CoQ10 benefit heart failure patients

June 4th, 2013

Presenting the study at Heart Failure Congress 2013 of the European Society of Cardiology Heart Failure Association, lead investigator Dr Svend Aage Mortensen(Copenhagen University Hospital, Denmark) reported that major adverse cardiovascular events (MACE), a composite of unplanned hospitalization due to worsening heart failure, cardiovascular death, and the need for urgent cardiac transplantation and mechanical support, occurred in 14% of patients treated with CoQ10 compared with 25% of patients who received a placebo, a statistically significant difference (p=0.003). All-cause mortality was also significantly lower in the CoQ10-treated patients, with 9% dying compared with 17% in the placebo arm (p=0.01).

In addition to these outcomes, the Q-SYMBIO investigators reported that cardiovascular mortality and admissions for heart failure were significantly lower in those who received CoQ10. In their conclusions, the researchers stated that “CoQ10 should be considered as a part of the maintenance therapy of patients with chronic heart failure.”

Some, however, considered the recommendations to alter clinical practice on the basis of this 420-patient clinical trial premature. Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles), for example, said he wants to reserve judgment on the data until they have stood up against the scrutiny of the peer-review process.

CoQ10 is an antioxidant involved in cellular-energy production. It is postulated that heart-failure patients, who have a measurable deficiency in CoQ10, would benefit from receiving the supplement.

The Q-SYMBIO study included 202 patients randomized to CoQ10 and 218 patients randomized to placebo. All patients included in the study had moderate to severe heart failure (NYHA class 3 or 4) and were receiving “current” pharmacologic therapy. Patients had an average ejection fraction of 31%, and the average age was 62 years. Within three months of treatment, investigators observed a trend toward lower levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The clinical improvements in MACE were observed after two years of receiving 100 mg of CoQ10 three times daily compared with those who received the placebo. In addition, 44% of those who received CoQ10 had an improvement in NYHA class compared with 45% of those who received placebo (p=0.047).

It is not clear as to the formulation used in the trial. The dose is 100 mg three times per day. We did discuss the difference between ubiquinone and ubiquinol in previous article. It would be good to also ascertain with measurable markers whether there was CoQ10 deficiency in the treated and placebo groups. It is not surprising to see benefits in such patients because coenzyme Q10 may be depleted in patients with heart failure and cardiomyopathy and those who are on statin treatment for high cholesterol.

The ratio of reduced to total Q10 concentration is also a useful biomarker of oxidative stress. Patients who have coenzyme Q10 deficiency also have increased risk of mitochondrial and cellular injury from excess production of free radicals.. Measurement of coenzyme Q10 concentrations in plasma can assist clinicians in detecting coenzyme Q10 deficiency states, and serve as a guide for dosing when oral supplementation is indicated.

We were not told of the formulation of the CoQ10 used in this study. Because significant inter-product variability in the absorption and bioavailability of coenzyme Q10 has been reported with over-the-counter (OTC) Q10 preparations, the Coenzyme Q10 test will also assist in verifying the extent of absorption of Q10 from those products.

Common PUFA oil products with linoleic acid increase all cause mortality, and mortality from cardiovascular and coronary heart disease.

February 27th, 2013

A recent report in the British Medical Journal signals the danger of substituting Omega-6 polyunsaturated fats, linoleic acid for saturated fats in diet. 

Advice to substitute linoleic acid for saturated fat is one component of dietary guidelines to reduce the risk of coronary heart disease; however, clinical benefits specific to linoleic acid have not been established. Linoleic acid is one of the commonest polyunsaturated fats in the diet and is present in many consumer products such as safflower oil and safflower polyunsaturated margarine and Corn oil.

A comprehensive analysis of the effects of linoleic acid on death from coronary heart disease and cardiovascular disease was previously not possible, owing to missing outcome data from the Sydney Diet Heart Study, a randomized controlled clinical trial. This is the first prospective randomized control study showing the potential harmful effects of linoleic acid.

In this cohort, substituting omega 6 linoleic acid for saturated fat did not provide the intended benefits, but increased all cause mortality, cardiovascular death, and death from coronary heart disease

An updated meta-analysis incorporating these missing data showed no evidence of benefit, and suggested a possible increased risk of cardiovascular disease from replacing saturated fat with omega-6 linoleic acid.

The proposed mechanism of underlying damage is via the oxidized LA metabolites. Omega-6 LA is the most abundant fatty acid in native low density lipoprotein particles. Oxidized LA metabolites (OXLAMs) are the most abundant oxidized fatty acids in oxidized low density lipoprotein, which is potentially more atherogenic than unmodified low density lipoprotein. A potential mechanism contributing to higher cardiovascular mortality in the LA intervention group is a diet induced increase in the production of bioactive OXLAMs, including 9- and 13-hydroperoxy-octadecadienoic acid, and 9- and 13-hydroxy-octadecadienoic acid. These OXLAMs are enriched in the lipid laden, macrophage foam cells; vascular endothelial cells; and migrating vascular smooth muscle cells of atherosclerotic lesions. OXLAMs, particularly the isomers and enantiomers produced by free radical mediated oxidation, have been mechanistically linked to cardiovascular disease pathogenesis. Mechanisms include inducing the formation of macrophage foam cells; endothelial cell activation;migration, proliferation, and foam cell formation of vascular smooth muscle cells; and inhibition of lysosomal hydrolysis of low density lipoprotein cholesteryl esters.

These findings could have important implications for worldwide dietary advice to substitute omega-6 linoleic acid (or polyunsaturated fatty acids in general) for saturated fatty acids. The key is the use of Omega-3 acid, which has EPA and DHA ; in PUFA that has a good content of Omega 3 FA does not increase the death from coronary heart disease.

Read the full article at this link:

Alzheimer plaques reduced by vitamin D and DHA

February 21st, 2013

The February 5, 2013 issue of the Journal of Alzheimer’s Disease published the finding of researchers at the University of California, Los Angeles that active forms of vitamin D3 and docosahexaenoic acid (DHA) improve the ability of immune cells known as macrophages to clear amyloid-beta, a toxic protein that occurs in elevated amounts in the brains of Alzheimer’s disease patients.

Milan Fiala and his colleagues “suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/resolvin D1 in peripheral blood mononuclear cells could contribute to Alzheimer’s disease onset/pathology.”

The team isolated macrophages from the blood of individuals with Alzheimer’s disease and healthy control subjects and incubated them with amyloid-beta prior to administering 1alpha, 25-dihydroxyvitamin D3 (1,25D3) or resolvin D1, an active form of DHA. While both nutrients increased the macrophages’ ability to remove amyloid-beta and decrease amyloid-beta-induced cell death, they did so by utilizing different receptors.

The authors observe that macrophages from Alzheimer’s disease patients express inflammatory genes in different ways than the controls and that transcription of specific inflammatory genes is increased or decreased in these patients. “Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer’s disease,” remarked coauthor Mathew Mizwicki.

“Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s,” Dr Fiala stated. “We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta. This is a first step in understanding what form and in which patients these nutrition substances might work best.”

Obesity can lead to vitamin D deficiency

February 6th, 2013

obesityTUESDAY Feb. 5, 2013 — Obesity can lead to vitamin D deficiency, a new study indicates.

British researchers looked at data from about 165,000 people, and found that a 10 percent rise in body-mass index (BMI) was linked with a 4 percent drop in concentrations of vitamin D in the body. BMI is a measurement of body fat based on height and weight.

The link between BMI and vitamin D levels was found in men and women, as well as in younger and older people, the investigators noted.

The findings suggest that a higher BMI leads to lower levels of vitamin D circulating in the body, while a lack of vitamin D has only a small effect on BMI, according to the authors of the study, published Feb. 5 in the journal PLoS Medicine.

Efforts to tackle obesity may also help reduce levels of vitamin D deficiency, said lead investigator Dr. Elina Hypponen, of University College London’s Institute of Child Health.

Previous studies have linked vitamin D deficiency with obesity, but it wasn’t clear whether a lack of vitamin D triggered weight gain or whether obesity led to vitamin D deficiency, the study authors noted in a university news release.

Vitamin D, which is essential for healthy bones and other functions, is produced by the skin when exposed to sunlight. It can also be obtained through foods and supplements.

“Vitamin D deficiency is an active health concern around the world. While many health messages have focused on a lack of sun exposure or excessive use of suncreams, we should not forget that vitamin D deficiency is also caused by obesity,” Hypponen said.

“Our study highlights the importance of monitoring and treating vitamin D deficiency in people who are overweight or obese, in order to alleviate adverse health effects caused by a lack of vitamin D,” she added.

Although the study reported that higher BMI leads to lower levels of vitamin D circulating in the body, it did not prove a cause-and-effect relationship.

More information

The U.S. National Institutes of Health, Office of Dietary Supplements, has more about vitamin D.

Millions May Be Taking Vitamin D Unnecessarily, Analysis Suggests

October 25th, 2012

Under the latest guidelines from the Institute of Medicine, it’s possible that almost 80 million Americans who’ve previously been considered as having low levels of vitamin D don’t need supplements of this nutrient at all, according to a new study.

Older guidelines had suggested that anyone with a blood level of vitamin D that was less than 30 nanograms per milliliter (ng/mL) needed to boost their levels, but the newer Institute of Medicine (IOM) guidelines say that a minimum level of 20 ng/mL is sufficient.

However, not all experts agree with the new guidelines from the IOM, a nonprofit American organization that dispenses health advice.

“The IOM guidelines are so different than the Endocrine Society’s guidelines that this study will just add to the controversy,” said lead study author Dr. Holly Kramer, an associate professor of medicine at Loyola University Medical Center in Maywood, Ill. “We really need clinical trials to settle the whole issue, but what’s clear is that these threshold levels make a huge difference in how many people would be taking vitamin D.”

The Endocrine Society is an international group of endocrinologists.

Why worry about your vitamin D intake? Vitamin D is essential for good bone health, and it’s necessary to prevent the disease known as rickets. The nutrient has also been implicated as potentially beneficial for a number of conditions. Low levels of vitamin D have been associated with higher risks of some autoimmune diseases, and may make people more susceptible to infection.

In addition, noted Dr. Robert Heaney, a professor of medicine at Creighton University in Omaha, Neb., low vitamin D has also been associated with high blood pressure, insulin resistance and the metabolic syndrome — a group of symptoms that signal higher risk for diabetes and heart disease.

Heaney is a member of the Endocrine Society’s task force on vitamin D guidelines.

“Vitamin D is necessary in most cells in our body, probably all cells,” Heaney said. “When you have adequate vitamin D, all of the body’s systems tend to work well.” But, “there is no consensus on what normal levels are in the field of nutrition,” he added.

For the current study, Kramer and her colleagues reviewed data on more than 15,000 adults from the third U.S. National Health and Nutrition Examination Survey and linked that information to 18 years of information from the National Death Index to determine if vitamin D had an effect on mortality rates.

The researchers found that in people with impaired kidney function, about 35 percent had vitamin D levels below 20 ng/mL. In people with healthy kidneys, about 30 percent had levels below 20 ng/mL, according to the study.

But for the older, higher vitamin D threshold, 76.5 percent of people with impaired kidney function would be considered to have low levels of vitamin D, as would 70.5 percent of people with healthy kidneys.

“Even under the new guidelines, there are still a fair number of people who are considered deficient or insufficient,” Kramer said.

There was a big difference in mortality rates for those who had the lowest levels of vitamin D — less than 12 ng/mL — compared to those with levels between 24 and 30 ng/mL. But after that, Kramer said, there wasn’t much difference in mortality between the groups.

Heaney also noted how findings varied according to vitamin D levels.

He said that while there wasn’t a huge effect from group to group depending on vitamin D levels, there was “a continuing downward trend” with less mortality as vitamin D levels went up.

So where does that leave people trying to decide whether to take the supplements?

Kramer said that right now the decision may depend on your personal situation, and suggested talking to your doctor about whether extra vitamin D is necessary for you. People with certain medical conditions need to be on vitamin D. But, she said that others are taking supplements who don’t need to and that it’s just a waste of their money.

For his part, Heaney noted that taking vitamin D and other nutrients may be akin to changing the oil in your car. “If you don’t change the oil, your car runs well now, but it may break down sooner,” he said.

In terms of side effects, Kramer said, too much vitamin D can increase the risk of kidney stones, but in general, it’s a well-tolerated supplement. The upper safe limit for daily intake is 4,000 international units, according to the U.S. Office of Dietary Supplements, though most people take a much lower dose.

Is hormone replacement therapy safe or not?

October 25th, 2012

It has taken a decade of research to arrive at a conclusion that is far from definitive: The evidence suggests it may help in the short term to manage  hot flashes and other symptoms of menopause in some younger, healthy women. But, taking it for long periods of time or later in menopause to help prevent certain chronic diseases isn’t recommended.

On Monday, the U.S. Preventive Services Task Force once again backed the idea that long-term use later in menopause is unwise when it released recommendations that said the increased health risks outweighed the benefits of using the treatment in that medical scenario.

That was not always the prevailing view in the medical community, however.

For years, it was common for women suffering from hot flashes, night sweats and other life-disrupting symptoms of menopause to go on hormone replacement therapy — typically a combination of estrogen and progesterone or progestin (a progesterone-like medication). That all changed in 2002, when the practice was halted by many after the landmark Women’s Health Initiative trial found that rates for breast cancer and stroke were higher in women on hormone replacement therapy compared to women who weren’t taking the treatment.

Although the study of more than 16,000 women reported some benefits, including lower rates of hip fractures and fewer cases of colon cancer, there were increases in heart disease, strokes and pulmonary embolisms (dangerous blood clots in the lungs) in women who took estrogen and progestin compared to women on placebo pills. The study, scheduled to run until 2005, was shut down early as a result.

“After 2002 and the Women’s Health Initiative study, people just stopped their hormone therapy. I think the study was an amazing study and gave us really good information, but you have to look at it in the time it was organized and developed, in early 2002, 2003,” said Dr. Anne Ford, associate professor of obstetrics and gynecology at Duke University School of Medicine.

Hormone replacement therapy formulations have since changed, and more recent research has teased out some groups of women who might benefit from the treatment, she added.

A Danish study of 1,000 women published earlier this month in BMJ suggested that women who began taking hormone replacement therapy early in menopause and who continued taking it for an average of 10 years cut their risk of having a heart attack, heart failure or dying without raising their risk for breast cancer or blood clots.

Two other recent reports also suggested that hormone replacement therapy holds benefits for some. One found that it was safe for the heart, and the other reported that it did not worsen memory in younger women.

“The new studies are well done and very important, since they address younger women,” said Dr. Judi Chervenak, a reproductive endocrinologist at Montefiore Medical Center in New York City.

Although the newer research does not necessarily negate the findings of the Women’s Health Initiative study, she said, it also does not have the power of that study in terms of how many women were followed. She said the new studies support that for some women — especially younger women without any health problems — hormone therapy might be a good option.

“Hormone therapy is no longer the arsenic it was once thought to be after the Women’s Health Initiative,” Chervenak said. A woman suffering from hot flashes, vaginal dryness or osteoporosis should discuss the pros and cons with her doctor, she said.

“They need to talk about family history of heart disease, blood clots and high cholesterol,” she explained. “For someone with very high triglycerides, for example, estrogen could adversely affect those levels.”

There are two issues at play, said Dr. Margery Gass, executive director of the North American Menopause Society.

“I want to get across the difference between taking something long term for prevention versus taking it short term when you’re younger and healthier to treat symptoms for a limited amount of time,” Gass said. “We recommend [hormone replacement therapy] as a viable option for treating menopausal symptoms in healthy women — in women not at high risk for blood clots, breast cancer and stroke.”

Gass said the newer research suggests that women should not be taking hormone therapy to prevent chronic diseases associated with aging.

That conclusion mirrors the latest opinion issued by the U.S. Preventive Services Task Force, an independent panel of experts in prevention and evidence-based medicine that makes screening recommendations for various conditions and diseases.

The panel’s review of 51 articles published since 2002 recommended that postmenopausal women, including those who have had a hysterectomy, not take estrogen alone to prevent chronic conditions.

The potential harms of hormone replacement therapy outweigh any possible disease-prevention benefits in these women, the task force said.

For women seeking non-drug options to manage the discomforts of menopause, Ford suggested exercise, such as yoga, and a healthy diet. Other strategies: Layer clothing, meditate, practice paced breathing (also called relaxation breathing), maintain a healthy weight and avoid smoking.

Ford said there is probably a lot to be learned by looking at different communities and cultures, too. “Ethnicity seems to play a role in how women manage menopause,” she noted.

Earlier research has shown that black and Hispanic women tend to enter menopause earlier than white women, and also tend to suffer more severe symptoms.

Low vitamin D level is linked to greater chance of risk factors for Type 2 diabetes

July 15th, 2012

We are getting more data on the effects of deficient vitamin D published in mainstream peer-reviewed journals. Bioactive vitamin D or calcitriol is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. More recently, it has become clear that receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism. {{{0}}}

The active form of vitamin D binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription.

The vitamin D receptor binds several forms of cholecalciferol. Its affinity for 1,25-dihydroxycholecalciferol is roughly 1000 times that for 25-hydroxycholecalciferol, which explains their relative biological potencies

A new study presents more evidence of a possible link between low vitamin D levels and a higher risk of Type 2 diabetes and heart disease. The results will be presented Saturday at The Endocrine Society’s 94th Annual Meeting in Houston (see also Type 2 Diabetes).

The study found an inverse relationship between the level of vitamin D in the blood and the presence of the metabolic syndrome, which is a group of risk factors that increases the risk of heart disease and Type 2 diabetes. People with the highest blood levels of vitamin D had a 48 percent lower risk of having the metabolic syndrome than did those with the lowest vitamin D levels, the authors reported.

“This association has been documented before, but our study expands the association to people of diverse racial and ethnic backgrounds,” said the lead author, Joanna Mitri, MD, a research fellow at Tufts Medical Center in Boston. “These include minority groups that are already at higher risk of diabetes.”

Furthermore, all study participants were at risk of developing diabetes because they had prediabetes, abnormally high blood sugar levels that are not yet high enough to be classified as diabetes. Prediabetes affects an estimated 79 million Americans ages 20 or older, according to 2010 statistics from the Centers for Disease Control and Prevention.

Mitri and her co-investigators conducted the study using data from participants of the Diabetes Prevention Program, a large, now-completed study funded by the National Institutes of Health. They divided study subjects into three groups based on plasma 25-hydroxyvitamin D level, which is the most common way used to measure vitamin D status in the body, according to Mitri. The Institute of Medicine recommends a 25-hydroxyvitamin D level of 20 to 30 ng/mL as adequate for healthy people.

In the new study, the group with the highest levels of vitamin D had a median vitamin D concentration of 30.6 nanograms per milliliter, or ng/mL, and those in the lowest group had a median vitamin D concentration of 12.1 ng/mL. The risk of having the metabolic syndrome with a high vitamin D level was about one half the risk with a low vitamin D level, Mitri said.

The researchers also found an association between vitamin D status and some of the individual components of the metabolic syndrome, which includes a large waist size, low HDL (“good”) cholesterol, high triglycerides (fats in the blood), high blood pressure and high blood glucose (sugar). Study participants with the best vitamin D status had a smaller waist circumference, higher HDL cholesterol and lower blood sugar.

Mitri cautioned that their research does not prove that vitamin D deficiency causes Type 2 diabetes, or even that there is a link between the two conditions


July 6th, 2012

Nothing feels better than a hard-earned massage to tame tension and curb nagging pain—but you might be surprised at just how much relief that rubdown can give your overworked muscles. Believe it or not, research shows that you could get serious cellular support against underlying inflammation within mere minutes, just by turning your aching b/dy over to professional hands.

Ten Minutes Is All It Takes

As part of a new study published in February 2012, researchers at McMaster University decided to take a closer look at exactly how massage works to relieve pain and restore damaged muscles. To do this, they assessed the exercise capacity of 11 men in their early 20s, after which each subject exercised to exhaustion on a bicycle for a total workout time of over 70 minutes.

A therapist then applied massage oil to both of each of the subjects’ legs during a brief, 10-minute rest period,kperforming a massage on one thigh muscle while leaving the other leg untreated as a control. Researchers took muscle biopsies from the subjects’ quadriceps before the exercise, immediately following this 10-minute massage, and then again two-and-a-half hours later.

The results of this laboratory analysis? In just 10 short minutes, therapeutic massage helped to reverse over an hour’s worth of exercise-induced muscle damage, one cell at a time.{{{0}}}

Soothe Inflammation and Power Up Your Cells

While the value of massage as a tension-busting, pain-relieving therapy is well established, this study is the first of its kind to explore the biochemical mechanisms behind massage’s time-tested benefits. And, as it turns out, stretching and manipulation signals more than one mode of healing within your muscles’ cellular infrastructure.

The McMaster researchers found that massage was able to stifle rises in NFkappaB, TNF-alpha and interleukin-6 (IL-6)—three cell-signaling factors that play a major role in the inflammatory cascade that follows exercise-induced muscle trauma. What’s more, the biopsies also showed an increase in mitochondrial biogenesis signaling—suggesting that massage sends messages to the body to create more mitochondria, the structures that serve as cellular power hubs.1-2

The end result of this chemical activity is a significant reduction in muscular inflammation, paired with less cellular stress and revitalized cellular energy, delivering pain relief via the same biochemical processes you’ll see with many pain medications. Given this ability, the study authors offer massage as one promising route to speedier injury recovery—not to mention its potential against other chronic diseases linked to muscular inflammation, such as arthritis and muscular dystrophy.

Either way, it looks like a little hands-on medicine is a win-win strategy where your sore, tired muscles are concerned—and this study serves up some compelling clinical evidence to prove it.


1. ScienceDaily. Accessed May 2, 2012.

2. J D Crane, et al. Science Translational Medicine. 2012;4(119):119ra13.


July 6th, 2012

Conventional wisdom on staying skinny seems to change with every day of the week—but the metabolism-boosting value of healthy snacking throughout the day is a common thread you’ll find running through just about every piece of diet advice out there.

Until now, that is.

That’s right: New research out of the University of California San Diego is shedding a dubious light on the good sense of “grazing”… with results suggesting that it may not be the foolproof weight loss strategy you think it is. {{{0}}}

Fasting Longer Can Keep You Stronger and fitter

The study, published in the journal Cell Metabolism just this past May, analyzed two sets of mice of matching gender, age and genetic makeup. Researchers fed both groups a high-fat diet, allowing one group to eat whenever they wanted—consuming roughly half their food during their waking hours in the evening, and the other half as “snacks” throughout the day—while the other group of mice was restricted to eight-hour eating periods each night, and 16-hour fasting periods through the day. Two control groups ate a typical diet, comprised of only 13 percent calories from fat (as compared to 60 percent in the high-fat experimental groups).

After 100 days, the mice that grazed on high-fat food throughout the day not only put on weight, they also developed high cholesterol, high blood sugar, poor motor control and liver damage. Surprisingly, however, the mice that ate the same amount of high-fat food under time restrictions weighed a substantial 28 percent less—and showed none of the diet-related health declines of their continually snacking counterparts.1

What’s more, the time-restricted mice performed better on exercise tests than both the high-fat grazers and the mice on a normal diet, indicating that extended fasting periods don’t just counteract the devastating effects of gut-busting dietary habits—they might actually play a critical role in keeping you fit, no matter how you eat.2

Scheduled Eating Helps Your Body Heal

This study may not be a golden ticket to a junk food free-for-all. But the results do suggest that the numbers on the scale may have less to do with your nutrition—and more to do with your body’s natural metabolic cycles and circadian rhythms—than once thought.

The researchers found that constant eating leads to constant generation and storage of fat, putting stress on your liver and raising blood sugar. Even a few hours of fasting, on the other hand, is enough to initiate fat-burning and cholesterol breakdown—while putting the brakes on glucose production and giving the body a chance to repair itself and generate new DNA. And this, in turn, alleviates disease-promoting inflammation for a leaner and longer life.

Obviously, this marks a serious departure from your usual diet-focused weight loss discussions. Still, while the findings of this particular study could be game changing, it’s too soon to say if the same results will apply to human subjects. But, in the meantime, simply closing up your kitchen a few hours earlier—and doing away with all impromptu snacking, especially on high-fat, sugary foods—might just prove to be the fat-burning breakthrough you’ve been looking for.




Aspirin and Metformin share common mechanism

July 5th, 2012

I have personally benefited from the use of Metformin as a pre-diabetic with a strong family history of type II diabetes mellitus. Recent American Diabetes Association (ADA) consensus panel recommends the use of Metformin to prevent or delay the development of diabetes. In a study published by Rhee MK et al  in Diabetes Care, 2010 Jan; 33(1):49-54. Epub 2009 Oct 6, more than 96% of individuals with both impaired fasting glucose and impaired glucose tolerance test are likely to meet ADA consensus criteria for consideration of metformin

A report by scientists from McMaster University, the University of Dundee and the University of Melbourne, published online on April 19, 2012 in the journal Science, suggests a common mechanism for salicylate—aspirin’s active compound—and the drug metformin in decreasing the risk of several diseases.

“Salicylate, a plant product, has been in medicinal use since ancient times,” Simon A. Hawley and colleagues write in their introduction to the article. “More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo.”

The authors explain that salsalate or aspirin administered in high doses result in the activation by salicylate of adenosine monophosphate-activated protein kinase (AMPK), a regulator of cell growth and metabolism. AMPK is known to be activated by exercise as well as the antidiabetic drug metformin. “We’re finding this old dog of aspirin already knows new tricks,” commented co-principle investigator Dr Greg Steinberg, who is an associate professor of medicine in the Michael G. DeGroote School of Medicine at McMaster University and the Canada Research Chair in Metabolism and Obesity. “In the current paper we show that, in contrast to exercise or metformin which increase AMPK activity by altering the cells’ energy balance, the effects of salicylate are totally reliant on a single Ser108 amino acid of the beta 1 subunit.

“We show that salicylate increases fat burning and reduces liver fat in obese mice and that this does not occur in genetically modified mice lacking the beta1 subunit of AMPK,” he noted.

The fact that both metformin and aspirin activate AMPK suggests that their recently publicized benefits in reducing the risk of cancer could be d5e to a shared mechanism. However, only further studies can confirm the validity of this interesting hypothesis.

Further elucidation of the action of metformin:

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Metformin activates AMPK in hepatocytes; as a result,

  1. Acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed – Phosphorylation and inactivation of ACC, as a result of AMPK activation,kserves to inhibit the proximal and rate-limiting step of lipogenesis. Reduced synthesis of the ACC product, malonyl-CoA, is also predicted to relieve inhibition of CPT-1, resulting in increased fatty acid oxidation. These effects are likely to contribute to metformin’s in vivo ability to lower triglycerides and VLDL.
  2. Suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; Known target genes for SREBP-1, which include FAS and S14, are also downregulated in liver, further contributing to metformin’s effects to modulate circulating lipids and to reduce hepatic lipid synthesis and fatty liver. It should be noted that increased SREBP-1 is postulated as a central mediator of insulin resistance in DM2 and related metabolic disorders and that increased liver lipid content is implicated in hepatic insulin resistance
  3. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. this effect is also additive with insulin (12). Thus, the observed association of increased glucose uptake and AMPK activation in isolated skeletal muscles suggests that metformin’s effect to augment muscle insulin action in vivo may be attributed to AMPK as well.
  4. Metformin-mediated effects on hepatic glucose production contribute to its glucose-lowering efficacy. AMPK activation is required for inhibition of hepatocyte glucose production by metformin. Additional studies will be required to further elucidate precise mechanism(s) by which metformin-stimulated AMPK activation could result in inhibition of hepatic glucose production.


Know your vitamin Ds – 3 beats 2

May 26th, 2012

From Reuters Health Information

Vitamin D3 Beats D2 for Raising Serum Levels: Meta-Analysis

NEW YORK (Reuters Health) May 18 – Vitamin D3 (cholecalciferol) is more effective than vitamin D2 (ergocalciferol) at raising serum levels of 25 hydroxyvitamin D – and that’s regardless of dosage, frequency or route of administration, according to a systematic review and meta-analysis of randomized controlled trials.

Vitamin D3 “could potentially become the preferred choice for supplementation,” the authors concluded in a paper online May 2nd in the American Journal of Clinical Nutrition.

However, they say more work is needed to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which their review was unable to verify.

First author Dr. Laura Tripkovic, from the UK’s University of Surrey in Guildford, and colleagues say there is a “widespread perception” that both vitamins D2 and D3 are equally effective in raising serum 25(OH)D levels, when in fact there is a “lack of clarity” in the literature on this issue.

They performed a comprehensive literature search for relevant studies in adults that directly compared vitamins D2 and D3, eventually selecting 10 studies for review (1,016 subjects total), seven of which were included in their meta-analysis.{{{0}}}

In these studies, vitamins D2 and D3 were used in varying ways. One study used a single bolus orally of 50,000 IU; one study used a single large bolus of vitamin D2 or D3 (300,000 IU) and compared IM with oral administration. Six studies tested daily oral supplementation strategies by using dosages between 1000 and 4000 IU. One study chose a weekly intervention of 50,000 IU. Another compared daily with monthly intervention by using 1600 and 50,000 IU, respectively. The final study compared a single IM injection of 300,000 IU of vitamin D2 vs a single oral dose of 300,000 IU of vitamin D3.

Treatment follow-up times varied from 28 days to 24 weeks for the bolus-intervention studies, whereas the daily and weekly study designs had intervention periods that ranged from 14 days to 12 months. The researchers say a “concern for all studies” was the lack of consensus in the analysis of serum 25(OH)D concentrations.

With these caveats in mind, the researchers report that vitamin D3 supplementation produced a significantly greater absolute increase from baseline of serum 25(OH)D in eight studies, no matter what the dose, frequency or route of administration. Two studies found vitamin D2 and D3 equally efficacious.

Likewise, in the seven-study meta-analysis, vitamin D3 supplementation had a significantly greater effect in raising serum 25(OH)D concentrations over time compared with vitamin D2 supplementation, with a weighted mean difference of 15.23 (p=0.001).

“When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (p=0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation,” the authors report.

Nevertheless, they say “regardless of whether supplementation with vitamin D was in small daily doses or in larger and more infrequent bolus dosages, the favoring toward cholecalciferol was still evident.”

Based on their findings, the authors say, “It is clear that there are stark differences in the metabolic fates of ergocalciferol and cholecalciferol that should not be ignored. When the evidence from the studies that focused on vitamin D metabolism at the cellular level is compared with the evidence from clinical trials, it is clear that, overall, there was consistency in the results that shows cholecalciferol appears to have advantageous biological qualities that allow it to sustain its systemic influences for far longer and at far greater concentrations than does ergocalciferol.”

Limitations of the analysis include the small number of studies available for review and the “high” heterogeneity between studies. The investigators also point out that all studies used doses of ergocalciferol and cholecalciferol “far above” the currently recommended daily allowance of 600 IU for males and females aged 1 to 70 years.

These factors “limit the ability to extrapolate the outcomes of this review toward realistic public health recommendations when referring to ergocalciferol and cholecalciferol supplementation,” the authors say.


Am J Clin Nutr 2012.


FDA adds warnings to Statin Label

March 1st, 2012

Reed Miller posted this latest FDA move on Statin Label on Heartwire on 28 Feb 2012. It is interesting to note that the FDA action came after our posting on WHI  findings on the increased risk of diabetes in women on statins.

February 28, 2012 (Silver Spring, Maryland) — Taking a statin can raise blood sugar and glycosylated hemoglobin HbA1c levels, according to a new labeling change approved by the Food and Drug Administration (FDA) today for the entire drug class. {{{0}}}

As reported by heartwire, recent studies of popular statins showed a significant increase in the risk of diabetes mellitus associated with high-dose statin therapy. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed a 27% increase in diabetes mellitus in patients taking rosuvastatin compared to placebo. Also, the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy showed that high-dose atorvastatin can worsen glycemic control.

The labeling changes approved by the FDA also include new information on the potential for usually minor and reversible cognitive side effects. Also, the label for lovastatin has been significantly updated to provide information on contraindications and dose limitations for the drug in patients taking other medicines that may increase the risk for muscle injury.

The FDA says it is also eliminating the recommendation that patients on statins undergo routine periodic monitoring of liver enzymes, because this approach is ineffective in detecting and preventing the “rare and unpredictable” serious liver injuries related to statins. Statin therapy should be interrupted if the patient shows signs of serious liver injury, hyperbilirubinemia, or jaundice. The statin therapy should not be restarted if the drugs cannot be ruled out as a cause of the problems, the labeling will now state.

Statin use associated with significantly increased risk of diabetes: WHI analysis

January 12th, 2012
The following article was published in Heartwire on JANUARY 9, 2012 by Michael O’Riordan

Boston, MA – Statin use in postmenopausal women is associated with a significantly increased risk of diabetes mellitus, research shows. New data from the Women’s Health Initiative (WHI) hint that the risk of diabetes is higher than suggested by previous studies, with investigators reporting a 48% increased risk of diabetes among the women taking the lipid-lowering medications.

“With this study, what we’re seeing is that the risk of diabetes is particularly high in elderly women, and this risk is much larger than was observed in another previous meta-analysis,” senior investigator Dr Yunsheng Ma (University of Massachusetts Medical School, Boston) told heartwire. “For doctors treating patients, we would like them to really look at the risk/benefit analysis, especially in different age groups, such as older women.” {{{0}}}

Annie Culver (Mayo Clinic, Rochester, MN), a pharmacist and lead investigator of the study, published online January 9, 2012 in the Archives of Internal Medicine, said that “close monitoring and an individualized risk-vs-benefit assessment is really a good thing, as well as an emphasis on continued lifestyle changes.” Culver added that as the population ages, and because these patients have a higher vulnerability to diabetes anyway, monitoring for diabetes in statin-treated patients becomes more important.

“I think the risk [of diabetes] is definitely there for statins,” Culver told heartwire, “and I think physicians are probably aware of this risk. I think we now need more information and more research about precisely how this risk translates to different people and different populations.”

Previously published data on statins and diabetes risk

Recently published data reported by heartwire highlighted the potential risk of diabetes with statin therapy. In June,Dr Kausik Ray (St George’s University of London, UK) and colleagues published a meta-analysis of PROVE-IT, A to Z,TNT, IDEAL, and SEARCH—five trials testing high-dose statin therapy—and found a significant increase in risk of diabetes with higher doses of the lipid-lowering drugs. A meta-analysis published in the Lancet in 2010 by Dr Naveed Sattar (University of Glasgow, Scotland) also showed that statin therapy was associated with a 9% increased risk of diabetes.

In the present study, Culver, Ma, and colleagues analyzed data from the WHI, an analysis that included 153 840 postmenopausal women aged 50-79 years old. Information about statin use was obtained at enrollment and year 3; the current analysis includes data until 2005. At baseline, 7.0% of women were taking statins, with 30% of women takingsimvastatin, 27% taking lovastatin, 22% taking pravastatin, 12.5% taking fluvastatin, and 8% taking atorvastatin. During the study period, 10 242 incident cases of diabetes were reported.

In an unadjusted risk model, statin use at baseline was associated with a 71% (95% CI 1.61-1.83) increased risk of diabetes. After adjustment for potential confounding variables, the risk of diabetes associated with statin therapy declined to 48% (95% CI 1.38-1.59). The association was observed for all types of statins.

“The association between diabetes risk and statin therapy was not observed with any one type of statin, and it seems to be a class effect,” said Ma.

Subgroup risk

A significantly increased risk of diabetes was observed in white, Hispanic, and Asian women (an increased risk of 49%, 57%, and 78%, respectively). Among African Americans, who made up 8.3% of the population studied, there was a nonsignificant 18% increased diabetes risk associated with statin use at baseline. Statin use and diabetes risk was also observed in women across a range of body-mass indices (BMIs <25.0, 25.0-29.9, and >30.0 kg/m2). Women with the lowest BMI (<25.0 kg/m2), appeared to be at higher risk of diabetes compared with obese women, a finding the investigators speculate is related to phenotype or hormonal differences between the women.

In an editorial, Dr Kirsten Johansen (University of California, San Francisco), editor of the Archives, noted that the increased risk of diabetes in women without CVD has “important implications for the balance of risk and benefit of statins in the setting of primary prevention, in which previous meta-analyses show no benefit on all-cause mortality.”

Ma agreed, noting to heartwire that statins are used with increasing frequency, including in primary prevention, and—based on the JUPITER trial—in patients with normal LDL cholesterol but elevated C-reactive protein (>2.0 mg/L). In the present study, baseline statin therapy was associated with a significant 46% and 48% increased risk of diabetes in women with CVD and without CVD, respectively.

Just 7% of women in the WHI study were taking statins in the analysis, but today that number would be significantly higher, making the potential risk of diabetes at the population level much more widespread. Ma said that physicians need to evaluate the risk of diabetes as well as the potential benefits of statin therapy in elderly female patients and start statins after lifestyle interventions have been attempted.

Stem Cell therapy may reverse Type 1 Diabetes

January 12th, 2012

January 10, 2012 — An immune regulator from healthy cord blood stem cells (CB-SCs) can “educate” the T cells of a person with type 1 diabetes (T1D), enabling the pancreas to produce insulin, according to a report published online January 10, 2012, in BMC Medicine.

Yong Zhao, MD, PhD, from the University of Illinois at Chicago, and colleagues base their “stem cell educator therapy” on observations that multipotent stem cells from human cord blood can alter regulatory T cells (Tregs) and islet B cell–specific T-cell clones. The new approach alters autoimmunity both in non-obese diabetic mice and in islet B cells from patients with diabetes. {{{0}}}

In a small, open-label trial, a single treatment reduced the median daily dose of required insulin by 38% at 12 weeks for patients with moderate T1D and some B-cell function (36 ± 13.2 U/day at baseline vs 22 ± 1.8 U/day 12 weeks post-treatment), and by 25% in patients with severe T1D and no residual function (48 ± 7.4 U/day at baseline vs 36 ± 4.4 U/day 12 weeks post-treatment). The investigators saw no change in insulin requirements among the control group.

The researchers circulated lymphocytes from patients’ blood in a closed-loop “stem cell educator,” co-culturing the cells for 2 to 3 hours with adherent CB-SCs from healthy donors. The device sandwiches CB-SCs between 9 discs of a hydrophobic material, with a top cover plate and a lower collecting plate through which the lymphocytes exit. The investigators infused the “educated” lymphocytes into the patients and measured both levels of C-peptide and glycated hemoglobin and indicators of immune function at 4, 12, 24, and 40 weeks.

Investigators conducted this open-label, phase 1/2 clinical trial at the General Hospital of Jinan Military Command in China from October 2010 until January 2011, 15 patients (median age, 29 years [range, 15 – 41 years]; median diabetic history, 8 years [range, 1 – 21 years]) received a single treatment. Three control patients received a sham treatment lacking cells.

Primary endpoints were feasibility (change in C-peptide secretion), safety by 12 weeks, and preliminary evidence of improved B cell function by 24 weeks. Immune modulation was a secondary end point.

Overall, the treated individuals displayed better C-peptide and glycated hemoglobin A1c values, lower daily requirement for insulin, and decreased autoimmunity.

Patients with moderate T1D had improved fasting C-peptide levels at 12 and 24 weeks. Those with severe T1D showed successive improvement in fasting C-peptide levels.

A1c levels for patients with moderate T1D fell from 8.73% ± 2.49% at baseline to 7.67% ± 1.03% at 4 weeks (P = .036), and to 6.82% ± 0.49% at 12 weeks post-treatment. For those with severe T1D, A1c levels fell 1.68% ± 0.42% at 12 weeks post-treatment, with no change seen in the control group.

Stem cell education significantly increased the percentage of Tregs in peripheral blood, as well as levels of CD28 and inducible co-stimulator. Cytokine balance improved. The CB-SCs produce an autoimmune regulator which may eliminate autoreactive T cells.

This innovative approach may provide CB-SC-mediated immune modulation therapy for multiple autoimmune diseases while mitigating the safety and ethical concerns associated with other approaches,” conclude the researchers.

BMC Med. Published online January 10, 2012. Full text

Low Cholesterol in Elderly Doubles Risk of Early Death

December 22nd, 2011

Study Finds that Low Cholesterol in Elderly Doubles Risk of Early Death

Study finds that elderly with cholesterol less that 189 had a double risk of dying.

Physicians were informed to consider very low levels of cholesterol as potential warning signs of a serious disease or as signals of rapidly declining health. {{{0}}}

The study included 4520 men and women between the ages of 65-84.

The study concluded that low total cholesterol was associated with a higher risk of death

Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may              be a surrogate of frailty or subclinical disease according to the research team.


Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D; ILSA Group. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging. J Am Geriatr Soc. 2003 Jul;51(7):991-6.

Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc. 2005 Feb;53(2):219-26.


Breakthrough in genetic and cellular therapy in cancer

November 18th, 2011

There is a recent breakthrough in genetic and cell therapy that could lead to a dramatic difference in the management of cancers; A team from University of Pennsylvania have been able to genetically modify the T cells of patients with B cell Chronic Lymphocytic Leukemia with a “chimeric antigen receptor” CAR targeting a CD 19 molecule on CLL cells.

How the therapy works:

  • Autologous T cells are immune cells taken from a
    patient’s own blood stream. These cells are then modified to express an
    antibody on their surface that will recognize and bind to a protein called
    CD19. (the genetic engineering bit)
  • This CD19 protein is on most B-cell CLL cells
    and B-cell non-Hodgkin lymphoma (NHL) cells.
  • These modified T cells are then grown (expanded)
    in the laboratory and given back to patients in an attempt to treat their
    leukemia. (the cell therapy bit)
  • When the patient’s own T-cells recognize and
    bind to the CLL cell, they have the ability to become activated and kill the
    leukemia cell. {{{0}}}

Initial Results

While only treated a small number of patients, the results were a breakthrough:

  • That a patient’s modified T-cells can survive
    for many months after administration, and have the ability to grow in the body
    in large quantities.
  • And they have been able to kill large quantities
    of CLL cells in all 3 patients treated.
  • Unfortunately, as CD19 antigen is expressed even
    in normal B lymphocyte cells, new clones of normal B cells that replace the B
    CLL cells are also killed and thus patients require immune support for the
    length of the observed successful treatment period, in one patient as long as
    one year. The investigators are now watching if the modified T cells will
    diminish and disappear over time since the work has been done. It is also not
    clear if the effect will last after that.

Another approach to modify the T cells is been explored in Israel at the lab of Vaxil Biotherapeutics where a breakthrough technology is applied to produce T cell therapeutic and preventive cancer vaccine.


The thrust of the technology is to identify good target cancer antigen and manipulate it with genetic engineering to reactivate the cell mediated immune response that have been obtunded by cancer cells.:Elicit the needed T-helper immune modulating response via the interaction of cancer antigen with MHC Class II surface antigen on antigen presenting cells such as dendritic cells that allows the complex interaction with CD4 T helper cells. The activation of these cells is

needed to provide the appropriate signals via cytokines to mobilise and activate the T cytotoxic cells. Foreign or invading antigens are processed after combining with ubiquitin in the cytoplasm by proteosome and would usually break the antigen to the TH via the endosomes and CTL epitopes via the endoplasmic reticulum to be combined with MHC Class II and Class I respectively.

  1. Elicit the T cytotoxic cells activation via expression of the canc er antigen with MHC Class I on the DC surface that allows recognition by T cytotoxic cells that will expand and activate leading to the lysis of target cells. The processing of the CTL epitopes in the endoplasmic
    reticulum is mediated by either Transport Associated Antigen Processing peptide
    (TAP) dependent or non TAP dependent channels. Many cancer cells are able to
    escape CTL immune response by modify the TAP channel.

The unique technology of Vaxil is in the antigen used as the cancer vaccine. The MU1 antigen that is expressed in more than 90% of solid and non-solid cancers. The first indication is in multiple myeloma. Trial started in September 2010 at the Hadassah Medical Center in Jerusalem under the
direction of Dr Michael Shapira.

Unlike the CAR approach, the T cells are not genetically engineered to express anti CD19 on their surface. The unique genetically engineered cancer antigen enhances the T cell immune response by a better Antigen Presenting and processing technology that would reactivate the body’s  own immune response; The breakthrough is in obliterating the mechanism to obtund the natural T cell mediated immune response by the cancer cells through its unique antigen presenting and processing technology.

The unique characteristic of the target antigen

  • The target antigen is the basis for every vaccine and will dictate its efficacy more than the delivery system or the adjuvant.
  • The immune system (in particular T cells) recognize the target antigen via binding to a set of molecules called MHC class I and MHC class II. There are hundreds of different types and  every individual has a different set of between 6 and 12 individual MHC molecules.
  • For a therapeutic vaccine to work it must be able to find and bind these MHC molecules which vary widely amongst different people.

There are 2 approaches:

  • Approach 1: use the entire antigen/pathogen/cancer cell as statistically this should bind an individual’s set of MHC molecules. However, this significantly reduces the specificity of  the immune response which may lead to reduced efficacy and higher side-effects.
  • Approach 2: identify a small section of the target antigen that bind to a single MHC molecule. This leads to a specific but weak immune response, applicable only to a small proportion of the population.
  • Vaxil offers a third revolutionary combined approach – VaxHit – which identifies and uses the  Key sequence of the target antigen which has the following major advantages:
    • Small & defined sequences which generate a highly specific immune response with less likelihood of side-effects.
    • Binds a very large proportion of the potential combinations of an individual’s MHC molecules. Hence it is more potent and applicable for the majority of the population and will thus be more effective.

The VaxHit technology can identify potential vaccines for many indications (cancer and infectious diseases). VaxHit vaccines have the unique ability to overcome the tumor/pathogens ability to evade and resist the efforts of the immune system to eliminate them. This is called the TAP

VaxHit vaccines are potent without a dedicated delivery system or adjuvant and are non TAP dependent.



The Central Dogma been challenged

October 31st, 2011

We spoke of epigenetics in the context that the Central Dogma of gene transcription and translation is not a simple linear relation but is part of a complex cellular network system. The old theory of genetic determinism based sole on the sequence of gene determining the coding of genetic messages to form amino acids and proteins that drive biological behaviour is now been challenged.

Even within the gene sequences, scientists are finding that the exons interspersed with many non-coding introns and their splicing prior to translation is variable . After transcription of a gene to messenger RNA, the way transcriptions of introns are removed, and the exons are spliced together by enzymes before translation and assembly of amino acids into proteins is complex and not linear. {{{0}}}

The cloning of Dolly turns the central dogma on its head. The ability of cytoplasmic factors in the oocyte whose nuclear DNA material is replaced with that of mature adult DNA material challenges the dogmatic linear relation of nuclear DNA transcription to mRNA that is translated to protein synthesis. Cytoplasmic factors are able to modify the mature DNA, in this case adult mammary cells and reprogram them into progenitor stem cells from which Dolly was cloned.

Epigenetic mechanisms such as methylation and histones acetylation provide a good explanation of how environmental factors affect gene expression. We are not doomed by the gene sequence we inherited. We could modify such expressions with proper diet and lifestyle. There are evidence such positive modifications on gene expression could occur within months rather than years that mutations would take in certain situations where the organism has to adapt to adverse environment. Example of mutations such as the 11p15.5 mutation in haemoglobin in sickle cell anemia is a longer term adaption to malaria infested environment. Epigenetic mechanisms are shorter term adjustments for quick adaptations. Such epigenetic mechanisms are in operation on the time and are just being studied more intensely in recent times.

The breakthrough of genetic sequencing and splicing has allowed genetic engineering to flourish in the biotech industry producing a number of breakthrough biological pharmaceutical products and GMO agricultural produce. However, the lack of understanding of how these transgenic material behave in the ecosystem might create serious environmental issues. Some of these issues are already surfacing in the GMO agricultural produce.

The pundits are arguing if we should regulate the use of genetic engineering until a better understanding of how the newly created genes and their products interact with the ecosystem before long term global catastrophes occur.

How do we access and arrest poor methylation in the body?

September 14th, 2011

We follow up our discussion on the epigenetic mechanisms that affect gene expression that are asserted by dietary intake, environment toxins and aging. In particular, we mentioned the importance of methylation. Today, I would like to discuss how we could access methylation status in the body and what could be done to prevent hypomethylation. Methylation is important for gene expression and repair. Methylation of proteins is equally important in the synthesis of neurotransmitter and phospholipids. Hypomethylation increases expression of certain promoter genes and could trigger oncogenesis. DNA methylation is established during embryonic development and is stable through multiple cell divisions (cellular memory). It is normally associated with gene silencing.  It targets the Cytosine-Guanine dinucleotides and up to 70% are methylated in human somatic cells. The CG islands that are located adjacent to suppressor genes are however hypomethylated to allow for expression of these suppressor genes. Hypermethylation in the CPG islands are seen in certain tumor types.

Poor methylation has been implicated in degenerative brain disorders such as Alzheimer’s disease and Parkinson’s disease, depression, autism and ADHD, cancers, arthritis and CVS diseases.

What governs the methylation process in the body? {{{0}}}

There are 3 critical steps in the methylation process:

  1. The primary carrier of the methyl group is the amino acid, methionine. It delivers the methyl group via SAME, S-adenosylmethionine which requires ATP.
  2. Methionine is formed from homocysteine accepting the methyl group from the single carbon pool via its final methyl tetrahydrofolate facilitate by vitamin B12
  3. The single carbon pool is contributed mainly by amino acids such as serine, glycine, histidine and tryptophan that needs the critical vitamin Folate. The pool of methylene-THF, methenyl THF and formyl THF is reversible but the final step to 5 methyl THF is a committed and irreversible step. Therefore, the buildup of methy THF would be “trapped” if vitamin B12 is not available to allow its transfer to homocysteine to methionine, a process known as the “Folate Trap”. If a patient is deficient in both B12 and folate but only takes folic acid supplements, the B12 deficiency may be masked. In such cases, the anemia associated with both may be resolved, but the underlying neuropathy of vitamin B12 will persist.
The methylation process is inhibited by oxidative stress in favour of another important process of converting homocysteine to important antioxidants such as glutathione and the sulphur containing amino acids such as taurine and sulphate which are also key in supporting phase II detoxification in the liver.

How do we access methylation in the body?

  1. Homocysteine – elevated levels suggest a blockage in methylation. Homocysteine has been investigated as a separate risk factor for coronary heart disease. It has been postulated as a putative factor in endothelial dysfunction and arteriosclerosis. It is also a very useful marker for poor methylation.
  2. The Critical Vitamins – Folate for the single carbon pool formation from the mentioned amino acids and vitamin B12 for the formation of methionine from homocysteine. While serum folate and B12 could be measured, there are more sensitive tests using urinary organix that are metabolites of folate and Vit B12 – FLGLU (formiminoglutamate) and methylmalonate respectively. The latter is present in the urine as short as 10 days of vitamin B12 deficiency.
  3. Measures of serum amino acids contributing to the single carbon pool such as serine, glycine, histidine and tryptophan are also useful in determining the methylation status.

What could we do to improve methylation status in the body?

  1. Ensure that dietary intake of critical vitamins such as folate and vitamin B12 is sufficient – this is especially so in patients who are pregnant or alcoholics and those with pernicious anemia or on prolonged antacids or PPI or H2 antagonists that reduce stomach acid that could affect absorption of vitamin B12. Adequate intake of the amino acids such as the single carbon pool precursors is also important especially in aged patients.
  2. Supplements such as SAM-e , the active compound for methylation. Caution is needed in patients who are taking antidepressants such as MAOI or SSRIs.

The clinical implications of the methylation status in the body have yet been fully investigated. We know of its importance in gene expression and repair but how does this translate to clinical benefits and well being has yet been fully investigated and validated in clinical studies. There is little incentive for such studies as there is little financial return expected since the solution is simple vitamin and dietary adjustments that are not patentable and thus is of little interest to the pharmaceutical industry. However, it is only prudent to ensure that the body is not at risk of poor gene repair and expression due to simple risk-free dietary measures that could be taken to ensure good methylation.  I would certainly advocate such dietary adjustment particularly if lab tests confirmed poor methylation status such as elevated homocysteine, urinary FIGLU and methylmalonate and low serum amino acids important in maintaining the single carbon pool.

Autism – metabolic and nutrition link

August 15th, 2011

A new study published in the June edition of Nutrition and Metabolism this year suggests that children with autism appear to suffer from a significantly higher percentage of metabolic issues compared to average children. Nutritionally, this may be compounded or even initiated by nutritional deficiencies that include low levels of glutathione, biotin, and SAMe, niacin and low plasma levels of amino acid. Markers of oxidative stress were noticed as being higher than normal as well, according to a new study.  {{{0}}}

Additionally, NADH and NAPDH were found to be depleted in a significant portion of the autistic test subjects. NAPDH and NADH are compounds utilized in reactions of energy transfer/transport. The low NADH results in low ATP synthesis which is critical for metabolic processes such sulfation and methylation.

Better insights through future research on such metabolic disturbances in autistic patients could provide opportunities for new therapeutic intervention in this increasing disorder among children.

Many metabolic concerns can be overcome with appropriate metabolic testing and subsequent nutritional supplementation

Source: Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity.


Epigenetics – an emerging area of gene research

August 12th, 2011

In biology, and specifically genetics, epigenetics is the study of changes in gene expression caused by mechanisms other than changes in the underlying  DNA sequence – hence the name epi- (Greek: ???– over, above, outer) -genetics. Examples of such changes might be DNA methylation or histone deacetylation, both of which serve to suppress gene expression without altering the sequence of the silenced genes. {{{0}}}

These changes may remain through cell divisions for the remainder of the cell’s life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism; instead, non-genetic factors cause the organism’s genes to behave (or “express themselves”) differently.

One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell – the zygote – changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others through the epigenetic process.

Currently, what have been well research and documentation are 2 known mediating processes – methylation and histone deacytylation. These processes could be activated by a number of environmental stimuli, in utero and childhood development, aging, diet and drugs.

Is this the beginning of the end for dietary supplements?

August 12th, 2011

There is an interesting development lurking in the US regarding the fate of supplements
that I thought would be of interest to some of you. I have copied the articles
of Warren Matthews, the founder and Chairman of Xtend-Life Natural Products
based in New Zealand and Bryon Richards that expressed their concerns and call
for consumers’ action. While there are concerns of the lack of regulation on dietary supplements,
there is a need to ensure that policies when put in place would not serve to profit certain vested interest at the
expense of the general public.{{{0}}}

Recently the US FDA issued a set of ‘guidelines’ for NDI’s
(New Dietary Ingredients). This has been anticipated for a long time but the
industry and others have been shocked at just how far the FDA have taken this.

What they are proposing would make the overwhelming majority
of supplements illegal because most ingredients being used have not been
approved. Even those which were in use prior to 1994 will still be affected.

Up until now it was OK to use an ingredient in a supplement
product provided that there was evidence that supported its safety. That system
has been working well and thousands of products have been developed on this
principle and millions of people have benefited by them. In other words, these
ingredients are OK to use in a variety of products.

However, the FDA has now suggested that not only each
ingredient has to be approved in its own right but each ‘product’ that contains
that ingredient will require an NDI approval specific for that ingredient in
that product. If the concentration of that approved ingredient in that specific
product is changed it will also trigger off a new NDI application. So, you
could have thousands of different NDI applications for the same ingredient but
in different products from hundreds of manufacturers.

To obtain that approval the manufacturer will have to come
up with hard scientific data that it is OK to combine that ingredient with another
ingredient in each specific formula. For example, combining grape seed extract
with grape skin extract. To provide that scientific proof is virtually
impossible even for a simple product…but, for a complex product such as many of
ours it is impossible.

Whilst these applications are being processed the product
will be withdrawn from the market. How the FDA will process what will amount to
10’s if not 100’s of thousands of applications are beyond comprehension. They
simply don’t have the resources and even if they did it would be an unwise use
of resources.

Synthetic versions exempt…

Some in the industry argue that this is the next step in an
attempt by the FDA to destroy the supplement industry or at least put the
majority of the industry ‘out of business’ and pave the way for synthetic
versions of natural ingredients. They may be right…particularly when you
consider that the synthetic versions of these natural ingredients as produced
by the pharmaceutical companies are exempt from these new proposed regulations!

This is not the only ‘unfair’ aspect of this proposed
regulation. There is a move by pharmaceutical companies to take effective
natural ingredients that have been proven in the dietary supplement industry
and start developing drugs from them. If they choose to do this then the FDA
can deny any NDI application for that ingredient from a dietary supplement
manufacturer even if that ingredient has been used for decades.

This is a very serious problem and the only way it is going
to be stopped is if enough people get up in arms about it and complain to their
law makers. I really do fear that the general public protest will not be strong
enough as so many people have so many other things on their minds in the
current difficult economic times. If you feel strongly about this issue please
let your lawmakers know your feelings.

The FDA’s Scheme to Reclassify Nutrients as Drugs

Tuesday, August 02, 2011 – Byron Richards, CCN

The FDA and Senator Durbin’s latest attack against the
dietary supplement industry should leave consumers for natural health options
at affordable prices up in arms. This attack will target some of the most
popular and effective dietary supplements, removing them from the free market
and placing them under control of large pharmaceutical companies. This move
will drastically drive up the price of dietary supplements while severely
limiting access to extremely safe and effective nutrients. For example, the
GlaxoSmithKline prescription drug version of DHA fish oil (at a therapeutic
dose) sells for $189 a month, whereas the equivalent, therapeutic amount of
molecularly-distilled DHA sells for $35 a month in the dietary supplement
marketplace. Proven to lower triglyceride levels at therapeutic amounts, it is
not surprising that DHA is one of the first nutrients the FDA plans to go
after. Other powerful nutrients, such as curcumin and resveratrol, are soon to

This is the second article in what will be a series of
articles on this critical topic. In my first article, “Senator Durbin & the
FDA Viciously Attack Dietary Supplements,” I outlined the scope and nature of
the attack and called readers to take action. And it is still critically
important that you do take action, so please visit our new TAKE ACTION page
immediately following reading this article.

The newly-proposed FDA regulations are complicated. We are just
beginning to understand the full scope of their ploy. The FDA is hoping that
the complexity of their regulations will confuse consumers so they do not
understand the coming changes and resulting repercussions. It is my job to give
you some concrete examples of how this will affect you.

It is not just DHA, curcumin and resveratrol that are slated
for pharmaceutical industry takeover, hundreds of other nutrients and herbs are
at risk. The unfortunate reality is if the FDA is allowed to carry out their illegal
strategy then thousands of products currently on the market are likely to be
deemed “misbranded drugs” and forced off the market under the FDA’s criminal
campaign to wipe out an industry, and ultimately gain even greater power and

The Pharmaceutical Industry’s Perfect Storm of Economic

Mapping the human genome was supposed to usher in the next
generation of pharmaceutical “wonder” drugs. Scientists would identify a gene
or set of genes causing each and every disease. New biotech drugs operating at
the genetic level would fix the problems or compensate for them, ushering in
“The Golden Age of Cures” and reaping huge 21st century profits for the
pharmaceutical conglomerate.

This wishful thinking is not the case. Their first biotech
drugs have caused more death and injury than benefit. At the same time, rapid
advancements in tools to analyze gene function made it obvious that Mother
Nature already provided a treasure trove of potential golden cures—natural,
safe and effective substances already widely utilized in the dietary supplement

Multiple circumstances threaten hundreds of billions in drug
company profits. Their pipeline of new drugs with widespread consumer
application is scant, as they gamble their future on dangerous biotech drugs
with limited use. Hundreds of their top-selling drugs are losing patent
protection in the next few years, exposing them to generic competitors and
massively driving down inflated profits. Widely-publicized adverse side effects
and unnecessary deaths caused by many commonly-used pharmaceutical drugs have
cast suspicion over their entire industry.

On the political front, Congress is looking for ways to
control health care costs, even suggesting incentives for making people well—a
far different tune than paying for lifetime drug prescriptions that seldom
improve health. In fact, the gene science is actually proving that Western
Medicine’s drugs are damaging the human genome and are a significant cause in
the onset of many of the diseases of aging—the very diseases they are
pretending to treat.

Pharmaceutical companies define their primary assets as
patent-protected drugs, giving the drug 15 to 20 years of product sales with no
competition. It is vital for them to figure out a strategy to turn dietary
supplement ingredients, especially those that could be used for type 2
diabetes, cardiovascular disease, obesity, depression, Alzheimer’s, and cancer
treatment into drug company “assets,” eliminating from the free market many of
the most helpful dietary supplement ingredients while drastically driving up
prices for consumers.

The Poison-Dispensing Era of Western Medicine

Until the advent of the new gene-regulating drugs, virtually
all medications worked on the principle of poisoning the function of a cell or
enzyme system to hopefully produce a change that the doctor thinks
“beneficial.” If taking a drug results in a better-looking blood sugar, blood
pressure, or cholesterol number, then doctors automatically assume the person
is healthier. Rather, health has nothing to do with it. It is in the financial
interests of drug companies to dispense more and more drugs, on an ongoing

There is a night-and-day difference in quality of health
between a person who has good numbers because they are healthy and a person who
has reasonably-looking numbers because they are poisoned with drugs. Studies
using high doses of metabolic and cardiovascular drugs to attempt to drive
numbers down to the levels of healthy people invariably injure and even kill
the participants—clearly failing to improve health quality and extend lifespan.

To make matters worse, the pharmaceutical industry
fraudulently hides the actual risks of the drugs from both patients and
doctors. This includes slanting, to blatantly falsifying, studies routinely
published in medical journals and used for marketing, illegally promoting
off-label use of drugs, using funding to bribe research universities to publish
only favorable results and blacklisting researchers who refuse to accept, and
paying influential doctors to present their data as independent research at
medical meetings.

The scope and magnitude of the drug safety issue is a
nightmare. In 2006 the Institute of Medicine (IOM) conducted interviews with
FDA management and hundreds of FDA employees to ascertain issues leading to
drug safety problems. Widespread conflict of interest and many other issues led
IOM investigators to label FDA management as dysfunctional. Little has changed.

The Gene-Experimentation Era of Western Medicine

The human body is no slouch when it comes to elaborate
complexity. It is often the case that the same exact gene signal is “good” or
“bad” depending on the context in which it is activated. In fact, the same
genes often behave differently in different areas of the body. Unlike earlier
toxic drugs that force cell and enzyme behavior at a rather crude level,
biotech drugs turn gene signals “on” or “off” at a powerfully fundamental level
of cell function. Unfortunately for consumers, our understanding of genes is in
its infancy. There is daunting complexity in gene regulation, making use of any
gene-regulating drug highly questionable.

One example of this problem involves diabetes drugs Avandia
and Actos, which turn on the gene PPAR gamma. This gene signal helps to break down
triglycerides. These drugs also stimulate the formation of new fat cells, which
are more metabolically fit and therefore produce more adiponectin that stops
insulin resistance. Thus, in theory, they are potentially great drugs for
lowering triglycerides and benefiting people with type 2 diabetes. As these
drugs became blockbusters it was soon observed that the patients taking them
were experiencing devastating side effects. These drugs have no way to know the
context in which they should be operating. They activate PPAR gamma in the
wrong places, such as the heart, leading to a 40 percent increased risk for
heart failure or heart attack. Additionally, inappropriate PPAR gamma
activation in bones causes them to break more easily.

The FDA rushed these drugs to market despite the objections
of its own safety supervisor who wanted to employ a black box warning for heart
failure. In other words, the FDA knew about the risks but prevented the public
from understanding them, and still allowed the drugs to go to market. This was
a major scandal at the FDA. The FDA has finally restricted Avandia, but Actos
remains available in full swing. Actos has recently been highly restricted in
Europe, but in America, the FDA continues to drag its feet. This is likely
because the FDA has mud on its face for approving these biotech nightmares in
the first place and would rather consumers suffer injury and even die than look
bad. The mainstream media fails to aggressively report on or investigate this
tragic issue as they are large recipients of drug company advertising dollars.
Even when one of their own, Tim Russert, was likely killed by Avandia or Actos,
they turned a blind eye.

DHA is a Superior and Intelligent Gene-Regulating

The plot thickens. Nature’s nutrient DHA, typically in fish
oil, is a powerful
activator of PPAR gamma
, helping to break down triglycerides as well as
make new metabolically-fit fat cells that boost adiponectin and help fight type
2 diabetes—the exact objectives of Big Pharma’s Avandia and Actos. DHA is a
near-miracle nutrient for the heart and overall cardiovascular health and also
supports strong bones. It has all of the benefits of Avandia and Actos and none
of the side effects.

And this is why Big Pharma is so interested in taking over
many dietary supplement ingredients. The nutrients know how to work in harmony
with gene function in the human body, since nutrition was a key part of human
evolution. These nutrients appear to have inherent intelligence that no drug
could possibly have. They understand the context of the gene signal and thus
support the beneficial gene activity. They know how to behave differently in different
areas of the body to promote
healthy function at every turn

Under the FDA’s new draft guidance that redefines the 1994
Dietary Supplement Health and Education Act (DSHEA), the FDA targets many
nutrients for elimination from the market, and DHA is one of them. DHA is a
component of fish oil, which is a pre-DSHEA nutrient. This means that it should
be grandfathered in and not subjected to the newly-published New Dietary
Ingredient (NDI) guidelines.

Various companies have been able to concentrate the DHA as
well as remove toxins from the oil, enabling consumers to take higher amounts
of the most important ingredient in fish oil. Consumers can now easily and
safely reach doses of DHA that are consistent with studies showing extreme
health benefit. Such doses of DHA are known to be safe, have been tested in
clinical trials sponsored by the National Institutes of Health (NIH), and are
consistent with the amounts consumed by people who regularly eat fish.

The FDA’s point man on NDI guidance issues, Daniel
Fabricant, has been telling the supplement industry what to expect. In a recent
he was asked, “Should it be necessary to submit an NDI notification
over a small change in the ratios of the long chain omega-3 fatty acids EPAto
DHA in one fish oil supplement versus another? Is this really a big safety
issue?” Shockingly, Fabricant responded “If it is a different ingredient, a
different chemical entity, then it should trigger an NDI notification.”

Fabricant is saying that any modification of basic fish oil
should trigger an NDI notification. This is utter nonsense, but it is exactly
what the FDA is attempting to do. What Fabricant did not bother to say to the
supplement industry webinar audience was that an NDI application for modified
fish oil would be denied, since GlaxoSmithKline already has a fish oil
prescription drug on the market called Lovaza. Again, shocking.

Yes, the new guidance document makes it clear that if an
existing drug contains any form of the nutrient DHA, a NDI will not be allowed
(section IV.C.8-11). In other words, if modified DHA did not require an NDI
notification, it qualified as a grandfathered nutrient, an obvious part of fish
oil. But if the FDA decides that the newly manufactured form of the nutrient,
in this case DHA, is different than its typical concentration in food, it can
require that nutrient to have an NDI notification. By retroactively applying
this definition to nutrients that compete with drug applications, that nutrient
will automatically be denied NDI status. As of now, this is the intended fate
of DHA. It is gravely unfortunate, as DHA is one of the most beneficial and
effective nutrients offered by the dietary supplement industry.

This is a blatant power play to hand the entire high-grade
DHA market to GlaxoSmithKline, one of the largest drug companies in the world.
Lovaza already costs five to seven times what a similar amount of high-grade
DHA costs—imagine how high their price will go up when there is no competition.

The Rise of Epigenetics

The new frontier of science is the field of epigenetics. A
true genetic change means there is a change in the DNA sequence. Epigenetics
explains factors that are not such DNA changes. Rather, epigenetic changes
relate to how genes are expressed. Some are set in response to early
environmental influences such as prenatal malnutrition or nutrient deficiency.
As cells split and divide, however, epigenetic factors play a large role in
determining life-long  human health and are strongly linked to poor health and the onset of
disease. Epigenetic weaknesses magnify during aging and are major factors in
the cause of cancer, heart disease, neurological and cognitive disorders,
obesity, diabetes, infertility and sexual dysfunction.

This new science is finding that when toxins interfere with
the human genome, they can cause lasting damage in the form of adverse
epigenetic changes which can occur at any point in one’s life. This is not
simply an issue of pollution. Researchers are now demonstrating that regular
use of many drugs
can cause adverse toxic epigenetic changes, a finding
that has alarming implications for today’s medical practices. Up to this point
in time, drug safety has not involved studying the impact of any drug on
epigenetics. Science now has the ability to see what is going on in this realm.
The pharmaceutical industry and the FDA, unsurprisingly, have no interest in
understanding and considering this new, ground-breaking information as the
public would significantly reduce their intake of drugs.

On the hand, research on dietary ingredients is showing them
to be powerful regulators of epigenetics and some show extreme promise for
helping to treat metabolic disease and even cancer. Nutrients are showing that
they possess “intelligence” and are able to tell the difference between a
stressed and struggling cell (one with epigenetic weaknesses) and a cell with
cancer. In the case of the stressed cell, the nutrients can fix it. In the case
of the cancerous cell, the exact same nutrient can actually help kill the
cancer without any adverse side effects—even overcoming mechanisms that make
cancer resistant to drug treatments. Two of the very best nutrients in this
category are curcumin and resveratrol, making them potential prizes for the
pharmaceutical industry.

As I reported in my recent article, “Curcumin Helps Change
Gene Function to Combat Cancer
,” curcumin and resveratrol are under
extensive genetic study at the MD Anderson Cancer Center. Regarding cancer,
these researchers are at the forefront of all things drug and biotech. The last
commissioner of the FDA, Andrew von Eschenbach, was in charge at the MD
Anderson Cancer Center before joining the FDA. Researchers at the MD Anderson
Cancer Center are practically drooling over the virtues of curcumin and
resveratrol. Some quotes from their recent study include the following:

Recently, natural compounds, such as curcumin,
epigallocatechin gallate (EGCG), and resveratrol, have been shown to alter
epigenetic mechanisms, which may lead to increased sensitivity of cancer cells
to conventional agents and thus inhibition of tumor growth. Curcumin
(diferuloylmethane), a yellow spice and the active component of the perennial
herb Curcuma longa, commonly known as turmeric, is one of the most powerful and
promising chemo-preventive and anticancer agents, and epidemiological evidence
demonstrates that people who incorporate high doses of this spice in their
diets have a lower incidence of cancer. Furthermore, epidemiological evidence
exists indicating that there is a correlation between increased dietary intake
of antioxidants and a lower incidence of morbidity and mortality…. How curcumin
exerts its powerful anticancer activities has been thoroughly investigated, and
several mechanisms of action have been discovered…. curcumin exerts its
biological activities through epigenetic modulation.

Extensive research over the past five decades has indicated
that curcumin reduces blood cholesterol levels; prevents low-density
lipoprotein oxidation; inhibits platelet aggregation; suppresses thrombosis and
myocardial infarction; suppresses symptoms associated with type II diabetes,
rheumatoid arthritis, multiple sclerosis, and Alzheimer disease; inhibits HIV
replication; suppresses tumor formation; enhances wound healing; protects
against liver injury; increases bile secretion; protects against cataract
formation; and protects against pulmonary toxicity and fibrosis. These
divergent effects of curcumin seem to depend on its pleiotropic molecular
effects, including the regulation of signal transduction pathways, and direct
modulation of several enzymatic activities. Most of these signaling cascades
lead to the activation of transcription factors.

Interest in the effects of dietary compounds such as
resveratrol which activate class III HDACs (sirtuins) is growing rapidly
because of their demonstrable role in extending lifespan and in reducing, or
delaying, age-related diseases including cancers…. Resveratrol, a natural
compound found in the skin of red grapes and a constituent of red wine, is
believed to play a significant role in the reduction of cardiovascular events.
Multiple studies have shown that resveratrol can activate sirtuin 1 (SIRT1), a
histone deacetylase, and inhibit p300. Sirtuins, the class III HDACs, are
widely distributed and have been shown to regulate a variety of
physiopathologic processes, such as inflammation, cellular senescence and
aging, cellular apoptosis and proliferation, differentiation, metabolism, stem
cell pluri-potency, and cell cycle regulation.

Experimental evidence accumulated in the recent years
clearly supports the idea that dietary nutraceuticals such as curcumin have
great potential as epigenetic agents.

These researchers go on to cite all of the human safety and
efficacy trials with curcumin, resveratrol and many other natural substances.

This is not dietary supplement companies extolling the
virtues of these powerful nutrients. These are mainstream drug development
researchers, stunned by the ability of nutrients to regulate epigenetics to
support health and at the same time combat diseases that plague large numbers
of people. The inherent capacity of these nutrients outshines that of any drug.

There should be no question in anyone’s mind as to why the
pharmaceutical industry wants to claim these powerful nutrients as patent-protected
drug assets. The question is more about how they plan to pull off this major
scheme, this heist, from the dietary supplement industry.

Curcumin (tumeric) has been around for thousands of years
and is consumed in very large amounts in Eastern and Middle Eastern cultures.
This means the basic spice is protected by DSHEA. Unfortunately, curcumin has
relatively poor bioavailability and raw material companies have sought to
produce purified extracts with advanced production technology and combine
curcumin with other nutrients such as piperine, which can elevate the
biological activity up to 2,000 percent. Researchers at MD Anderson Cancer
Center have conducted cancer research specifically with one such curcumin
product, made by Sabinsa, and found it very promising.

Under the proposed FDA guidelines for NDIs, such curcumin
extracts would retroactively become NDIs as they were not available prior to
1994. The immediate impact would be the removal of curcumin from the dietary
supplement market while submitting an NDI application. Sabinsa, however, has
already been granted several investigational new drug applications for their
curcumin complex as they work with researchers at MD Anderson Cancer Center.
Under the new FDA guidelines the net result would be eliminating all high grade
curcumin extracts from the dietary supplement market, as no NDI will be granted
for any ingredient that is under investigation as a new drug. Sabinsa, a
dietary supplement raw material supplier, will be able to sell its rights to
its curcumin compound to the highest pharmaceutical bidder while all other
competing curcumin extracts, including Sabinsa’s product, will be forced off
the dietary supplement market.

It is a similar story for resveratrol, which is also under
investigation as a new drug. In fact, numerous highly-effective and therapeutic
extracts will be targeted in this way by the pharmaceutical industry. The FDA
has a glaring conflict of interest and can easily approve investigational new
drug applications for any nutrient of interest to the pharmaceutical cartel,
automatically blocking them from entry or existence in a competitive dietary
supplement marketplace. Dietary supplement companies could spend millions
trying to get the FDA to pass a NDI application. The FDA just sits on the NDI
application, to ultimately approve the nutrient as an investigational new drug
and deny the dietary supplement company’s NDI application.

Consumer options for therapeutic nutrition will rapidly
dwindle. What is left on the market will be far more expensive and many
nutrients will no longer be available without prescription. Once the
pharmaceutical industry gains control of the nutrient, the new price will be
ten to fifty times what consumers pay now.


Acupuncture in Cancer Care

July 7th, 2011

We are pleased have a guest writer Kate Flaherty in today’s blog. Kate is an outreach and awareness coordinator for the Mesothelioma Cancer Alliance in the US.  She is passionate about the role of complementary therapies during comprehensive cancer treatment as well as cancer prevention education.  Kate resides in Upstate New York.

The Benefits of Acupuncture in Cancer Care

Cancer is physically and emotionally taxing. Coping with the disease can be overwhelming. While there are numerous treatments for cancer, many are aggressive and produce an abundance of adverse side effects. Acupuncture is an alternative therapy that can provide relief without the unpleasant side effects. If you or someone you know has cancer, acupuncture may be beneficial.

Acupuncture is used in many hospital settings as therapy for people with mesothelioma and other cancers. It can be used in combination with chemotherapy, biological therapy, radiation and surgery. Acupuncture works by causing physical reactions in the nerve cells and brain. This sets off a chain reaction by releasing hormones and brain chemicals like endorphins, which are the body’s natural painkillers.

The National Cancer Institute provides useful information about the success of this alternative therapy. Acupuncture plays a role in symptom management as well as preventative care. It can reduce pain and nausea, increase energy and enhance stamina. People with digestive problems due to cancer treatment can benefit as well. Acupuncture also reduces the hot flashes and fatigue associated with chemotherapy. {{{0}}}

Acupuncture can enhance the therapies that are already in use. Conventional treatments like chemotherapy and radiation can cause hair loss, anemia and skin burns. Acupuncture addresses these issues by encouraging the body to heal itself. The Cancer Treatment Centers of America often use acupuncture in conjunction with traditional treatments to attack cancer on all fronts.

In addition to treating the symptoms associated with cancer therapy, acupuncture can also accelerate a patient’s recovery. Various aspects of the procedure will increase white blood cells, which can greatly affect the person’s prognosis. Acupuncture boosts the immune system as well. This means a person receiving chemotherapy may be susceptible to fewer infections.

The procedures involved in acupuncture affect various parts of the body. Not only does this therapy reduce physical symptoms, it affects a person’s emotions. Patients can undergo acupuncture treatments to lower anxiety and relax the mind. This is especially beneficial prior to chemo or radiation appointments.

If you have been diagnosed with mesothelioma or another form of cancer, you may have concerns about what to expect in the future. An initial prognosis is not always accurate. There are many factors that can affect the outcome of any cancer. While the mesothelioma life expectancy varies from person to person, the choice of treatments can make a difference in how each person views his or her future.

The use of alternative treatments like acupuncture is continuously expanding. Acupuncture addresses cancer care with a full-body approach. Traditional cancer treatments such as chemotherapy and radiation can cause numerous complications. Acupuncture is a safe, effective adjunct for cancer treatment, and it can provide cancer patients with new options.


American Cancer Society

National Cancer Institute

National Center for Complementary and Alternative Medicine


Please note that while we welcome contributions from individuals with a passion for patient care, the views of guest writers do not necessarily reflect the views of the editorial team and it is for the readers to validate the scientific evidence of the claims in peer-reviewed journals. We do not permit articles that are promoting any commercial products and services.

Female athlete triad

July 6th, 2011


Female athlete triad in Asia is not well studied although the prevalence is not that low (about 2-4%). Many of us as practitioners could easily miss the diagnosis as the presenting symptoms might be vague and thus a high degree of suspicion is needed.

There was a study in 2009 among 67 elite female athletes in Malaysia aged between 13-30 years that were subdivided into the ‘leanness’ and ‘non-leanness’ groups. {{{o}}}

The findings:

  1. Prevalence of the female athlete triad was low (1.9%) as compared to studies in Europe and the USA of about 4% , but the prevalence for individual triad component especially eating disorder was high, especially in the leanness group.
  2. The prevalence of subjects who were at risk of menstrual irregularity, poor bone quality and eating disorders were 47.6%, 13.3% and 89.2%, respectively, in the leanness group; and 14.3%, 8.3% and 89.2%, respectively, in the non-leanness group.

As eating disorder is the dominant innocuous presenting feature and precedes the other components, it is thus easy to miss the diagnosis in Malaysia due to the low prevalence of the typical triad disorders. It is therefore prudent for coach and nutritionist working with such athletes to be vigilant in seeking out any one of the components of the triad especially among those participating in sports that emphasize a lean physique as it would allow early treatment and prevent further complications.


Ye Vian Quah; Bee Koon Poh; Lai Oon Ng; Mohd Ismail Noor Ye Vian Quah; Bee Koon Poh; Lai Oon Ng; Mohd Ismail Noor The female athlete triad among elite Malaysian athletes: prevalence and associated factors. Asia Pacific Journal of Clinical Nutrition 2009, Vol. 18 Issue 2, p200-208Retrieved on 21 June 2011 from

Ergogenic aids in sport performance

July 6th, 2011

There was an enquiry on the affects of combination supplementation of ephedrine compounds (including ma huang, ephedra, and synephrine) and caffeine to enhance sport performance. Here is my response:

Liu et al. (1995) demonstrated that the thermogenic response by ephedrine was mediated by all three beta-adrenoceptors subtyptes and at least 40% of by the beta 3-adrenoceptor. Astrup et al. (1986) the beta-adrenergic stimulation of ephedrine increases glucose (or diet)-induced thermogenesis, respiratory quotient and higher lipid oxidation.

Berlin et al showed that low doses decrease tiredness, while there was a significant increase in blood pressure and orthostatic hypotension which the authors pointed out as increasing the cardiovascular risk during physical exercise.

What are the effects on enhancing exercise and sports performance?.{{{0}}} Bell et al. (2001) noted that both caffeine and ephedrine singularly and in combination are known to improve athletic performance in high-intensity aerobic activity that lasts 10-20 min. In this first study, exercise performance was improved by both caffeine and ephedrine, with ephedrine stimulating the CNS and caffeine stimulating the skeletal muscle.  In an effort to investigate whether this effect was sustained after 20 min., 12 subjects who were running a 10-km run were given (90 minutes before the run began) either a placebo (P), caffeine (C, 4 mg/kg), ephedrine (E, 0.8 mg/kg) or ephedrine plus caffeine (E+C).  The run times for the ephedrine containing trials (E and E+C) were significantly reduced compared to the C and P trials. Heart rate and pace (in the last five km) for the ephedrine containing trials (E and E+C) were significantly reduced compared to the C and P trials.  The rating of perceived exertion was similar for all trials.  Caffeine was found to increase epinephrine and norepinephrine response, and blood lactate, glucose, and glycerol levels; whereas, ephedrine reduced the epinephrine response and increase dopamine levels (Bell et al., 2002).

What medical conditions and medications would using these be contraindicated or even deadly?

Ephedra seems to mostly be dangerous if taken at higher than the recommended dosages and in combination with other adrenergic drugs especially in high risk patients such as patients with severe hypertension and coronary heart disease, decompensated heart failure and cardiomyopathy and chronic renal disease.  It is also contraindicated in patients with psychosis. Of the cases published, the outcomes have varied from mild side effects, cardiovascular effects, death, disability, and even acute psychosis (Tormey and Bruzzi, 2001; McKenna et al., 2002). Reviews are ongoing into finding out the personal susceptibility of Ephedra-related risk, and this could be personal aberrations in adrenoceptors.

Could these compounds be addictive? Berlin et al did not show ephedra supplements do not cause dependency in a study in 2001.

Is there an efficacy issue here? While ephedrine on its own has not been consistent in enhancing exercise performance, its combination with caffeine seems to have better evidence especially with lower dose pharmaceutical gradecombination(from 4-5 mg/kg caffeine and .8-1mg/kg ephedrine) resulted in the maintenance of ergogenic effect while reducing the negative side effects such as nausea and vomiting. (Bell et al).

I am rather philosophical about caffeine and ephedra as ergogenics. The 2 issues that need to be considered are:

  1. Health effects – would the use of such ergogenic drug or beverage cause harmful or even fatal effects? So long as it is within a wide therapeutic index i.e. the dose for providing well documented ergogenic effects are much lower than the dose producing the adverse side effects including addictive effects both physical and psychological, I would certainly use them – this would be the primary consideration even more important than the second consideration. On balance, the therapeutic index of ephedra is much narrower than caffeine. For that reason, I would be reluctant to use ephedra and it has rightly been banned by FDA since 2004.
  2. Would the use provide unfair advantage? This is the case with caffeine, as more beverages contain the stimulant in moderate doses, the WADA and IOC took it off their doping list since the common consumption would not confer any advantage over other athletes.


  1. Melvin Williams Nutrition for Health, Fitness and Sport 9th edition page 542
  2. Shawn Talbott, Review of Ephedra SupplementWatch Retrieved on 21 June from

Cancer – a nutritional disease?

March 6th, 2011

There is an emerging school of thought that is supported by evidence in research that cancer could be a nutritional disease. Cancer cells are known to plump for aerobic glycolysis and substrate phosphorylation energy system when mitochondria, the power generator of cellular energy are impaired from exotoxins or endotoxins. Normal cells use oxidative phosphorylation as their main energy system. Mitochondrial DNA that code for the enzymes needed for efficient oxidative phosphorylation is vulnerable to oxidative stress damage from reactive oxygen species that are produced in the routine production of cellular energy in the mitochondria. These ROS are responsible for mitochondria destruction if they are not mopped up by antioxidants.{{{*}}}

Warburg described the aerobic glycolysis energy system of the cancer cells. Cancer appears to be a form of intracellular lactic acidosis caused by a block in the oxidation of glucose at the level of PDH (pyruvate dehydrogenase). The glycolysis metabolism of glucose increases cancer cells’ lactic acid and reduces the intracellular pH resulting major shifts in the intracellular biochemistry. Aerobic glycolysis, known as the “Warburg Effect”, inactivates mitochondrial respiration which allows cancer cell growth.

Impairment of mitochondria leads to genomic instability and through a phenomenon known as retrograde response causes the cells to up-regulated oncogenes such as AKT and Myc that transactivate glycolytic enzymes and RAS that promotes HIF1 (hypoxic inducible factors) that stimulates PDH kinase which inhibits PDH that converts pyruvate to acetyl CoA driving the Kreb Cycle in the oxidative phosphorylation process. Loss of p53 the “policeman gene” that regulates cell death of cells with damaged DNA is common in cancer cells. P53 is also responsible for the coding of cytochrome complexes that are responsible for the electron transport system in the mitochondria. Deletion or mutation of p53 leads to dysfunction of the cytochrome complexes. The release of cytochrome C is also involved in the initiation of apoptosis. Hence, mitochrondrial dysfunctions could contribute to carcinogenesis in a number of ways.

Targets for enzymes that drive aerobic glycolysis have been studied as a possible anticancer strategy. One such candidate is dichloroacetate that promotes oxidative phosphorylation and turn off aerobic glycolysis. As a medicinal, DCA is generally well tolerated from dosages between 10mg/Kg and 50mg/Kg, although prolonged exposure is associated with peripheral neuropathy. Its activation of the pyruvate dehydrogenase enzyme (PDH) of the mitochondria decreases glycolysis and reactivates glucose oxidation, a favorable approach to ameliorate lactic acidosis.

Cancer cells predominantly utilize a system of glycolysis for energy instead of the glucose oxidation used by healthy cells.  DCA reverses this glycolysis causing several major detrimental changes in the cancer tumor cells.

The mechanism of actions of DCA is as follows:

  1. First and foremost DCA inhibits pyruvate dehydrogenasekinase (PDK). PDK blocks pyruvate dehydrogenase (PDH) through its phosphorylation activity. When this kinase is inhibited by DCA, the PDH is reactivated causing the mitochondria to no longer be hyperpolarized, instead the membrane and the mitochondria are depolarized, reactivating the mitochondrial K+ channels which then decreases cytosolic K+. When PDH is inhibited in cancer cells by PDK, an excess cytosolic K+ occurs that inactivates the caspases 3 and 9, important factors in apoptosis. DCA reactivates these caspases along with an increase in H2O2 intracellularly, allowing the release of cytochrome c from the mitochondria.
  2. The release of cytochrome c is a major activating step for cell apoptosis as it triggers the caspase cascade. The results of DCA on cancers are seen both in vitro and in vivo. These effects are not seen in normal cells.
  3. Dichloroacetate’s other major effect on cancer cells is the release of mitochondrial calcium (Ca++). The increase of Ca++ in cancer cells is associated with the increase and proliferation of transcription factors. Calcium also activates ornithine decarboxylase, the rate limiting enzyme in DNA synthesis, and the antiapoptosis factor NFAT (nuclear factor of activated T lymphocytes). When the calcium decreases with the introduction of DCA, the cell is further directed toward apoptosis and a decrease in cell replication. In addition to DCA causing a major shift in the mitochondria, cytoplasm, and cellular membrane, the end effect of DCA is a cell cycle arrest in the Gap 1 phase (G1), which also increases apoptosis.

The medical community is seeing more and more patients who are seeking forms of therapy on their own with varying results; some are deleterious and endangering while others may prolong their lives but should still be done under medical supervision. Understandably physicians frequently cannot ethically advise or administer the use of the patents’ preferences, leaving the patient to their own devices. Controlled research needs to be conducted for validation and confirmation of DCA’s efficacy and maintenance levels in the spectrum of cancer therapies.

The Journal of Oncology July 2010 reported a Non-Hodgkin’s lymphoma patient taking 10 mg/kg [750 mg] of dichloroacetate daily of his own accord, had a complete remission of his Non-Hodgkin’s lymphoma cancer after four months that has continued to date by his maintaining his DCA dosage in addition to taking 750 mg thiamine to protect against the slight tingling and numbness in the nerves of the fingers and toes, without compromising his quality of life or affecting the treatment’s efficacy. Ignoring medical advice not to self-medicate he has continued his DCA/thiamine regimen, stating his concern that discontinuing DCA may allow a recurrence of the disease.


  1. Retrieved from on March 6, 2011 Cancer Res 2006; 66: (18).
    Jung-whan Kim and Chi V. Dang; Cancer’s Molecular Sweet Tooth and the Warburg Effect September 15, 2006 8928 DOI:10.1158/0008-5472.CAN-06-1501
  2. Dana F. Flavin, Case Report Non-Hodgkin’s Lymphoma Reversal with Dichloroacetate; Journal of Oncology Volume 2010, Article ID 414726, 4 pages doi:10.1155/2010/414726



WHI studies in perspective

February 14th, 2011

First, let’s take a deeper look at the Women’s Health Initiative (WHI) studies that change the medical perspective of menopausal hormone therapy (MHT) and drop the use of hormones significantly.

The menopausal hormone therapy clinical trial had two parts. The first involved 16,608 postmenopausal women with a uterus who took either estrogen plus-progestin therapy or a placebo. (The added progestin protects women against uterine cancer.) These were the first randomized placebo controlled trials for MHT. The past trials were all observational studies.

The second involved 10,739 women who had had a hysterectomy and took estrogen alone or a placebo. (A placebo is a substance that looks like the real drug but has no biologic effect.)

The estrogen-plus-progestin trial used 0.625 milligrams of conjugated equine estrogens taken daily plus 2.5 milligrams of medroxyprogesterone acetate (PremproTM) taken daily. The estrogen-alone trial used 0.625 milligrams of conjugated equine estrogens (PremarinTM) taken daily.

Prempro and Premarin were chosen for two key reasons: They contain the most commonly prescribed forms of estrogen-alone and combined therapies in the United States, and, in several observational studies, these drugs appeared to benefit women’s health.

Women in the trials were aged 50 to 79—their average age at enrollment was about 64 for both trials. They enrolled in the studies between 1993 and 1998.Their health was carefully monitored by an independent panel, called the Data and Safety Monitoring Board (DSMB).{{{*}}}

Both hormone studies were to have continued until 2005, but were stopped early. The estrogen plus-protestin study was halted in July 2002, and the estrogen-alone study at the end of February 2004.

The two WHI studies’ findings should not be compared directly.  Women in the estrogen-alone study began the trial with a higher risk for cardiovascular disease than those in the estrogen-plus-progestin study.  They were more likely to have such heart disease risk factors as high blood pressure, high blood cholesterol, diabetes, and obesity.

Here are the main findings:

Estrogen Plus Progestin

With 5.2 years of followup.  For every 10,000 women each year, estrogen plus progestin (combination therapy) use compared with a placebo on average resulted in:

Increased risk for

Breast cancer

  • 26 percent increased risk—8 more cases (38 cases on combination therapy and 30 on placebo)


  • 41 percent increased risk—8 more cases (29 cases on combination therapy and 21 on placebo)

Heart attack

  • 29 percent increased risk—7 more cases (37 cases on combination therapy and 30 on placebo)

Blood clots (legs, lungs)

  • Doubled rates—18 more cases (34 cases on combination therapy and 16 on placebo)

Increased benefits

Colorectal Cancer

  • 37 percent less risk—6 fewer cases (10 cases on combination therapy and 16 on placebo)


  • 37 percent fewer hip fractures—5 fewer cases (10 on combination therapy and 15 on placebo

No difference


Total cancer case

Estrogen Alone

With 6.8 years of followup.  For every 10,000 women each year, estrogen-alone use compared with a placebo on average

resulted in:

Increased risk for


  • 39 percent increase in strokes—12 more strokes (44 cases in those on estrogen alone and 32 in those on placebo)

Venous thrombosis (blood clot, usually in a deep vein of legs)

  • About a 47 percent higher risk—6 more cases (21 cases in those on estrogen alone and 15 in those on placebo.) An increased risk of pulmonary embolism (blood clots in the lungs) was not statistically significant. There were 13 cases in those on estrogen alone and 10 in those on placebo.

No difference in risk (neither increased nor decreased) or of uncertain effect

Coronary heart disease

  • No significant difference—5 fewer cases (49 cases in those on estrogen alone and 54 in those on placebo).  During the first 2 years of use, the risk was slightly increased for estrogen alone, but it appeared to diminish over time.

Colorectal/total cancer

  • No significant difference—1 more case for colorectal cancer and 7 fewer cases for total cancer (for colorectal cancer, 17 cases with estrogen alone and 16 with placebo; for total cancer, 103 cases in those on estrogen alone and 110 in those on placebo.)

Deaths (all or specific cause)

  • No significant difference—3 more deaths (for all deaths, 81 in those on estrogen alone and 78 in those on placebo)

Breast cancer

  • Uncertain effect—7 fewer cases (26 cases in those on estrogen alone and 33 in those on placebo).  This finding was not statistically significant.

Increased benefit

Bone fractures

  • 39 percent fewer hip fractures—6 fewer cases (11 cases in those on estrogen alone and 17 cases in those on placebo)

These findings are best summarized in this diagram:

U.S. Food and Drug Administration (FDA) Approved Use of Menopausal Hormone Therapy

  • Menopausal hormone therapy products are effective for treating moderate-to-severe hot flashes and night sweats, moderate-to-severe hot flashes and night sweats moderate-to-server vaginal dryness and prevention of osteoporosis associated with menopause, but carry serious risks. Therefore post-menopausal women who use or are considering using estrogen or estrogen with progestin treatment should discuss with their health care providers whether the benefits outweigh the risks.
  • If these products are prescribed solely for vaginal symptoms, health care providers are advised to consider the use of topical vaginal products (gel or cream applied locally).
  • If menopausal hormone therapy is used for osteoporosis, the risks for osteoporosis must outweigh the risk of estrogen or estrogen with progestin. Health care providers are encouraged to consider other treatments before providing menopausal hormone therapy for osteoporosis.
  • Menopausal hormone therapy has never been approved for the prevention of cognitive disorders such as Alzheimer’s disease or memory loss. In fact, the WHI found that women treated with menopausal hormone therapy have a greater risk of developing dementia.
  • Menopausal hormone therapy should be used at the lowest doses for the shortest duration to reach treatment goals, although it is not known at what doses there may be less risk of serious side effects.

Here are my comments:

  1. It is a fact that the incidence of breast cancers among post-menopausal women has declined since the decline of the use of MHT in the early 2000s especially those with positive estrogen receptors which is the majority of breast cancers.
  2. There has also been an increase in bio-identical hormone replacement such as the use of phytoestrogens and micronized natural progesterone during the same period. Many experts criticized the use of equine conjugated estrogens and synthetic progestin in the WHI trials. Could this contribute to the higher risks of breast cancer, stroke and clots? There are studies, mainly animal studies, that confirmed the differences of synthetic and natural female hormones on estrogen receptor bindings and their physiological effects. Could the type of hormones account for the adverse risks?
  3. New insights from more studies and follow up of the WHI studies:
    • Could progestin mediates the CHD risk when the 2 studies were compared? E+P has higher risk than E alone. It is also interesting to note that in this group of women ,those on statins have beneficial efforts for risk of CHD when taking together with the hormones.
    • Could progestin mediates risk of breast and colorectal cancers?  E+P has higher risk of invasive breast cancer vs P alone where there is no difference to placebo. The reverse is true for colorectal cancers, E+P reduces CRC while E alone shows no difference, could progesterone confers lower risk to colorectal cancer?
    • It is important to get the perspective right in terms of the added risk from MHT. The attributable risk which is the difference of the risk from the MHT over the prevalence of these risks in the studied population is what should be looked at. In these 2 groups of patient average age of 63 years, the overall number of major disease events was low only 1 in 300 major outcomes per year i.e. one third of 1 percent. E+P added less than one tenth of 1 percent to that rate. If you compare these risks to other risk factors for breast cancers, late menopause, obesity, lifetime alcohol excess and lack of exercise, the risks related to MHT are smaller compared to these other factors. The same is true for the E alone study.
    • Timing of MHT since menopause is also important. The risk for example to CHD is higher the longer the start of MHT from menopause e.g. more than 20 years as compared to the benefits rather than harm from CHD in the group that starts MHT early in menopause i.e. less than 10 years from start of menopause. This was the same observation for E alone and the E+P studies. The theory proposed for this difference is the “estrogen gap” theory. In premenopausal period, endogenous estrogens protect the arterial lining from plagues. If there was an interval immediate post menopausal when estrogens are not replaced, the theory proposes that there will be no benefit due to estrogen resistance or gap. The arterial wall will no longer respond to estrogen due to the gap period. In fact, animal studies show that if estrogen is given when estrogen resistance developed, the plague progression could be worst.  This was confirmed from coronary calcium score studies in early menopausal women where estrogen and progestin use has less calcium score as compared to placebo.

My recommendations:

Is MHT still a rational choice – Yes, but it depends on the profile of the woman who is looking for treatment.

Women with symptoms of MHT early menopause especially vasomotor symptoms, estrogen alone seem better than the combined E+P in terms of risk. But 60% of women have a uterus. Here one could consider milder progesterone. The FDA’s position is that there is no evidence to justify the use of bioidentical hormones. We will cover this in another post. The methods of delivery e.g. transdermal do not seem to change the risk situations in MHT.

Vasomotor symptom relief:

There are definite benefits for those with vasomotor symptoms. What is not included in this analysis is the sleep disturbances associated with menopausal. These could be very debilitating and estrogen has helped with these sleep disturbances.

I would therefore recommend hormonal replacement for early menopausal patient – low dose estrogen and transdermal is preferred for patients with vasomotor symptoms such as hot flashes, night sweats and sleep disturbances. Natural progesterone such as micronized progesterone would be my preference. Usually the symptoms improved within 2 weeks of treatment. After second month of unopposed estrogen, cyclic micronized progesterone should be initiated. I would then review the continuation after 1 year of treatment. Some cases might need up to 2 years of replacement to settle the vasomotor symptoms.

The use of MHT in prevention of CHD, breast cancer and dementia needs further evaluation in robust clinical studies. MHT is definitely beneficial for osteoporosis. However, there are other options (see future post). I would not recommend its use until we fully understand the mechanisms of the hormones in driving some of these risks with further research.

Surgical management of obesity

November 20th, 2010

In this article we will discuss the surgical treatment of obesity which is the last resort in resistant weight control. This will conclude our thread on Resistant Weight Control. We will be starting a new thread next month and we hope you have enjoyed our series on this global epidemic that is now getting to be known as “GLOBESITY”.

Surgical treatment of obesity is also known as bariatric surgery or weight loss surgery. Surgery is currently the most effective treatment for morbid obesity resulting in durable and sustainable weight loss and accompanying health improvements.{{{*}}}

Classifications of Surgery

Surgeries for weight loss can be classified as follows:

  • Restrictive procedures that limit the amount of food intake by reducing the size of the stomach
  • Malabsorptive procedures that interfere with absorption of food from the digestive tract
  • Combined restrictive and malabsorptive procedures

The 2 most commonly performed operations for weight loss in the United States are the Roux-en-Y gastric bypass (RYGB) and the adjustable gastric band (AGB). Both procedures could be done laparoscopically with smaller incisions than those required for traditional open approach (laparotomy). Small incisions result in less pain, early ambulation, and rapid postoperative recovery and less chance for wound complications (wound infection, fluid collection, and hernia).

Preoperative Workup

Careful preoperative patient screening, selection, preparation, and education are the keys for postoperative success. A comprehensive multidisciplinary approach to patients’ screening and education, including consultations with a dietitian, psychologist,internist, and bariatric surgeon is mandatory. In selected cases, cardiac, pulmonary, and endocrine evaluation may be needed. Patients should have a clear understanding and realistic expectation of benefits, risks, and long-term consequences of surgical treatment.

Operative Procedures

Gastric bypass

Roux-en-Y gastric bypass is the most commonly performed weight loss procedure in the United States. This operation both restricts food intake and limits absorption of food. A part of the stomach is closed off, creating a small pouch. This restricts the amount of food that you can eat at one time. The small pouch of the stomach is connected directly to the small bowel. As the name implies, food bypasses the stomach and the first portion of the small intestine. Because a part of the small bowel is bypassed, less food is absorbed.

Most people find they can eat less than 1 cup of food at a time after the operation. Food must be chewed very well. Overeating or not chewing food finely will result in cramping, nausea, and vomiting.

Laparoscopic adjustable gastric binding

This is a purely restrictive procedure. It involves placing an inflatable silastic band around the uppermost part of the stomach. This results in a smaller upper stomach pouch and a narrow opening between the upper and lower parts of the stomach. This induces and early feeling of fullness and thereby decreases food intake. It is adjustable by changing the volume of saline in a surgically placed subcutaneous reservoir, thereby tightening or loosening the band.

Biliopancreatic diversion

Biliopancreatic diversion (BPD) is a malabsorptive procedure with some restrictive component. A part of the stomach is removed and the remaining part is attached directly to the small intestine near its end. BPD is used much less often than Roux-en-Y because it has a greater risk of complications.

Vertical banded gastroplasty

Vertical banded gastroplasty (VBG, stomach stapling) is a restrictive procedure that traditionally was done by applying bands or staples to the stomach. This procedure is rarely performed today due to the high failure rate.

More information about these procedures can be obtained by visiting the American Society for Bariatric Surgery or the Bariatric Multidisciplinary Institute.

Benefits and Risks of Weight-Loss Surgery

Like all surgical procedures, weight-loss operations have benefits and risks. No one should decide to have surgery without being completely informed of both the pros and cons. This is a decision that you make with your family members, your health care provider, and your surgeon.

Benefits of weight-loss surgery

  • Weight loss: Most patients begin to lose weight right away. Some gain some of the weight back, but most are able to keep the weight off for long periods.
    • In general, combined restrictive and malabsorptive procedures (like gastric bypass) are more successful than restrictive procedures (like adjustable gastric banding) at promoting weight loss.
      • Gastric bypass is the most successful procedure. In the first 2 years after gastric bypass, average weight loss is 65% of excess weight. On the other hand, average weight loss with AGB is 35% of excess weight.
      • With gastric bypass, no band is introduced into the body. Also, it is a good operation for a sweet eater because eating sugar makes the patient feel ill (referred to as “dumping”).
      • The lap-band system has the advantages of being less invasive, providing a faster recovery, and avoiding alteration of anatomy of the gastrointestinal tract. It is adjustable and reversible with normal stomach restoration. No opening of the stomach or intestines occurs that could cause a leak.
    • People who undergo one of these procedures are much more likely to reach their goal and keep weight off if they also adopt a plan of healthy eating and regular exercise.
  • Improved health: Most obesity-related medical conditions improve drastically after surgery, especially diabetes, sleep apnea, and hypertension.
    • After surgery mortality rate is reduced and improvements are seen in many of the health risks associated with obesity.
    • Overall, quality of life, self image, and mobility are reported to be better.

Risks of weight-loss surgery

All surgical procedures have complications. Talk to your surgeons about this and make sure that your surgeons are specialists in bariatric surgery.

  • Disadvantages of gastric bypass – A patient who has gastric bypass may develop the following complications:
  • “Dumping syndrome” – Patients experience nausea, abdominal cramping, and diarrhea after eating sugar. Other symptoms include weakness or faintness.
    • Narrowing or ulcer formation or leak at the stomach to intestine connection – These may require reoperation.
    • Incisional hernia – This is more common in open bariatric surgery.
    • Blood clot in the leg – This may migrate to the lung.
    • In addition to surgical complications, long-term consequences of themalabsorption arise if patients with gastric bypass do not take supplemental vitamins, iron, and calcium. These nutritional deficiencies include the following:
      • Vitamin deficiencies (A, B-12, D, E, and K)  – Deficiencies of vitamin B-12, folate, and iron can cause anemia.
      • Mineral deficiencies (calcium, iron, and folic acid) – Calcium deficiency is a concern because it may lead to osteoporosis and other bone disorders.
  • Disadvantages of adjustable gastric band
    • The lap-band system is not the operation of choice in sweat eaters or patients with severe gastroesophageal reflux disease (GERD).
    • There is a low possibility of port leak or infection, as well as slippage,erosion, or migration of the band. This may require reoperation. High conversion rates of band to gastric bypass have been reported in American studies. However, this may represent the surgeon’s learning curve.

In experienced hands, the benefits of surgery are typically viewed to outweigh the risks. The immediate operative mortality rate for both adjustable gastric band and Roux-en-Y gastric bypass is about 1%.

Weight regain after bariatric surgery

Some patients may regain weight after bariatric surgery. This may be due to many factors, among them the following:

  • Noncompliance with postoperative diet
  • Noncompliance with postoperative exercise
  • Stretching of the stomach pouch
  • Communication between the pouch and the rest of the stomach
  • Band problems

Costs of weight loss surgery

Surgery seems to be much more expensive than other treatments for obesity; however, rates vary depending on choice of surgeon and hospital and region in which you live. Insurance coverage of weight-loss surgery varies by insurance carrier. Check with your carrier to see whether such operations are covered.

Postoperative Care

If you undergo weight loss surgery, you will continue to receive close medical care for the rest of your life. Laparoscopic adjustable gastric banding will require more frequent visits for band adjustment. Postoperative dietary (including vitamin, mineral, and possibly liquid protein supplementation), exercise, and lifestyle changes should be reinforced by counseling, support groups, and working with your primary care physician. Postoperative care may include planning for reconstructive operations after weight stabilization for certain patients.

For More Information

Web Links

MedlinePlus, Weight Loss Surgery
MedlinePlus, Obesity
American Obesity Association, Obesity Surgery


September 28th, 2010

Wonder why it is so difficult for some of your patients to lose weight? There have been many studies that documented substantial reduction in calorie diet intake of some patients and yet their weight remains the same.  We have covered some of the undetected hypothyroidism and leptin resistance as causes. However, there is another interesting study on the effect of adaptive thermogenesis on resistant weight control. The hypothesis is that the body has an adaptive mechanism in thermogenesis to balance energy expenditure. When dietary intake is down or energy expenditure is up, the body decreases its thermogenesis to maintain weight. Many well-designed studies have demonstrated some thermogenic deficit or related physiological vulnerability in individuals predisposed to obesity.{{{*}}}

In a study by Tremblay et al from Canada, the authors defined Adaptive thermogenesis as the decrease in energy expenditure beyond what could be predicted from body weight or its components (fat-free mass and fat mass) under conditions of standardized physical activity in response to a decrease in energy intake. As expected, energy expenditure, be it in the resting or the active state, was significantly more decreased compared with what was predicted by morphological changes. In addition, the authors recently reported the maximal decrease in resting energy expenditure in this study, which was sufficient to completely compensate for the prescribed energy deficit.

Body weight instability, which is also generally referred to as the ‘yoyo phenomenon’, seems to be the normal biological reaction to uncontrolled and quantitatively important negative energy balance. The weight regain that generally follows this large energy deficit may exceed weight loss so that a net weight gain may be the outcome of such a weight cycle. . Approximately two decades ago, the yoyo effect was tested as a factor that could explain, per se, the proneness to a positive energy balance in animals.

The authors had the opportunity to complete two case studies in which they could test the effect of weight cycling on adaptive thermogenesis under well-standardized conditions. In the first study, an athletic male explorer was first tested in the Laval University respiratory chamber under well-standardized experimental conditions. As shown in Figure 1, this measurement was followed by pre-expedition overfeeding that induced a 5 kg weight gain. After overfeeding, he engaged in a 22-day cross-country skiing expedition through Greenland that resulted in a weight loss of 8.5 kg. Figure 1 also shows that indirect calorimetry measurements were repeated after he had recovered his baseline morphological profile. It is also important to note that this post-expedition measurement was performed under conditions similar to baseline measurement for energy and macronutrient intake, as well as for spontaneous physical activity in the chamber. Despite this optimal standardization for factors influencing ‘obligatory thermogenesis’, daily energy expenditure was reduced by 1.4 MJ (approximately 350 kcal) following the expedition.

Figure 1.  Variations in body weight and daily energy expenditure in response to a weight cycle imposed by an expedition in Greenland (Subject 1) and in Antarctica (Subject 2).

A comparable result was obtained in the second study, which involved the testing of another male explorer who was also subjected to whole-body indirect calorimetry measurements before and after a 65-day expedition in Antarctica. As expected, the expedition induced a considerable body weight loss (13.2 kg) that had to be recovered following the expedition before a second series of measurements could be performed in the respiratory chamber. Thus, as for case study 1, this subject was tested at the same body weight and composition status before and after the expedition as well as under standardized nutritional and activity conditions in the chamber. Figure 1 shows that the weight loss/regain cycle again resulted in a marked decrease (1.0 MJ/day) in daily energy expenditure, which provides further evidence of the impact of weight cycling on adaptive thermogenesis.

The main implication that can be derived from the observations presented above is that adaptive thermogenesis can be sufficiently pronounced in some individuals to interfere with successful weight loss. On the basis of the studies of Leibel et al.and those performed in Laval University, this phenomenon could appear as an adaptation that promotes the early occurrence of resistance to lose fat. Indeed, in these two series of studies, greater than predicted decreases in energy expenditure were observed in subjects having experienced some weight loss.

The authors’ clinical experience also reveals that such an adaptation can happen sufficiently early during the course of a weight-reducing program to totally prevent the achievement of weight loss

In summary, there seem to be some obese individuals who clearly overreact in energy expenditure when they are exposed to a negative energy balance. This adaptive thermogenesis may then clearly reduce the ability to achieve a successful body weight loss. To date, there is no clear explanation for the occurrence of such a phenomenon but, as discussed in the next posting, the authors proposed a the possibility that it might happen so as to protect body homeostasis due against the influence of environmental pollutants.

Obesity – genes or diet?

August 24th, 2010

Obesity – nature or nurture….genetic factors are at play in obesity. But you are not doomed by your genetic fate…nutrients have been demonstrated to regulate your fat genes..{{{*}}}

There is a constant debate over the causative factors of obesity. Are diet and lifestyle habits more important than genetic predisposition. I must say that these factors are not mutually exclusive. Dean Ornish and his colleagues have demonstrated that while genetic predisposition might handicap and put certain population segments at higher risk, dietary intervention do have tremendous influence on gene regulation even in a very short period of time.  In May 2008, he and his colleagues published an article in the Proceedings of the National Academy of Sciences that after only 3 months of making lifestyle and nutritional changes, gene expression in over 500 genes was beneficially affected – upregulating disease-preventing genes and downregulating disease promoting genes including oncogenes involved in prostate cancer(1).

The purist of the dieting influence is of the view that obesity is entirely due to bad dietary behaviour. Dr David Heber (Director, UCLA Center for Human Nutrition) is a proponent of that view. He said, “Genes load the gun, but environment pulls the trigger. The idea that it’s all in your genes is nonsense. The human genome changes only one half of one percent every million years. The obesity epidemic is only about 30 years old, so changes in genes do not explain the recent dramatic rise in obesity, not only in this country but also worldwide”.

However, small gene variations called SNPs or single-nucleotide polymorphisms are much more common than major gene changes that happen only over millions of years. Such polymorphisms could affect huge populations that could account for their role in obesity and risk factors such as hypercholesterolemia. In a recent study, researchers at the University of Oxford found in 13 cohorts of 38,759 participants, approximately 50 percent of white Europeans have one defective copy of the FTO gene which increased the risk of obesity by about one third, while 16 per cent of people have two altered copies of the gene have a 70 percent increased risk of obesity(2). The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and expressed in the neurons of feeding-related nuclei of the brain. Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.

A recent study by investigators in Finland(3) randomly assigned men and women with metabolic syndrome to a rye-pasta diet (low glycemic index) or an oat-wheat-potato diet (high glycemic index). After only 12 weeks, those in the low glycemic index LGI group had 71 genes showing decrease expression and none showing increased expression. In the high glycemic index group, 62 genes showed increased expression and none showed decreased expression. Two specific genes that were down regulated in the LGI  are particularly important. HSL (hormone sensitive lipase), a key enzyme in the release of fatty acids from adipose tissue and stimulation of insulin are downregulated in the LGI group. The other important transcription factor, TCF7L2 is the strongest known predictor of type 2 diabetes. This factor occurs with increased frequency in individuals with type 2 diabetes.

The editorial that accompanies this article is really pertinent “Molecular pathways involved in hormone action have been the target of multibillion-dollar pharmaceutical research effort. However, many of these pathways, may normally be under dietary regulation. The results of the present study emphasize the age-old wisdom to “use food as medicine” – in this case, for the targeted prevention and treatment of obesity, diabetes and heart diseases.

This has great relevance in the area of nutrigenomics. Your genes especially bad genes need not seal your destiny, many of the molecular pathways dictated by such genes could be regulated by simple inexpensive dietary interventions that need not be protracted as well. Herein lies the mystery of the gene and dietary interactions that is driving the debate in our current thread.


  1. Dean Ornish, Mark Jesus M. Magbanua, Gerdi Weidner, Vivian Weinberg, Colleen Kemp, Christopher Green, Michael D. Mattie, Ruth Marlin, Jeff Simko, Katsuto Shinohara,Christopher M. Haqq, and Peter R. Carroll Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention Proceedings of the National Academy of Sciences June 17, 2008 vol. 105 no. 24 8369-8374
  2. Frayling, N. Timpson, M. Weedon, et al. 2007. A common variant in the FTO gene is associated with body mass index and presidsposes to childohood and adult obesity. Sciewnce 316 (5826):889-94
  3. Salsberg S.L and D. S Ludwig, 2007 putting your genes on a diet: The molecular effects of carbohydrate. Am J Clin Nutr 85(5): 1169-70.

Clearing some confusions on Vit D

July 17th, 2013

Why is Vit D important?

Vit D is appearing in many peer-reviewed journals these days. especially in cardiology, endocrine and cancer journals. Low vitamin D status has been associated with cardiovascular disease, certain cancers, cognitive decline, depression, diabetes, pregnancy complications, autoimmune diseases and even a 78 percent increase in all-cause mortality risk (<17.8 ng/ml 25(OH)D compared to >32.1 ng/ml)

What is the current RDA?

In 2010, the IOM decided to revise and raise the DRI for vit D. This is now the official US government position adopted by the Food and Nutrition Board.. These guidelines are still low compared to those recommended by the Endocrine Society and the Vit D Council.


  Vitamin D Council Endocrine Society Food and Nutrition Board
Infants 1,000 IU/day 400-1,000 IU/day 400 IU/day
Children 1,000 IU/day per 25lbs of body weight 600-1,000 IU/day 600 IU/day
Adults 5,000 IU/day 1,500-2,000 IU/day 600 IU/day, 800 IU/day for seniors
Recommended daily intakes from various organizations:



What is the best test for Vit D deficiency and why?

The accepted blood test is 25OHD3 and the range accepted by the current pundits is






To understand which of the metabolites of Vit D is the best for clinical measure, one need to understand the natural synthesis of Vit D and the various metabolites.


 Vit D is derived from 2 sources: the skin and dietary source. The precursor of Vit D is a cholesterol derivative, 7 dehydrocholesterol and it is converted via UVB component of sunlight to vit D3 (cholecalciferol – inactive unhydroxylated form). Likewise, diet rich in Vit D such as milk and fish is digested and absorbed as Vit D3. It is then converted to 25OHD3 (Calcifediol or Calcidiol) in the liver and further converted to the physiologically active 1,25 OH2D3 (Calcitriol) in the kidney. This process has many cofactors and regulates level of Calcium and Phosphate via the PTH hormone through the bone and intestine. Why don’t we use the physiologically active 1,25 OH2 D3 as the measure of deficiency in the body? Although cholecalciferol and 1,25(OH)2D3 (calcitriol) can be measured in the circulation, the best estimates of vitamin D status are provided by measurement of 25OHD3 (calcidiol). This is due to its long serum half-life (approximately 3 weeks) and because the 25-hydroxylation step is unregulated, thus reflecting substrate availability. A number of commercial kit assays are available for the clinical laboratory.

In contrast, cholecalciferol has a short half-life (approximately 24 h) so that serum levels depend on recent sunlight exposure and vitamin D ingestion and is a better indicator of the conversion phase in the kidney, hence kidney function.. The assay is difficult due to the lipophilic nature of the molecule and no commercial versions are available.

What is the optimal level of 25OHD3 to ensure optimal health?

The challenges today with 25OHVit D3 is the lack of standardization of the measure and even if we have a sense of the level of storage in the body, it is not useful as a clinical tool as there are so many functions of the active 1,25 OH vit D3 in particular bone and immune health. By the time we get to osteoporosis and cancer to evaluate its level, it would have been too late. There seems to be a suggestion that the level adequate for the prevention of osteoporosis (some suggest 30 ng/ml calcidiol) may not be high enough for cancer prevention (some suggest 50 ng/ml calcidiol). Therefore there is a need for better downstream functional markers of Vit D3 in various diseases for the measure to be clinical relevant and useful. One thing is certain, it is not recommended that the level of 25OHD3 exceeds 150 ng/ml which is the maximal tolerable level when toxicity will set in.

Current forms of Vit D supplements and what should be the target level:

 The other issue is that most supplements sold in the US and Australia are plant based vit D2. Ergocalciferol (vitamin D2) is produced commercially by ultraviolet irradiation of a provitamin D sterol (ergosterol) that occurs in plants. It differs from vitamin D3 in having an additional methyl group at C24 and a double bond at C22-23. It undergoes the same hydroxylation reactions as cholecalciferol to form 25OHD2 and 1,25(OH)2D2. Ergocalciferol is the only prescription pharmaceutical available in Australia and the only high dose preparation available in the USA so D2 metabolites can represent a significant fraction of the circulating hormone in patients treated with these preparations. Not all available lab tests could measure 25OHD2.

Furthermore, the half life of 25OHD2 is shorter and clinical potency is less than one third of 25OHD3. Most vit D supplements in Europe and Asia are now in D3 form.  I certainly would recommend the D3 form for those who are keen on supplementation. I would also encourage that the 25OHD3 be kept at about 30-60 ng/ml for optimal health, in particular in boosting immune health and prevent cancer.