Magnesium can help reduce hot flashes

Posted on January 19, 2012 by Dr. Jonathan

Summary: Magnesium, important for the human body for many reasons, can help with hot flashes due to menopause and treatment for breast and prostate cancer.

Hot flashes occur during the onset of menopause as abrupt changes in estrogen levels elicit vasomotor reactions through the hypothalamus, and they can also occur as estrogen levels are suppressed by chemotherapy in breast cancer treatment. A study recently published in the journal Supportive Care in Cancer presents evidence that magnesium helps to reduce menopausal hot flashes in breast cancer patients.

The authors derived a hot flash score from frequency and severity of hot flashes in breast cancer patients who had been experiencing at least 14 hot flashes a week, before and after taking 400 mg of magnesium oxide 400 mg for 4 weeks. The study subjects were allowed to increase the dose to 800 mg if needed. The results were impressive…

“The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 to 27.7, a 41.4% reduction… Hot flash score was reduced from 109.8, a 50.4% reduction. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial.”

These results are welcome because magnesium, the fourth most abundant mineral in the human body plays a vital role in hundreds of important pathways and is frequently subject to depletion. It is the ‘calming mineral’. The patients whose hot flashes were reduced likely obtained other benefits. The authors conclude:

“Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal.”

These findings are echoed in another report published in the Journal of Clinical Oncology. The author states:

“Hot flashes are common with natural menopause or induced estrogen deficiency from chemotherapy, tamoxifen, raloxifene, or the aromatase inhibitors. As many as 90% of perimenopausal women have hot flashes, and 40% of survivors of breast cancer rate their hot flashes rate the effect as “quite a bit” to “severe”.”

He notes that the common medications for hot flashes…

“…have potential adverse effects. Antidepressants can cause mental, emotional, and physical adverse effects. Megestrol acetate and medroxyprogesterone acetate, while effective, can potentially cause fluid retention, premenstrual symptoms, and deep vein thrombosis.”

He goes on to report clinical experience consonant with the previous study:

“Recently I saw two patients with breast cancer who volunteered that when they began magnesium supplements for reasons other than hot flashes, their hot flashes diminished within 24 hours and had not returned. In each case, the person was not expecting any relief from magnesium, so placebo effect is unlikely.”

It should be noted that men undergoing hormone blockade therapy for prostate cancer can also suffer from hot flashes. The potential benefits of magnesium apply to them too.

Dietary macronutrient composition for weight loss and weight maintenance

Posted on October 22, 2011 by Dr. Jonathan

Summary: When designing a dietary strategy for weight loss and maintenance the individual patient’s functional and genetic constitution must be carefully considered, but there is an accumulation of evidence indicating that a high protein, low carbohydrate regimen is a good starting point.

There is a large body of evidence that can instruct us in how to fashion an eating plan to promote both short and long-term success in weight loss and healthy body composition. As a paper published in the journal Obesity demonstrates, the way many Americans eat—referred to as a ‘cafeteria diet’ (CF)—is worse than a diet high in lard. The authors note:

“Obesity has reached epidemic proportions worldwide and reports estimate that American children consume up to 25% of calories from snacks. Several animal models of obesity exist, but studies are lacking that compare high-fat diets (HFD) traditionally used in rodent models of diet-induced obesity (DIO) to diets consisting of food regularly consumed by humans, including high-salt, high-fat, low-fiber, energy dense foods such as cookies, chips, and processed meats.”

They investigated the effects on weight gain and inflammation of a cafeteria diet (CAF) compared to a lard-based 45% HFD by feeding their rodent models either HFD, CAF or a chow control for 15 weeks. Their data clearly show that even consuming almost half the diet in lard is better than the lethal mix that many now consume:

“Body weight increased dramatically and remained significantly elevated in CAF-fed rats compared to all other diets. Glucose- and insulin-tolerance tests revealed that hyperinsulinemia, hyperglycemia, and glucose intolerance were exaggerated in the CAF-fed rats compared to controls and HFD-fed rats.”

Moreover, the cafeteria diet was markedly worse in promoting inflammation:

“It is well-established that macrophages infiltrate metabolic tissues at the onset of weight gain and directly contribute to inflammation, insulin resistance, and obesity. Although both high fat diets resulted in increased adiposity and hepatosteatosis, CAF-fed rats displayed remarkable inflammation in white fat, brown fat and liver compared to HFD and controls. In sum, the CAF provided a robust model of human metabolic syndrome compared to traditional lard-based HFD, creating a phenotype of exaggerated obesity with glucose intolerance and inflammation.”

A study published in The New England Journal of Medicine examined specific dietary factors that stand out in their contribution to obesity noting that they…

“…may affect the success of the straightforward-sounding strategy “eat less and exercise more” for preventing long-term weight gain.”

They performed investigations involving 120,877 U.S. women and men who were free of chronic diseases and not obese at baseline for as long as twenty years. Relationships between changes in lifestyle factors and weight change were evaluated every four years. There were several factors that stood out:

“Within each 4-year period, participants gained an average of 3.35 lb. On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (−0.22 lb), whole grains (−0.37 lb), fruits (−0.49 lb), nuts (−0.57 lb), and yogurt (−0.82 lb)…Other lifestyle factors were also independently associated with weight change, including physical activity (−1.76 lb across quintiles); alcohol use (0.41 lb per drink per day), smoking (new quitters, 5.17 lb; former smokers, 0.14 lb), sleep (more weight gain with <6 or >8 hours of sleep), and television watching (0.31 lb per hour per day).”

Potatoes are clearly ‘sugar grenades’, but in my opinion further studies are required to examine the difference between red meat from animals treated with hormones and fed a grain diet versus those that are free of growth-stimulating medications and eat mainly grass.

With the most egregious insults to a metabolically healthy diet out of the way, we can proceed to the roles of glycemic index and glycemic load on weight loss as examined in a study published recently in the Journal of Nutrition:

“This study assessed the effect of changes in glycemic index (GI) and load (GL) on weight loss and glycated hemoglobin (HbA1c) among individuals with type 2 diabetes beginning a vegan diet or diet following the 2003 American Diabetes Association (ADA) recommendations.”

99 subjects with type 2 diabetes were randomized to follow 1 of 2 diet treatments for 22 weeks. Glycemic index and glycemic load changes were assessed and their relationships with changes in weight and HbA1C were calculated. (Glycemic index is a metric for rate which a food will cause blood sugar to rise. Glycemic load is determined by multiplying the glycemic index by the amount of carbohydrate in grams provided by a food and dividing the total by 100; this amounts to the sum of the glycemic loads for all foods consumed in the diet.) Interestingly, glycemic index predicted weight gain while glycemic load did not:

“…the vegan group reduced GI to a greater extent than the ADA group, but GL was reduced further in the ADA than the vegan group. GI predicted changes in weight, adjusting for changes in fiber, carbohydrate, fat, alcohol, energy intake, steps per day, group, and demographics, such that for every point decrease in GI, participants lost ~0.2 kg (0.44 lb)…Weight loss was a predictor of changes in HbA1C. GL was not related to weight loss or changes in HbA1C.”

Thus glycemic index takes precedence over glycemic load in choosing foods for weight loss and blood sugar regulation. Also notable was the finding regarding GI and HbA1C:

“GI was not a predictor for changes in HbA1C after controlling for weight loss.”

Every wonder why a patient’s HbA1C didn’t go down even though they were eating a low GI diet? This shows that if they don’t lose weight as a result, the the HbA1C will tend to stay the same. The authors conclude:

“A low-GI diet appears to be one of the determinants of success of a vegan or ADA diet in reducing body weight among people with type 2 diabetes. The reduction of body weight, in turn, was predictive of decreasing HbA1C.”

The interesting difference between the effects of glycemic index and glycemic load revealed here help to explain the inconsistency noted in a review published earlier in journal IUBMB (International Union of Biochemistry and Molecular Biology) Life:

“Recently, due to its possible link to appetite control and metabolism, several clinical studies have assessed the effect of low glycemic index (GI) and glycemic load (GL) diets on weight loss. To determine the application of GI/GL in the prevention and treatment of obesity, we searched several databases and identified 23 clinical trials that examined low GI/GL diets and weight loss as the primary outcome measure.”

Here the pooling of GI and GL seems to have obfuscated the issue. The authors conclude:

“Over the past decade, the body of research that links low GI/GL diets to weight loss has grown rapidly and significantly. While there is a significant amount of inconsistency in the current findings, the majority of studies found a trend that favored low GI/GL diets in weight loss.”

Moreover…

“…the benefits of low GI and GL diets extend beyond weight loss and have favorable effects on obesity-related risk factors such as heart disease and diabetes by mechanisms that are independent of weight loss.”

What about protein versus carbohydrate for weight loss? A number of investigators have examined this question, but an interesting study published recently in the Nutrition Journal corrects some important limitations in earlier work:

“Studies have suggested that moderately high protein diets may be more appropriate than conventional low-fat high carbohydrate diets for individuals at risk of developing the metabolic syndrome and type 2 diabetes. However in most such studies sources of dietary carbohydrate may not have been appropriate and protein intakes may have been excessively high. Thus, in a proof-of-concept study we compared two relatively low-fat weight loss diets – one high in protein and the other high in fiber-rich, minimally processed cereals and legumes – to determine whether a relatively high protein diet has the potential to confer greater benefits.”

They eighty-three overweight or obese women to either a moderately high protein (30% protein, 40% carbohydrate) diet (HP) or to a high fiber, relatively high carbohydrate (50% carbohydrate, > 35 g total dietary fiber, 20% protein) diet (HFib) for 8 weeks. During that time their energy intakes were reduced by 478 to 955 calories per day to achieve weight loss of between 0.5 and 1 kg per week. Which diet resulted in better weight loss?

“Participants on both diets lost weight (HP: -4.5 kg and HFib: -3.3 kg), and reduced total body fat (HP: -4.0 kg and HFib: -2.5 kg, and waist circumference (HP: -5.4 cm and HFib: -4.7 cm), as well as total and LDL cholesterol, triglycerides, fasting plasma glucose and blood pressure. However participants on HP lost more body weight (-1.3 kg) and total body fat (-1.3 kg). Diastolic blood pressure decreased more on HP (-3.7 mm Hg).”

High protein wins out over high carbohydrate, even when the carbohydrate is high fiber. The authors conclude:

“A realistic high protein weight-reducing diet was associated with greater fat loss and lower blood pressure when compared with a high carbohydrate, high fiber diet in high risk overweight and obese women.”

Importantly, the benefits of a high protein to carbohydrate ratio diet include the slowing of tumor growth and prevention of cancer initiation as described in an excellent paper (you may wish to read it in its entirety) published recently in the journal Cancer Research. It includes a significant consideration for reducing carbohydrate by increasing protein rather than fat. The authors state:

“Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction–induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein.”

They were able to formulate diets that demonstrated that the tumor inhibiting effects were due to factors other than weight loss from calorie restriction (CR):

“To exploit the fact that cancer cells rely more heavily on glycolysis than normal cells, we designed low CHO, high protein diets to see if we could limit BG and tumor growth. In designing our diets, we wanted to avoid NCKDs [no calorie ketogenic diets] because of the difficulty in achieving long-term compliance with no CHO diets in potential future human studies and because Masko and colleagues recently reported that a 10% or 20% CHO diet slows tumor growth as effectively as NCKDs. Following early studies with 8% CHO diets, using 10% and 15% CHO, high protein diets in which 70% of the CHO was in the form of amylose, we found that, compared with a Western diet, they were indeed capable of reducing BG, insulin, and lactate levels and, importantly, in slowing the growth of implanted murine and human tumors, with little or no effects on mouse weight.”

There is good reason to apply these finding to human case management:

“Consistent with the notion that reducing BG in humans can be beneficial, there is a wealth of epidemiologic evidence showing a clear association between BG and/or insulin levels (which are determined by BG levels) and the incidence of human cancers. Thus, although our studies were conducted, out of necessity, with mice, the fact that human BG can be significantly reduced with low CHO diets and the association of many cancers with high BG levels suggest that our findings are very likely relevant to human cancers as well, particularly in cancers that have been associated with higher baseline BG and/or insulin levels, such as pancreatic, breast, colorectal, endometrial, and esophageal cancers.”

This also has application to prostate cancers:

“In addition to these cancers, a low CHO diet may also be beneficial in early-stage prostate cancer, even though it is not typically detectable by PET. This is because the metastases of these tumors kill the patients and, given the pivotal role of lactate in promoting metastasis, our low CHO diets could significantly reduce metastasis by reducing tumor-associated lactate levels.”

Regarding concerns about the impact on kidney function…

“In terms of macronutrient composition, even though high protein has been shown to promote satiety—thus reducing obesity, BG, and insulin levels—and enhance both antitumor immunity, through amino acid supplementation, and life span, we were concerned, based on the literature, that high protein levels might cause kidney damage. More recent data, however, suggest that this may only occur in individuals with existing chronic kidney disease and that in normal people, the increase in glomerular filtration rate and kidney cellularity that occur with long-term high protein consumption may be a normal response.”

Incidentally, amylose starch prevents DNA damage in the colon that may otherwise be caused by red meat:

“Interestingly, colonic cancer-inducing damage caused by red meats may be avoided with high amylose, low CHO diets. These studies suggest that macronutrient sources and combinations are very important…”

The authors conclude:

“Our study, herein, shows that a high amylose containing low CHO, high protein diet reduces BG, insulin, and glycolysis, slows tumor growth, reduces tumor incidence, and works additively with existing therapies without weight loss or kidney failure. Such a diet, therefore, has the potential of being both a novel cancer prophylactic and treatment, warranting further investigation of its applicability in the clinic, especially in combination with existing therapies.”

Regarding weight loss, what if exercise is added to the program? Will high protein still beat high carbohydrate. A study published in the journal The Physician and Sports Medicine studies this question as the authors set out to…

“…determine whether sedentary obese women with elevated levels of homeostatic model assessment (HOMA) insulin resistance (ie, > 3.5) experience greater benefits from an exercise + higher-carbohydrate (HC) or carbohydrate-restricted weight loss program than women with lower HOMA levels.”

221 women who participated in a 10-week supervised exercise and weight loss program were assigned low-fat (30%) diets that consisted of 1200 kcals per day for 1 week (phase 1) and 1600 kcals per day for 9 weeks (phase 2) with either high carbohydrate (HC) or higher protein (HP). Fasting blood samples, body composition, anthropometry, resting energy expenditure, and fitness measurements were obtained at the beginning and end. Again we see high protein win out over high carbohydrate:

“Subjects in the HP group experienced greater weight loss (−4.4 ± 3.6 kg vs −2.6 ± 2.9 kg), fat loss (−3.4 ± 2.7 kg vs −1.7 ± 2.0 kg), reductions in serum glucose (3% vs 2%), and decreases in serum leptin levels (−30.8% vs −10.8%) than those in the HC group.”

The authors conclude:

“A carbohydrate-restricted diet promoted more favorable changes in weight loss, fat loss, and markers of health in obese women who initiated an exercise program compared with a diet higher in carbohydrate. Additionally, obese women who initiated training and dieting with higher HOMA levels experienced greater reductions in blood glucose following an HP diet.”

Regarding the use of vegetable or fruit juices in programs designed for weight loss, a study published in the journal Obesity demonstrates that this is counter-productive:

“Beverage consumption has been implicated in weight gain, but questions remain about the veracity of the association, whether the relationship is causal and what property of beverages is responsible. It was hypothesized that food form is the most salient attribute. Thus, a randomized controlled trial of food form was conducted. Energy-matched beverage or solid forms of fruits and vegetables were provided to 34, lean or overweight/obese adults for two 8-week periods with a 3-week washout interspersed.”

During the solid food arm of the study the lean group had no significant weight change while the overweight/obese group had weight gain, but during the juice phase…

“In contrast, incomplete dietary compensation and weight gain occurred in both the lean (43%) and overweight/obese (61%) groups during the beverage arm…These data demonstrate energy consumed as beverages may be especially problematic for weight gain.”

And for the carbohydrates that are consumed, a curious study also published in Obesity offers evidence that eating them mainly at dinner further aids in weight loss, satiety and more:

“This study was designed to investigate the effect of a low-calorie diet with carbohydrates eaten mostly at dinner on anthropometric, hunger/satiety, biochemical, and inflammatory parameters. Hormonal secretions were also evaluated. Seventy-eight police officers (BMI >30) were randomly assigned to experimental (carbohydrates eaten mostly at dinner) or control weight loss diets for 6 months. On day 0, 7, 90, and 180 blood samples and hunger scores were collected every 4 h from 0800 to 2000 hours. Anthropometric measurements were collected throughout the study.”

Amazingly…

“Greater weight loss, abdominal circumference, and body fat mass reductions were observed in the experimental diet in comparison to controls. Hunger scores were lower and greater improvements in fasting glucose, average daily insulin concentrations, and homeostasis model assessment for insulin resistance (HOMAIR), T-cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were observed in comparison to controls. The experimental diet modified daily leptin and adiponectin concentrations compared to those observed at baseline and to a control diet.”

Wow…all that just from shifting carbohydrates to dinner. The authors conclude:

“A simple dietary manipulation of carbohydrate distribution appears to have additional benefits when compared to a conventional weight loss diet in individuals suffering from obesity. It might also be beneficial for individuals suffering from insulin resistance and the metabolic syndrome.”

The scientific data addressing various aspects of dietary fat is treated in a separate post, but it’s suitable here to consider a study published in The Journal of Clinical Endocrinology & Metabolism offering evidence that a low carbohydrate diet is equivalent to a low fat diet for weight loss:

“Overweight and obese men and women (24–61 yr of age) were recruited into a randomized trial to compare the effects of a low-fat (LF) vs. a low-carbohydrate (LC) diet on weight loss…Subjects on the LF diet consumed an average of 17.8% of energy from fat, compared with their habitual intake of 36.4%, and had a resulting energy restriction of 2540 kJ/d [585 calories]. Subjects on the LC diet consumed an average of 15.4% carbohydrate, compared with habitual intakes of about 50% carbohydrate, and had a resulting energy restriction of 3195 kJ/d [763 calories].”

At the end of the study period the LC group lost as much weight and had better insulin regulation:

“Both groups of subjects had significant weight loss over the 10 wk of diet intervention and nearly identical improvements in body weight and fat mass. LF subjects lost an average of 6.8 kg and had a decrease in body mass index of 2.2 kg/m2, compared with a loss of 7.0 kg and decrease in body mass index of 2.1 kg/m2 in the LC subjects. The LF group better preserved lean body mass when compared with the LC group; however, only the LC group had a significant decrease in circulating insulin concentrations.”

The authors conclude:

“”These data suggest that energy restriction achieved by a very LC diet is equally effective as a LF diet strategy for weight loss and decreasing body fat in overweight and obese adults.”

Bottom line: When designing a dietary strategy for weight loss and maintenance the individual patient’s functional and genetic constitution must be carefully considered (inflammation, immune regulation, insulin sensitivity, allergy, intestinal permeability, sleep disordered breathing and hormonal function are fundamentals); but there is an accumulation of evidence suggesting that a high protein, low carbohydrate regimen is a good starting point.

The advantages of intermittent versus continuous calorie restriction for long term weight loss

Posted on October 14, 2011 by Dr. Jonathan

There is an accumulation of fascinating scientific evidence that intermittent calorie restriction (ICR) offers a number of advantages over continuous calorie restriction (CCR) for successful long term weight loss and the ‘turning on’ of genes that favor longevity. Consider a study published recently in the International Journal of Obesity in which the investigators compared ICR and CCR for weight loss and metabolic disease risk markers in overweight women. The authors state:

“Excess weight and weight gain during adult life increases the risk of several diseases including diabetes, cardiovascular disease (CVD), dementia, certain forms of cancer including breast cancer, and can contribute to premature death. Observational and some randomised trials indicate that modest weight reduction (>5% of body weight) reduces the incidence and progression of many of these diseases. Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known.”

Moreover…

“Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation. Sustainable and effective energy restriction strategies are thus required.”

In other words, a method that can be comfortable enough to be accepted into daily life for the long that also avoids loss of improvements due to adaption is required.

“One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction.”

So the authors set out to…

“…compare the feasibility and effectiveness of IER with CER for weight loss, insulin sensitivity and other metabolic disease risk markers…This is the largest randomised comparison of an isocalorific intermittent vs. continuous energy restriction to date in free living humans..”

They designed a randomised comparison of a 25% energy restriction as IER (~2266 kJ/day which equals 541 calories per day for 2 days/week) or CER (~6276 kJ/day equaling 1499 calories each day for 7 days/week) in 107 overweight or obese premenopausal women for a 6 month study period. They measured an extensive list of biomarkers at baseline and after 1, 3 and 6 months: weight, anthropometry (size, weight and proportions), biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, IGF-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain derived neurotrophic factor. What did the data show?

“Last observation carried forward analysis showed IER and CER are equally effective for weight loss, mean weight change for IER was −6.4 kg vs. −5.6 kg for CER. Both groups experienced comparable reductions in leptin, free androgen index, high sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than CER; difference between groups for fasting insulin −1.2 μU/ml, and insulin resistance −1.2 μU/mmol/L.”

Regarding concerns about tolerance…

“A recent blinded trial of a 2 day VLCD [very low calorie diet] (1311 kJ/day [313 calories per day!]) reported no adverse effects on cognition, energy levels, sleep or mood, suggesting symptoms are expected with VLCD and therefore experienced and could potentially be overcome with appropriate counselling. Importantly IER did not lead to overeating on non-VLCD days.”

The authors briefly summarize the results of their comparison of IER and CER by concluding:

“IER is as effective as CER in regards to weight loss, insulin sensitivity and other health biomarkers and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.”

That’s not all though. The authors additionally note an extremely interesting observation with profound implications and potential for benefit regarding additional benefits of an intermittent very low calorie method:

“Recent reviews speculate that IER may be associated with greater disease prevention than CER due to increased cellular stress resistance, in particular increased resistance to oxidative stress. This is thought to be mediated by ‘hormesis’ whereby the moderate stress of energy restriction increases the production of cytoprotective, restorative proteins, antioxidant enzymes and protein chaperones. Alternate day fasting has been linked to increased SIRT-1 gene expression in muscle, and to greater neuronal resistance to injury compared to CER in C57BL/6 mice. The tendency for greater improvements in oxidative stress markers in our IER than in the CER group may support these assertions. Declines in long term protein oxidation product aggregates suggest IER as a possible activator of catabolism and autophagy.”

In other words, intermittent calorie restriction can be as effective as continuous calorie restriction for weight loss, but have the added advantage of ‘turning on’ genes beneficial for health and longevity and preventing adaptation that would result in regaining weight.

Other investigators also have compared intermittent with continuous calorie (daily) calorie restriction as in a study published recently in the journal Obesity Reviews. The authors set out to…

“…evaluate and compare the effects of daily CR versus intermittent CR on weight loss, fat mass loss, lean mass retention and visceral fat mass reduction, in overweight and obese adults.”

They undertook a review of studies that were randomized control trials, had a primary endpoint of weight loss and/or body composition changes, used daily CR or intermittent CR as the primary focus of the intervention; had a study duration of 4–24 weeks, and involved adult populations who were overweight or obese subjects but not diabetic. These included 11 daily continuous calorie restriction trials and five intermittent CR trials published between 2000 and 2010, along with two unpublished trials of intermittent CR from their own lab. What did all these studies add up to?

“Results reveal similar weight loss and fat mass loss with 3 to 12 weeks’ intermittent CR (4–8%, 11–16%, respectively) and daily CR (5–8%, 10–20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR.”

This is a significant advantage of ICR over CCR (continuous = daily calorie restriction). The authors conclude by stating:

“In sum, intermittent CR and daily CR diets appear to be equally as effective in decreasing body weight, fat mass, and potentially, visceral fat mass. However, intermittent restriction regimens may be superior to daily restriction regimens in that they help conserve lean mass at the expense of fat mass. These findings add to the growing body of evidence showing that intermittent CR may be implemented as another viable option for weight loss in overweight and obese populations.”

Numerous other studies have examined the distinctive benefits of intermittent calorie restriction. A paper published recently in the journal Oncogene investigates the positive effects of brief ICR compared to CCR for cancer patients. The authors state:

“The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.”

They point out that cancer cells are unable to respond to the positive stimuli of calorie restriction:

“Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells.”

Moreover…

“Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans.”

They go on to review studies on fasting, cellular protection and chemotherapy resistance, and futher compare them to those on continuous calorie restriction and cancer treatment. The authors conclude:

“Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.”

A study published in the Journal of Molecular and Cellular Cardiology offers evidence that intermittent calorie restriction activates genes that help in the recovery from heart damage. The authors state:

“Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI).“

Two weeks after myocardial ischemia was induced in their study animals, they were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks the authors evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival. The results were truly striking:

“Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4 ± 0.17 versus 3.9 ± 0.18. Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group. Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-α (3010 ± 350% versus 650 ± 151%), BDNF (523 ± 32% versus 110 ± 12%), and VEGF (450 ± 21% versus 170 ± 30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone.”

This is a dramatic indication that intermittent calorie restriction can be used to protect and repair heart tissue. The authors conclude:

“Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.”

Another fascinating study published recently in the journal Cancer Prevention Research demonstrates that intermittent calorie restriction is clearly superior to both continuous calorie restriction and an unrestricted diet for breast cancer prevention. Specifically, the authors studied…

“The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels…in relation to mammary tumorigenesis.”

Their subjects were assigned to ad libitum fed, ICR (3-week 50% caloric restriction followed by 3-wks 100% AL consumption), and CCR groups.

“Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad.”

This amounts to an impressive ‘turning on’ of genes that protect against breast cancer for ICR. In conclusion…

“…we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.”

A paper published in the journal Nutrition and Cancer demonstrates that ICR offers a greater protective effect than CCR for prostate cancer. The authors state:

“Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development.”

Their animal models for prostate cancer were assigned to ad libitum (AL), ICR, and CCR groups. There were distinctive differences according to the manner of calorie restriction that dramatically favored the ICR over both the AL and CCR cohorts:

“ICR mice were older at tumor detection than AL and CCR mice. There was no difference for age of tumor detection between AL and CCR mice. Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups.”

Not only did the subjects on CCR live longer with healthier biomarkers than the ones on either the free diet or CCR, there was no difference between the AL and CCR groups for age of tumor detection or survival. The implication is exciting: the benefits were due not to the weight loss component but to the way in which ICR affects gene expression. The authors conclude:

“These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.”

A paper published in the The Journal of Nutritional Biochemistry also offers evidence that intermittent calorie restriction protects heart tissue:

“It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats.”

The authors showed by echocardiographic analysis of heart structur and function that intermittent fasting attenuates the disease related increase in heart thickness, end systolic and diastolic volumes, and ejection fraction. Additionally…

“The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI.”

There is now a large body of evidence showing that ICR increases the protective hormone adiponectin much more than CCR. The authors conclude:

“Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.”

A paper published in the journal Ageing Research Reviews discusses how IFR and CCR can protect the brain from accelerated neurodegeneration associated with aging. The authors note:

“The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span.”

As we’ve seen regarding cardioprotection and tumorigenesis…

“CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease.”

These studies comprise the first post that illustrates the scientific basis for the Lapis Light Weight Loss & Gene Modulation Program that customizes intermittent calorie restriction according to the individual’s weight management and other health needs. Subsequent posts will offer additional scientific evidence important for other aspects of the program.

A middle path in the debate over PSA testing for prostate cancer

Posted on October 10, 2011 by Dr. Jonathan

Summary:

The use of PSA as a screening tool for aggressive prostate cancer (PCa) is not supported by scientific studies of its effectiveness.
Many men are subject to disabling, sometimes even fatal, interventions based on PSA tests when they would never have developed aggressive prostate cancer.
The U.S. Preventive Services Task Force has prepared a draft recommendation to stop screening in those who have not been diagnosed with prostate cancer.
There are many who, having benefited from PSA screening for PCa, feel strongly that this recommendation by the USPSTF is irresponsible.
A broader understanding of the underlying causes of elevated PSA and PCa offers a ‘middle path’ of judicious PSA screening, with a meaningful action plan that doesn’t corner patients and doctors into risky invasive procedures or the anxiety of doing nothing. Factors such as insulin resistance and estrogen-testosterone balance are of vital importance for prostate and general health.

Anyone reading this is surely aware of the controversy swirling around the draft recommendation statement of the U.S. Preventive Services Task Force (USPSTF) that…

“…recommends against prostate-specific antigen (PSA)-based screening for prostate cancer…This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history.”

The Task Force did not evaluate the use of the PSA test for men with highly suspicious symptoms or those with a diagnosis prostate cancer. This recommendation is based on a number of studies finding that PSA (including PSA velocity, the rate at which PSA goes up) is a poor predictor of prostate cancer in general and aggressive prostate cancer in particular, and the assertion that widespread screening has resulted in many unnecessarily invasive and debilitating procedures that themselves can be disabling and even fatal. Feelings are riding high as a large body of public health statistics is pitted against those who feel that a PSA test may have saved their life or the life of a patient. But practitioners and patients face more than a quandary—the debate as it’s currently framed is flawed by a glaring omission.

The PSA discussion is presently structured to assume that the response to a rising PSA can only be ignored (in favor of ‘watchful waiting’) or acted on with invasive biopsies that can seriously damage quality of life and aggressive therapies for what may in fact be indolent, slow growing tumors. That’s it, the clinical decision-making path would appear to fork into only those two roads. Here’s the problem: there is a surprising blind spot for the extensive body of science done on the underlying causes of prostate cancer that offer important opportunities to benefit. Bear in mind that inflammation or enlargement of prostate tissue caused by various disrupting factors can elevate PSA. These can often be treated with lifestyle or wholesome, non-invasive measures that also reduce the risk of other conditions like diabetes and cardiovascular disease. You may wish to read earlier posts on this topic by typing ‘prostate’ in the search box above. For now consider a couple of the most glaring omissions:

To ignore the role of insulin resistance and metabolic syndrome in prostate disease is gigantic clinical error. Consider just one paper published recently in Nature Reviews Urology in which the authors state:

“The metabolic syndrome is common in countries with Western lifestyles. It comprises a number of disorders—including insulin resistance, hypertension and obesity—that all act as risk factors for cardiovascular diseases. Urological diseases have also been linked to the metabolic syndrome. Most established aspects of the metabolic syndrome are linked to benign prostatic hyperplasia (BPH) and prostate cancer. Fasting plasma insulin, in particular, has been linked to BPH and incident, aggressive and lethal prostate cancer.”

Moreover…

“Overall, the results of studies on urological aspects of the metabolic syndrome seem to indicate that BPH and prostate cancer could be regarded as two new aspects of the metabolic syndrome, and that an increased insulin level is a common underlying aberration that promotes both BPH and clinical prostate cancer.”

This is so important yet has been so ignored. Here it is again:

“Key points

The metabolic syndrome is a cluster of disorders, including type 2 diabetes, atherosclerotic disease manifestations, hypertension, obesity and dyslipidemia, and is prevalent in countries with Western lifestyles

The most important common underlying endocrine aberration of these disorders is an increased insulin level, which is also linked to benign prostatic hyperplasia (BPH) and prostate cancer

Most aspects of the metabolic syndrome are risk factors for BPH and prostate cancer, which seems to suggest that these tumors are themselves aspects of the metabolic syndrome”

Insulin at high levels due to receptor resistance damages sensitive tissues and can act as a tumor promoter. The authors conclude:

“Urologists need to be aware of the effect that the metabolic syndrome has on urological disorders and should transfer this knowledge to their patients.”

Another of the most egregious omissions in prostate cancer management and prevention is attendance to the role played by estrogens in PCa development and progression. Consider a paper published in 2007 in the Journal of Cellular Biochemistry in which the authors observe:

“Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer.”

Furthermore…

“Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression…In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells.”

After reviewing other aspects estrogen stimulation of prostate tissue including the opposing role of ERα and ERβ receptors, the authors conclude:

“In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest.”

The authors of a review published subsequently in European Urology recognized the dual role of estrogen receptors in prostate cancer when they set out to…

“…examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.”

They report evidence for the effects of estrogenic stimulation of prostate tissue:

“The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models…The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor…The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth.”

Moreover…

“The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling.”

The authors also conclude:

“Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression.”

A paper just published in the journal Endocrinology and Metabolism Clinics of North America echoes the theme:

“The mainstay targets for hormonal prostate cancer (PCa) therapies are based on negating androgen action. Recent epidemiologic and experimental data have pinpointed the key roles of estrogens in PCa development and progression. Racial and geographic differences, as well as age-associated changes, in estrogen synthesis and metabolism contribute significantly to the etiology.”

The authors go on to report on how estrogens and estrogen mimics contribute to development of PCa, and the roles of the different estrogen mediators in the process.

As is often the case, the principle of balance comes into play as examined in a fine paper published in The Journal of Steroid Biochemistry & Molecular Biology on the estrogen:androgen ratio in the prostate gland. The authors state:

“Although androgens and estrogens both play significant roles in the prostate, it is their combined action – and specifically their balance – that is critically important in maintaining prostate health and tissue homeostasis in adulthood. In men, serum testosterone levels drop by about 35% between the ages of 21 and 85 while estradiol levels remain constant or increase. This changing androgen:estrogen (T:E) ratio has been implicated in the development of benign and malignant prostate disease.”

They review the role of the aromatase enzyme in the production of estrogens from androgens, and the fact that its aberrant expression plays a critical role in the development of malignancy in a number of tissues. In the case of PCa, it leads to an altered T:E ratio that is associated with the development of disease. And since we do have for treatment purposes wholesome modulators of estrogen receptor function as well as aromatase enzyme inhibitors…

“The role of estrogen and the T:E balance in the prostate is further complicated by the differential actions of both estrogen receptors, α and β. Stimulation of ERα leads to aberrant proliferation, inflammation and pre-malignant pathology; whereas activation of ERβ appears to have beneficial effects regarding cellular proliferation and a putative protective role against carcinogenesis.”

Clinicians who manage, support patients with, or endeavor to prevent prostate cancer must bear their conclusion in mind:

“Overall, these data reveal that homeostasis in the normal prostate involves a finely tuned balance between androgens and estrogens. This has identified estrogen, in addition to androgens, as integral to maintaining normal prostate health, but also as an important mediator of prostate disease.”

A more comprehensive perspective on the use of PSA

There far more evidence for the application of these and other factors in prostate cancer development and expression that are equally important for conditions ranging from cardiovascular disease and diabetes to dementia than can be presented in this post. It is clear, however, that we must go beyond the fascination with the false promise of ‘silver bullet’ medications and lure of lucrative procedures to properly examine and treat the more complex web of underlying factors that support prostate cancer. In the judicious hands of a skilled clinician who has the knowledge and experience to evaluate the risk of prostate cancer in the context of the total health of their patient, observing an elevation of PSA offers more than a specter of indecision over the stark choices of invasive procedures or doing nothing. It is an opportunity to intervene in positive and wholesome ways that advance the overall, not just prostate, health of the patient in their care.

Chronic fatigue syndrome and the XMRV virus

Posted on May 24, 2011 by Dr. Jonathan

There are many ways to fall prey to simplistic linear thinking when desperately seeking solutions to complex problems. Chronic Fatigue Syndrome can be a devastating illness; as attractive as a viral culprit may be to some, there is abundant evidence that attributing this complex condition to a singular cause unrealistically ignores the complexity of CFS and related conditions. A study just published in the Journal of Virology is the most recent ‘nail in the coffin’ for the notion that CFS is caused by the XMRV virus. The authors state:

“Chronic fatigue syndrome (CFS) is a multi-system disorder characterized by prolonged and severe fatigue that is not relieved by rest…Recently CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations.”

They analyzed blood samples from 100 CFS patients and 200 self-reported healthy volunteers using molecular, serological and viral replication assays. Interestingly, they also analyzed samples from patients in the original study that attracted so much media attention when it reported XMRV in CFS. What were the results?

“We did not find XMRV or related MLVs, either as viral sequences or infectious virus, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies.”

Attention to their conclusion may prevent clinicians and CFS sufferers from a fruitless diversion:

“Our findings do not support an association between CFS and MLV-related viruses including XMRV and off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.”

This is a thorough and detailed study, but is there any other evidence to support the assertion that we shouldn’t depend on XMRV as a linear viral cause for CFS? A study recently published in the journal Retrovirology also finds no association in cases across the US:

“Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases.”

Additional research published shortly after in the same journal came up with the same negative results for both CFS and prostate cancer in Japan:

“To evaluate the risk of XMRV infection during blood transfusion in Japan, we screened three populations–healthy donors (n = 500), patients with PC (n = 67), and patients with CFS (n = 100)–for antibodies against XMRV proteins in freshly collected blood samples. We also examined blood samples of viral antibody-positive patients with PC and all (both antibody-positive and antibody-negative) patients with CFS for XMRV DNA.”

Their data led them to the following conclusion:

“Our data show no solid evidence of XMRV infection in any of the three populations tested, implying that there is no association between the onset of PC or CFS and XMRV infection in Japan.”

A study recently published in PLoS ONE (Public Library of Science) goes a step further in examining the issue. The authors state:

“The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS.”

In addition to the PCR protocol used in the original study, the authors also assayed the sera of CFS patients for the presence of both the xenotropic virus envelope protein and a serological response to it. What did their data show?

“The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK.”

Subsequent research also conducted in the UK and published in PLoS examined a highly susceptible cohort of patients for XMRV virus:

“We extracted peripheral blood DNA from a cohort of 540 HIV-1-positive patients (approximately 20% of whom have never been on anti-retroviral treatment) and determined the presence of XMRV and related viruses using TaqMan PCR.”

Even for this very vulnerable group XMRV was not proven to be a concern:

“In view of these negative findings in this highly susceptible group, we conclude that it is unlikely that XMRV or related viruses are circulating at a significant level, if at all, in HIV-1-positive patients in London or in the general population.“

The authors of a study just published in the Annals of Neurology go a step further in investigating whether XMRV could be a causative agent in CFS. Having acknowledged the pre-existing research, they state:

“A useful next step would be to examine cerebrospinal fluid, because in some patients CFS is thought to be a brain disorder. Finding a microbe in the central nervous system would have greater significance than in blood because of the integrity of the blood–brain barrier.”

The brain is at the core of the experience of fatigue; if the virus were to show up anywhere it should be there. What did they find?

“We examined cerebrospinal fluid from 43 CFS patients using polymerase chain reaction techniques, but did not find XMRV or multiple other common viruses, suggesting that exploration of other causes or pathogenetic mechanisms is warranted.”

Just because a virus may be found in the body of a patient with CFS or any other condition does not mean that it is a significant causal factor for their complaint. The authors of a paper published in the British Medical Bulletin undertook a survey of…

“…All papers including the wording XMRV were abstracted from the NIH library of medicine database and included in the analysis.”

They make the point that…

“An increasing number of papers now refute the association of XMRV with human disease in humans although there is some evidence of serological reactivity to the virus. While it is unlikely that XMRV is a major cause of either prostate cancer or CFS, it can infect human cells and might yet have a role in human disease.”

But there is a big difference between being present in human cells and being a cause of disease. This is illustrated by a fascinating study published in the Journal of Virology showing that XMRV does not efficiently replicate and spread in human tissue. The authors state:

“To determine whether XMRV can replicate and spread in cultured PBMCs even though it can be inhibited by A3G/A3F, we infected phytohemagglutinin-activated human PBMCs and A3G/A3F-positive and -negative cell lines (CEM and CEM-SS, respectively) with different amounts of XMRV and monitored virus production by using quantitative real-time PCR.”

They summarize their findings by concluding:

“We found that XMRV efficiently replicated in CEM-SS cells and viral production increased by >4,000-fold, but there was only a modest increase in viral production from CEM cells (<14-fold) and a decrease in activated PBMCs, indicating little or no replication and spread of XMRV…Overall, these results suggest that hypermutation of XMRV in human PBMCs constitutes one of the blocks to replication and spread of XMRV.”

Wishing for a single linear cause that will lend itself to the discovery of a ‘magic bullet’ for conditions that are engendered by a multi-causal systemic web of factors is a flaw that has hindered progress in the treatment of chronic disease. In the case of CFS, dysregulation of the brain-immune axis is a core component. This demands that the clinician integrate a panoramic systems view with a nuanced investigation of individual functional elements. There is a world of science to delve into here; research just published in the journal NMR In Biomedicine offers a taste of the brain aspect. The authors in order to:

“…explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR [magnetic resonance] images has been extended to voxel-based regressions against clinical scores.”

The compared MR signal levels in 25 CFS subjects and 25 normal controls, including such clinical scores as fatigue duration, another score based on the 10 most common CFS symptoms, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24 hour blood pressure monitoring. What did their data show?

“In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1-weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction.”

In other words, there were strong correlations between CFS symptoms and pathological changes in the brain. The authors conclude:

“These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).“

How might such neurodegenerative changes come about? A paper published earlier in Autoimmunity Reviews discusses the autoimmune component of CFS:

“The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed.”

The main point: practitioners and patients should not be seduced by the wish for a ‘magic bullet’ treatment of a single linear cause for complex conditions that require a systems biology perspective. In the case of chronic fatigue syndrome, the brain-immune axis comes to the fore, with all its multifaceted considerations for functional assessment and treatment.

Prostate-specific antigen velocity not such a good indicator for prostate biopsy and cancer detection

Posted on March 2, 2011 by Dr. Jonathan

Many practitioners have used PSA velocity (the rate at which prostate-specific antigen values increase) as an important indicator to gauge the risk of aggressive prostate cancer and weigh the decision to proceed to biopsy. A study just published in the Journal of the National Cancer Institute reveals that PSA velocity is not a reliable indicator and can lead to many needless interventions. The authors state their intention to examine pre-existing assumptions about the significance of the rate of PSA change:

“The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE)…To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.”

The current guideline based on an unproven assumption was clearly contradicted by their data:

“Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied.”

The implication of these findings is starkly articulated in their conclusion:

“We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.“

The authors of an accompanying editorial thoughtfully state:

“The results…suggest that using PSA velocity may not provide more information to either physician or patient as we try to come to a decision about interpreting the results of any screening…The studies by Zeliadt et al. and Vickers et al. help us refine and focus our clinical approach, but they also remind us that the use of PSA as a screening tool still leaves much to be desired. Indeed, after more than 20 years of PSA screening, it has been estimated that approximately 1 million men may have been unnecessarily treated for clinically insignificant prostate cancer.”

Hormone blockade therapy for prostate cancer entails risks of diabetes and cardiovascular disease

Posted on October 31, 2010 by Dr. Jonathan

A recent FDA MedWatch announcement alerts doctors to the increased risk of diabetes, heart attacks and strokes for patients with prostate cancer undergoing hormone blockade therapy, specifically treatment with Gonadotropin-Releasing Hormone (GnRH) agonists such as Lupron.

“Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.”

The normal action of gonadotropin-releasing hormone is to stimulate the secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle stimulating hormone) from the pituitary. These hormones in turn stimulate the production of testosterone and sperm by the testes. The GnRH agonists flood the pituitary receptors causing an inhibition of gonadotropin secretion in the same way that over-stimulation of any hormone receptor suppresses the system (as occurs with topical hormone replacement, insulin resistance, etc.)

Incidentally the FDA also notes:

“The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established.“

I have personally seen how GnRH agonists exacerbate tendencies for metabolic syndrome and cardiovascular disease and appreciate the seriousness of their advice to practitioners:

“Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice.”

Metabolic syndrome accelerates prostate cancer

Posted on October 10, 2010 by Dr. Jonathan

An important study just published in the Annals of Oncology adds more evidence of the exceptional importance of metabolic syndrome for prostate cancer. The authors state:

“Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer.”

They proceeded to examine the impact of metabolic syndrome on prostate cancer patients treated with androgen deprivation therapy (ADT, blocking the production or signaling of male hormones). Comparing the data between patients with and without metabolic syndrome for the average time to PSA progression and overall survival (OS) yielded a stark contrast:

“Median time to PSA progression for patients with MS was 16 versus 36 months without MS. The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS.”

The authors sum up their evidence in the usual understated fashion:

“This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.”

It’s troubling to see how often clinicians fail to emphasize the great importance of blood sugar and insulin control when managing prostate cancer. Patients need to be aware that the lifestyle factors that address this are among the most important things they can do.

Sex hormones and cancer progression

Posted on September 12, 2010 by Dr. Jonathan

A paper published recently in the Journal of Clinical Oncology is a reminder of the importance of hormones on cancer progression that must be carefully considered by both clinician and patient. The authors set out to:

“…review the influence of sex hormones on the progression of breast, prostate, gynecologic, and colorectal cancer.”

The authors’ investigation encompassed a review of studies offering evidence of the impact of basal levels of androgens and estrogens on a range of cancers along with the effect of hormone withdrawal or antagonism of host steroids. Their conclusions need to be borne in mind by doctors and patients alike:

“Demonstration of the correlation of the completeness of withdrawal with clinical outcome together with direct evidence of progression from studies looking at the influence of tissue and circulating levels of sex hormones more recently in conjunction with gene expression profiles all provide compelling evidence for the involvement of steroids in the progression of disease. The involvement of steroids in the progression of cancer in hormone-sensitive tissues is well established and an important target for therapy.“

Higher insulin is a major risk factor for prostate cancer

Posted on September 2, 2010 by Dr. Jonathan

An important paper was just published in the journal Cancer Epidemiology that provides further evidence of insulin as a tumor promoter in prostate cancer. The authors state:

“A higher insulin level has been linked to the risk of prostate cancer promotion…the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder.”

They proceeded by following 389 patients who had lower urinary tract symptoms without prostate cancer over 8-12 years. There were notable differences between the 44 who developed prostate cancer and the rest who didn’t:

“”Men with prostate cancer diagnosis had a higher systolic and diastolic blood pressure, were more obese as measured by BMI, waist and hip measurements than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level, and a higher fasting serum insulin level than men who did not have prostate cancer diagnosis at follow-up.”

All of these accessory factors—blood pressure, BMI, waist and hip circumference, uric acid—are directly related to elevated insulin. Considering the prevalence of both prostate cancer and metabolic syndrome (high insulin), it’s important for clinicians and the public alike to bear in mind the authors’ conclusion:

“Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.“