely overstated.

A double-blind, randomized, placebo-controlled 12-week trial in 2001 found that chromium picolinate offered moderately obese women participating in an exercise program no significant changes to body composition, resting metabolic rate, plasma glucose, serum insulin, plasma glucagon, serum C-peptide or serum lipid concentrations (1).

The 2001 study’s results supported at least three previous studies of which had also shown that chromium picolinate had been ineffective in changing body composition in obese women, in military personnel and in weight-lifting football players (2-4).

A 12-week randomized, placebo-controlled trial in 2008 combined chromium picolinate with conjugated linoleic acid and evaluated effects on body composition changes of young, overweight women for 12 weeks (5).; still, no significant changes were found (5).

Lastly, because of chromium’s known effects on enhancing insulin signaling and glucose uptake, a randomized, placebo-controlled clinical trial in 2006 investigated effects of chromium picolinate on glycogen synthesis on overweight men after intense exercise (cycling) and high-carbohydrate feeding (6). Chromium picolinate did not appear to augment glycogen synthesis, but did appear to lower activity of phosphoinositol-3-kinase, an enzyme involved in regulating glucose uptake (6).

Chromium nicotinate, however, does appear to have effects on body composition.

One study on young, obese women who were given either chromium picolinate or chromium nicotinate found that chromium picolinate while "resulted" in weight gain for subjects, it also found that chromium nicotinate, when combined with exercise, did produce weight loss and lower insulin response (2).

Another randomized, double-blinded, placebo-controlled, crossover study on African American women gave 200mcg chromium nicotinate for over 2 months (2). The study did find significant fat loss and "sparing of muscle" in the women taking chromium nicotinate when combined with moderate exercise (7).

Reference List

1. Volpe SL, Huang HW, Larpadisorn K, Lesser II. Effect of chromium supplementation and exercise on body composition, resting metabolic rate and selected biochemical parameters in moderately obese women following an exercise program. J Am Coll Nutr 2001;20:293-306.
2. Grant KE, Chandler RM, Castle AL, Ivy JL. Chromium and exercise training: effect on obese women. Med Sci Sports Exerc 1997;29:992-8.
3. Trent LK, Thieding-Cancel D. Effects of chromium picolinate on body composition. J Sports Med Phys Fitness 1995;35:273-80.
4. Clancy SP, Clarkson PM, DeCheke ME et al. Effects of chromium picolinate supplementation on body composition, strength, and urinary chromium loss in football players. Int J Sport Nutr 1994;4:142-53.
5. Diaz ML, Watkins BA, Li Y, Anderson RA, Campbell WW. Chromium picolinate and conjugated linoleic acid do not synergistically influence diet- and exercise-induced changes in body composition and health indexes in overweight women. J Nutr Biochem 2008;19:61-8.
6. Volek JS, Silvestre R, Kirwan JP et al. Effects of chromium supplementation on glycogen synthesis after high-intensity exercise. Med Sci Sports Exerc 2006;38:2102-9.
7. Crawford V, Scheckenbach R, Preuss HG. Effects of niacin-bound chromium supplementation on body composition in overweight African-American women. Diabetes Obes Metab 1999;1:331-7.

Selenium and Prostate Cancer

Prostate cancer has been associated with low serum selenium concentration. To investigate the mechanisms by which selenium affects gene expression prostate tissue, researchers set out to measure activity of glutathione peroxidase in men with relatively high serum selenium concentration (1).

The researchers measured serum selenium concentration in 98 men using atomic absorption spectrometry. Afterward, 12 men were selected for having the highest serum selenium concentration and another 12 were identified as having the lowest serum selenium concentration. Fresh prostate tissue samples were taken of the selected men to measure selenium concentration and glutathione peroxidase activity.

The study, which was published in July 2007, reported a positive correlation found between a higher serum selenium concentration and a prostate tissue concentration. However, there was no significant increase of glutathione peroxidase activity associated with the higher concentration of selenium concentration.

Discussion: Because the subjects of this study were already were identified as having high serum selenium concentrations, the results indicate simply that glutathione peroxidase activity is not increased by greater concentration of selenium beyond a certain requirement. The data suggest selenium dietary intake exceeding established amounts to correct deficiency do not present any additional benefit in prevention of prostate cancer.

Reference List

1. Takata Y, Morris JS, King IB, Kristal AR, Lin DW, Peters U. Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 2009.

DHA May Assist in Preventing Alzheimer's Disease

Summary:

Complementary preventive therapy for Alzheimer’s disease should include DHA for its biochemical implications, especially in apoE4-genotype obese-diabetic patients. DHA mechanisms involve reducing adiposity and secretions, improving insulin sensitivity, guarding against oxidative stress, and guarding against beta-amyloid plaque, neurofibrillary tangles and advanced glycation end-products.

Background: Urgent Call for Alzheimer’s Disease Preventive Therapies

Foresight warns that the present epidemic of obesity and diabetes in the United States of America will lead to future medical epidemics and among them will be Alzheimer’s disease (AD), the most common neurodegenerative disease seen in aging. AD is seriously debilitating and at present time has no cure. Current treatments are limited to cholinesterase inhibitors to improve function of signaling pathways in memory, but are not intended to prevent or slow further brain damage. Preventive strategies are currently being studied to assist in avoiding Alzheimer-type dementia in the population. Obese-diabetic persons are predisposed to AD, particularly if they are of the apoE4 genotype (Luchsinger & Gustafson, 2009). ApoE4-genotype obese-diabetic individuals, at high risk for AD, represent an ideal population for testing AD-prevention therapies. The last decade has witnessed popularity of researching fish-derived omega-3 fatty acids, notably docosahexaenoic acid (DHA), and their relationship with brain health. New research has begun to associate the use of fish oil with less cognitive decline and lowered risk of AD (Martin, 2008). Along with dieting and exercise directed at improving insulin sensitivity, DHA intake in apoE4-genotype obese-diabetic subjects may reduce the progression of AD. The following are four potential mechanisms that could explain how DHA operates: (a) improving insulin sensitivity to reduce continual hyperglycemia, hyperinsulinemia, and hypertension (b) inhibition of beta-amyloid (Abeta) and plaque production, (c) inhibition of hyperphosphorylation of tau protein, which leads to neurofibrillary tangle formation, and (d) reduction of oxidative stress and advanced glycation end-product (AGE) formation and cross-linking. This paper will discuss the literature supporting this hypothesis.

Biochemistry of AD

The underlying condition seen with AD is impairment of memory and learning, or dementia. It is primarily caused by Abeta plaques. At the core of the plaques is amyloid protein. Autopsy of AD brains shows that plaques are widely distributed over the cerebral cortex. The Abeta aggregates when under oxidative stress, which worsens the AD (Carr, Goate, Phil, & Morris, 1997). The Abeta protein binds to proteases inhibitors suppressing the normal catabolism of proteases, which allows them to damage neurons and other proteins. Neurofibrillary tangles are a secondary factor induced by Abeta. They become localized mainly in the hippocampus, entorhinal cortex and amygdala. The tangles are made up of the tau protein. Tau protein is one of the microtubule associated proteins used to stabilize microtubules and for providing attachment to other cells. The tangles are produced by abnormal hyperphosphorylation of the tau protein. The protein when hyperphosphorylated, also called “paired helical filaments,” becomes aggregated. Neurons affected by plaques and tangles eventually die (Carr et al., 1997). As described before, the tangled up mess causes considerable interference and attenuates damage in the brain. The tangles are susceptible to glycation. Advanced glycation end-products (AGEs) and cross-linking occur. The AGEs are formed by nonenzymatic Maillard reactions, when glucose molecules open and attach to lysine in proteins producing Schiff bases, which form Amadori products. The Amadori products—as also found in glycated hemoglobin—are more stable, but when attacked by free radicals produce oxoaldehydes, otherwise called AGEs. Glycations alter function of proteins causing their degradation. The Maillard reactions also lead to production of reactive oxygen species, which, in turn, promote more glycation (Kikuchi et al., 2003). Glycation on tau protein enhances formation of tangles and is thought to enhance aggregation of Abeta (Sasaki et al., 1998). The AGEs also activate glia producing inflammation and dysfunction as well as fragmentation into glyoxal and methylglyoxal (Kuhla et al., 2005). Thereby, AGEs are implicated as a cause of inflammation, oxidative stress, neuronal dysfunction (Yan et al., 1995). The Abeta aggregation, tangles and AGE cross-linking are ultimately cause for AD pathogenesis.

ApoE4 Genotype

Apolipoproteins are proteins that form lipoproteins to transport fats in the blood stream. They are produced in the liver and their amount in the bloodstream is reflective of dietary fats. An apolipoprotein involved with chylomicron transport across the blood-brain barrier is apolipoprotein E (apoE). These apoE proteins are also found along with Abeta in plaques and along with tau proteins in neurofibrillary tangles. Genetic variations of ApoE are associated with risk of AD. The allele variation episilon2 (E2) appears to be protective while episilon3 is protective to a lesser extent; however, the variant epsilon4 (E4) allele or two alleles has been found to increase AD risk 2.5-fold and 5.6-fold, respectively (Martins, Oulhaj, de Jager, & Williams, 2005; Scarmeas et al., 2002). The E4 allele is not a cause of AD, but predisposes individuals to risk.ApoE4 genotype individuals have increased susceptibility to developing Abeta plaques and neurofibrillary tangles. The mechanism is thought to be dependent on lipidated apoE4. It binds to a specific receptor, apoER2, in brain cells more easily than the other alleles. The receptor allows endocytosis of apoE4 as well as amyloid precursor protein and beta-secretase. Beta- and gamma-secretases then fragment the proteins (He, Cooley, Chung, Dashti, & Tang, 2007). The amyloid precursor protein is fragmented to Abeta. Presence of ApoE4 is also thought to slow clearance of occurring Abeta in the brain. Lipoprotein receptor-related protein-1 (LRP1) is an Abeta-binding molecule that clears Abeta at the blood-brain barrier. Abeta-apoE2 or Abeta-apoE3 complexes are cleared at a much faster rate than Abeta-apoE4 complexes (Deane et al., 2008). These factors lead to risk of “early onset” AD, which is defined as those with AD before age 65. ApoE4 genotype can lead to development of AD as early as ages 30 and 40, especially if obese and diabetic. The apoE4-genotype obese-diabetic population represent ideal candidates for study of AD preventive strategies.

AD Risk Increased by Adiposity and Hyperinsulinemia

Obesity has been consistently linked to the development of dementia and AD (Salihu, Bonnema, & Alio, 2009; Razay, Vreugdenhil, & Wilcock, 2006). Elevated adiposity promotes insulin resistance, an increase of adipokines (cytokines produced from adipocytes) including resistin and tumor necrosis factor-alpha (TNFα). The insulin resistance exacerbates the process leading to metabolic syndrome and diabetes. When obesity is combined with diabetes, the risk of AD increases more than four-fold (Pasinetti et al., 2007). Diabetes and glucose intolerance occurs once the amount of insulin is not enough to overcome elevated plasma glucose. The pancreas secretes more insulin to abnormally high levels to maintain adequate glucose levels in the blood. Abnormal insulin signaling in the brain leads to prolonged elevated insulin levels. Normally insulin would bind to insulin receptors. Under conditions of AD, however, neurons have few insulin receptors and are resistant to insulin. Elevated insulin in the brain that is unable to bind to neurons accumulates in the serum. Hyperinsulinemia stimulation of inflammation is thought to induce formation of Abeta plaques. The loss of appropriate insulin signaling alters activity of phosphorylation leading to increased phosphorylation of tau proteins (Schubert et al., 2004). Prolonged levels of elevated insulin was also suggested by at least one study to peripherally stimulate abnormal signal transduction pathways causing hyperphosphorylation of tau proteins (Freude et al., 2005). The hyperphosphorylation and formation of Abeta plaques caused by hyperinsulinemia in the brain are major factors leading to AD.

Elevated insulin interferes with Abeta degradation. Insulin-degrading enzyme (IDE) breaks down both insulin and Abeta. In addition, it breaks down amylin, which is another amyloidogenic peptide. With all three substrates—insulin, Abeta and amylin competing for the same enzyme—less Abeta and amylin is broken down (Qiu & Folstein, 2006). ApoE4 is also thought to possibly downregulate IDE expression in neurons because it binds to its receptor (Du, Chang, Guo, Zhang, & Wang, 2009). A present target for AD preventive therapy may be to help increase effectiveness of IDE with drugs or by preventing hyperinsulinemia.

Clearance of Abeta is also affected by elevated insulin. The abnormal insulin signaling and inappropriate neuron function causes reduced levels of transthyretin. Transthyretin is a protein that normally supports transport of Abeta out of brain. Therefore, Abeta and amylin elevate in the plasma and becomes aggregated in the environment of inflammation forming plaques (Qiu & Folstein, 2006). In one prospective study, hyperinsulinemia was found to double the risk of AD in subjects ages 65 and older in Manhattan (Luchsinger, Tang, Shea, & Mayeux, 2004). Therefore, the indirect effects of elevated insulin on the brain is one more reason to closely monitor plasma glucose in both diabetics and metabolic syndrome.

Hyperinsulinemia also increases the risk of hypertension. Insulin stimulates sodium reabsorption in the kidneys and causes vasoconstriction that can lead to elevated blood pressure (Ritz, 2008). A seven-year longitudinal study found diabetics patients who had hypertension have a six-fold increased risk of AD (Posner et al., 2002). Hypertension may be involved mainly in progression of AD by producing dysfunction in the blood-brain barrier as well as increasing oxidative stress (Skoog, 1997). Increased permeability in the blood-brain barrier is thought to create greater transport of Abeta across the barrier and less to leave the brain. The oxidative stress presents additional effects by promoting glycation.

Hyperglycemia naturally increases glycation in the brain. Combined with oxidative stress, the excess glucose lead to rapid progression of AGEs (Sato et al., 2006), which can be attenuated by AGEs found in the diet (Gil & Bengmark, 2007). Increased glyoxal levels, resulting from fragments of amadori products, also inactivates enzymes such as superoxide dismutase, needed for neutralizing free radicals, promoting more aggregation, more glycation and more damage to cells (Jabeen, Saleemuddin, Petersen, & Mohammad, 2007). Formation of AGEs and occurrence of AGEs cross-linking neurofibrillary tangles and Abeta aggregates limits neuronal function, produces oxidative stress, increases susceptibility to oxidative stress, and leads to neuronal apoptosis.

Mechanisms of DHA Against AD

The human brain is made up of approximately 60 percent fatty acids. PUFAs make up a major portion of which DHA is in greatest amount followed by EPA. The greatest concentration of DHA in the nervous system is in the membrane phospholipids. Functionally, DHA is heavily involved in retinal and brain processes. Lack of DHA predisposes for neuron dysfunction and stress in various ways, of which some is discussed here, and not of which are all understood. Because DHA and EPA are omega-3 fatty acids, their occurrence in the body relies on dietary intake from fish, crustaceans or other animals, or, to a poorer extent, synthesis from dietary alpha-linolenic acid from plants. DHA is found in greatest amounts in cold-water fatty fish.

The last decade of research has revealed a strong association between DHA and AD. For example, one of the first studies to suggest a role of fish oil and cognitive decline was an observational, prospective study at Rush’s Institute for Healthy Aging. They found elderly subjects who ate fish at least once a week had 60 percent less risk of AD (Morris et al., 2003). Observational and clinical trials on DHA have yet to show benefit in reducing existing AD. According to a systemic review of 11 observational studies and four small clinical trials—of which most only used cognitive decline as an outcome—did not find convincing evidence for prevention or treatment of AD, only that fish-derived omega-3 fatty acids slowed cognitive decline in those without dementia (Fotuhi, Mohassel, & Yaffe, 2009). As a complementary therapy, however, omega-3 fatty acid biochemical nature (especially DHA) should not go ignored. In one large cohort in France involving three cities in 1999-2000, for example, it was found that omega-6 fatty acid intake that was not also met with omega-3 fatty acid intake increased risk of dementia and AD while a diet rich in omega-3 fatty acids from fish, and fruits and vegetables reduced risk of AD, particularly in ApoE4-genotype subjects (Barberger-Gateau et al., 2007). While dieting and exercise may still play the majority role in prevention, DHA’s biochemical implications suggest that there should be continued search for the right dosages of DHA for complementary AD preventive therapy.

DHA and Insulin Sensitivity

DHA as a polyunsaturated fat (PUFA) does not adversely affect insulin sensitivity. Unlike saturated and trans fats, PUFAs are not associated with insulin resistance. Research relating to PUFAs led to a commentary in J Am Diet Assoc recommending displacement of saturated fats with PUFAS, specifically 1 to 2 g of fish-derived omega-3-PUFAs, because of reports of lower glucose intolerance along with lower blood pressure, reduced triglyceride levels, and improved endothelial function (Nettleton & Katz, 2005). The mechanisms are various. PUFAs, particularly DHA and EPA, are thought to improve insulin sensitivity by more than one pathway. The mechanisms are beyond glycemic control (Kuda et al., 2009). In adipose tissue and the liver, PUFAs influence gene transcription to increase amount of proliferator-activated receptors, sterol regulatory element-binding proteins and liver X receptors (Al-Hasani & Joost, 2005). The greater presence of these proteins and receptors result in more sensitivity to various nutrients and insulin. PUFAs also improve lipid metabolism improving prevention of obesity an diabetes. Adipose tissue secretion of adipokines decreases improve insulin sensitivity. PUFAs stimulate mitochondrial beta-oxidation, thereby promoting reduced adiposity (Flachs, Rossmeisl, Bryhn, & Kopecky, 2009). The effects are independent of PUFAs role in eicosanoid synthesis. DHA, in particular, induces lipolysis while reducing lipogenesis in what appear to be various biochemical pathways in the liver and adipocytes. PUFAs regulate gene transcription of lipogenic enzymes—such as glucose-6 phosphate dehydrogenase and fatty acid synthase—and desaturatases—such as stearoyl-C desaturase (Riserus, 2008). DHA is thought to increase lipolytic gene expression and suppressing lipogenic gene expression (Wang et al., 2009). DHA enhances expression of serum amyloid A protein, involved in lipid metabolism, and increases lipases (Wang et al., 2009). All of these are biochemical changes effective for reducing adiposity, subsequent secretions, and the factors leading to insulin resistance.

DHA also improves insulin sensitivity through docosanoid pathways. DHA and EPA immunomodulatory effects are well-known because they inhibit pro-inflammatory cytokine production (Sijben & Calder, 2007). Apart from this role, they increase formation of EPA-derived eicosanoids and DHA-derived docosanoids, resolvins and protectins (Gonzalez-Periz et al., 2009; Pauwels, Volterrani, Mariani, & Kairemo, 2009). The resolvins and protectins then help guard against inflammation as well as insulin resistance. These effects all naturally lead to decreased hyperglycemia, hyperinsulinemia and resulting hypertension.

DHA Lowers Risk of Hypertension

Blood pressure levels are lowered by DHA in various ways. Reduced insulin reduces salt reabsorption in the kidney stemming hypertension. PUFAs such as DHA guard against hypertriacylglycerolemia associated with hypertension (Viljoen & Wierzbicki, 2009). DHA also may help to regulate aldosterone and corticosterone levels associated with hypertension (Engler et al., 1999). A dose of 5 g found to lower blood pressure (Dusing, 1989). In higher amounts (50g), fish oil quite effectively reduces diastolic blood pressure, lowers triglycerides and increases bleeding time, as shown in a six-week randomized, double-blind, parallel-group study on patients with mild hypertension (Levinson, Iosiphidis, Saritelli, Herbert, & Steiner, 1990). Without hypertension to attenuate oxidative stress in the brain, damage in AD may be reduced, but studies are unclear if omega-3 fatty acids would compensate for hyperinsulinemia-induced hypertension.

DHA can also protection against cardiogenic dementia, which can affect AD. Metabolic syndrome factors leading to atherosclerosis and possible thrombosis can result in major cardiac events. DHA improvement of endothelial function, its anti-inflammatory effects from adipokine andiponectin, its inhibition of tumor necrosis factor-alpha protect against factors, and blood platelet effects help protect against heart failure and myocardial infarction (Duda et al., 2009). Heart failure and myocardial infarction can cause cardiogenic dementia, which is a heavy burden on AD patients.

DHA Guards Against Inflammation and Oxidative Stress in the Brain

Depletion of DHA in older adults leads to greater oxidative stress in the brain. Older adults who have not consistently had DHA dietary intake slowly progress to DHA depletion. The depletion leaves membrane phospholipids at greatest risk for oxidative stress insults (Lukiw & Bazan, 2006). DHA-derived neuroprotectins have direct effects on oxidative stress. Because DHA is also involved directly in neuron-to-neuron signaling and in synaptic terminals, depletion and oxidative stress directly affects learning and memory (Lukiw & Bazan, 2006). Its involvement in brain and retinal function is combined with anti-inflammatory effects reducing oxidative damage to brain and retinal cells; thus, DHA may prevent brain damage through antioxidant properties (Farooqui, Horrocks, & Farooqui, 2007). Inhibition of inflammation and oxidative stress as well as antioxidant effects suggest a dual role of DHA protection. DHA antiflammatory properties act via anti-apoptotic and neurotrophic pathways (Orr & Bazinet, 2008).

The omega-3 fatty acid mechanisms are through DHA-derived resolvins, protectins, and neuroprotectins. Each act against the three greatest brain insults occurring in AD: neuroinflammation, oxidative stress and neuron apoptic death (Farooqui, Ong, Horrocks, Chen, & Farooqui, 2007; Farooqui et al., 2007). The effects of DHA depletion is highlighted in animals, which leads to learning and memory deficits with noticeable damage to neurons and synaptic defts; levels of cognitive function are somewhat corrected after DHA supplementation (Farooqui, Horrocks, & Farooqui, 2007). As noted earlier, humans must include DHA in the diet to effectively guard against depletion. DHA-derived neuroprotectin D1 (NPD1) offers main protection against oxidative stress. Along with sphingosine 1-phosphate, DHA inhibits cytokine-mediated cyclooxygenase-2 expression (Farooqui et al., 2007). Cyclooxygenase-2 is an enzyme that produces eicosanoids in the brain. NDP1 also triggers further neuroprotectins and gene-encoding for anti-apoptic proteins (Lukiw & Bazan, 2006). These new findings all point to preservation of DHA amounts during aging.

DHA Guards Against Abeta

DHA-derived protectins protect against Abeta formation and neurotoxicity. NDP1 protects against both. NDP1 synthesis is enhanced by Abeta occurrence. The production of NDP1 is stimulated through activation of growth factors and neurotrophins in the brain, a process that is affected directly by DHA deficits (Lukiw & Bazan, 2008). NDP1 is enhanced especially at times of oxidative stress and the lower the DHA levels, the lower the levels of NDP1 production (Lukiw & Bazan, 2008). NDP1’s effects on Abeta include regulatory interaction with gene-encoding for beta-amyloid precursor protein and Abeta formation. The reduced production of Abeta delays
AD progression by allowing more Abeta to be cleared.

NDP1 inhibits formation of Abeta, thereby against aggregation. NDP1 also displays anti-amyloidogenic effects and suppression of Abeta aggregation significantly in Abeta-infused AD-model rats (Hashimoto et al., 2008). In this way, NDP1 protects against against neurotoxicity and, in the retina, against retinal damage from aggregation and glycation from diabetes (Bazan, 2009). Protection of Abeta would be secondary benefits after DHA’s support for improving insulin sensitivity.

DHA Reduces Tangles and AGEs

DHA inhibits formation of neurofibrillary tangles. Two mechanisms are involved apart from improving helping to reduce risk of elevated insulin. Indirectly, DHA inhibition of Abeta formation reduces hyperphosphorylation. Abeta induces hyperphosphorylation by kinases, which lead to the production of the paired helical filaments that end up in tangles (Cole, Ma, & Frautschy, 2009). The second mechanism is by inhibiting hyperphosphorylation directly. DHA inhibits the enzyme c-Jun N-terminal kinase that leads to tau hyperphosphorylation (Ma et al., 2009). The inhibition of the kinases help keep in check hyperphosphorylation and help correct abnormal insulin signaling. In prolonged hyperinsulinemia, this may offer important protection to brain cells.

DHA antioxidant properties make an impact in suppressing AGE and cross-linking formation. Just as other antioxidants, DHA reduces susceptibility to free radicals. The reduced susceptibility to formation of AGEs while in presence of diabetes and hyperglycemia has been demonstrated in rats (El-seweidy, El-Swefy, Ameen, & Hashem, 2002). According to studies, the suppression of neurofibrillary tangles and AGEs cross-linking by DHA may be even more effective when used with other antioxidants from fruits and vegetables (Cole et al., 2009; Ono & Yamada, 2006). By reducing glycation, DHA suppresses AGEs cross-linking of neurofibrillary tangles and Abeta aggregation as well as inhibition of enzyme pathways. The stemming of Maillard reactions and production of free radicals contributes to less oxidative stress. Reduced glyoxal levels inhibit binding to superoxide dismutase, thereby increasing antioxidant protection. The cascade of benefits suggest DHA intake and suppression of AGEs may improve of protecting neurons from progression to dysfunction and death in AD. DHA Should Be Used

Complementary Therapy in AD

DHA has various biochemical implications that all assist in guarding against factors that lead to risk of AD. Its mechanisms involve docosanoid pathways and genetic expression that lead to reducing adiposity and secretions and improvement of insulin sensitivity. Increased insulin sensitivity helps to guard against hyperinsulinemia, hyperglycemia and hypertension, which lead to abnormal insulin signaling, glycation and oxidative stress, respectively. DHA also directly guards against AD progression through inhibition of formation of Abeta. Reduced Abeta combined with improved insulin sensitivity can lead to greater Abeta degradation from IDE and greater Abeta clearance from the brain across the blood-brain barrier. DHA also inhibits neurofibrillary tangles through suppression of Abeta formation and by modulation of tau phosphorylation. Lastly, DHA antiflammatory and antioxidant effects in the brain reduce glycation, inhibit oxidative stress from glycation and reduce advanced glycation end-product cross-linking. All of these effects support DHA’s role in assisting prevention of AD.In light of epidemiological studies and clinical trials, dieting and exercise combined with DHA should be used in the therapy of obese-diabetes patients, especially those of apoE4-genotype. The most recent of reports suggest patients adhere to a Mediterranean diet (with fish at least once a week) along with daily exercise such as walking (Scarmeas et al., 2009; Scarmeas, Luchsinger, Mayeux, & Stern, 2007). A symposium in 2008 announced the first-ever preventive trial using multi-domain interventions of which results will be available in 2013. The Multidomain Alzheimer Preventive Trial (MAPT) will examine effects of fish-derived omega-3 fatty acids in AD in a three-year, randomized, controlled study conducted in hospitals of four French cities (Gillette-Guyonnet et al., 2009). Four groups of 300 elderly subjects with specific criteria of memory complaints, slow walking speed and one instrumental activity of daily living, will be given either omega-3 fatty acid supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or a placebo (Gillette-Guyonnet et al., 2009). The trial will enlighten omega-3 fatty acid research further. However, more clinical studies are needed to determine effects of omega-3 fatty acids, specifically DHA, on apoE4-genotype obese-diabetic patients who are at highest risk of developing AD. DHA’s biochemical nature presents strong evidence that it will affect the elderly subjects and apoE4-genotype obese-diabetic patients positively.

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