Another Simple Food Weight Loss Experience

Whole Health Source reader Sarah Pugh recently went on a six-week simple food (low reward) diet to test its effectiveness as a weight loss strategy, and she was kind enough to describe her experience for me, and provide a link to her blog where she discussed it in more detail (1). 

Consistent with the scientific literature and a number of previous reader anecdotes (2), Sarah experienced a reduction in appetite on the simple food diet, losing 15 pounds in 6 weeks without hunger.  In contrast to her prior experiences with typical calorie restriction, her energy level and mood remained high over this period.  Here's a quote from her blog:

Well, it looks like the theory that in the absence of nice palatable food, the body will turn quite readily to fat stores and start munching them up, is holding up. At the moment, the majority of the energy I use is coming from my insides, and my body is using it without such quibbles as the increased hunger, low energy, crappy thermo-regulation or bitchiness normally associated with severe calorie restriction.

I can't promise that everyone will experience results like this, but this is basically what the food reward hypothesis suggests should be possible, and it seems to work this way for many people.  That's one of the reasons why this idea interests me so much.

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A Brief Response to Taubes's Food Reward Critique, and a Little Something Extra

It appears Gary Taubes has completed his series critiquing the food reward hypothesis of obesity (1).  I have to hand it to him, it takes some cojones to critique an entire field of research, particularly when you have no scientific background in it.

The food reward hypothesis of obesity states that the reward and palatability value of food influence body fatness, and excess reward/palatability can promote body fat accumulation.  If we want to test the hypothesis, the most direct way is to find experiments in which 1) the nutritional qualities of the experimental diet groups are kept the same or at least very similar, 2) some aspect of diet reward/palatability differs, and 3) changes in body fat/weight are measured (for example, 2, 3, 4, 5, 6, 7, 8, 9).  Taubes repeatedly stated in his series that controlled studies like these have not been conducted, apparently basing this belief on a 22-year-old review paper by Dr. Israel Ramirez and colleagues that does not contain the word 'reward' (10).  Another way to test the hypothesis is to see if people with higher food reward sensitivity (due to genetics or other factors) tend to gain more fat over time (for example, 11, 12, 13, 14, 15, 16).  In addition, studies that have examined the effect of palatability/reward on food intake in a controlled manner are relevant (17, 18, 19, 20, 21, 22), as are studies that have identified some of the mechanisms by which these effects occur (reviewed in 23).  Even if not all of the studies are perfect, at some point, one has to acknowledge that there are a lot of mutually buttressing lines of evidence here.  It is notable that very few of these studies appeared in Taubes's posts. 
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Ways to make your skin healthy by : Chloe park

The primary step to keeping your skin healthy is preventing damage. Pollutants, air, sun as well as by just natural aging can certainly mortify the form of your skin. Frequent grumbles incorporate dry along with itchy skin, sagging, wrinkles, color alterations, together with age spots. Luckily, there are various methods that you can readily apply in order to maintain a healthy skin, feeling and looking at its most excellent appearance.

Keeping yourself fit, having enough rest, as well as getting healthy diet can set the basis for fine-looking and vigorous complexion. Moreover, a proper diet is not only the excellent way in attaining good health in general but it as well assists you to guarantee that your skin will get all of the vitamins and minerals, along with the nutrients that it requires to preserve and fix itself.

Another way to keep your skin healthy is to apply the right skin care products to your skin. The best anti aging skincare products that can aid you to hydrate the skin are now available at your favorite skin care product store online. Having a clean skin by using the best skin cleanser is also a great way of preventing skin damages.

One of the most essential ways to protect your skin is to keep it away from the harmful rays of the sun. Ultraviolet radiation harms the skin as well as it can result to wrinkles, premature aging, age spots or even cancer as well. An individual should really get further preventative measures in order to be certain that his or her skin is not totally exposed under the harmful rays of the sun. Do not fail to remember that one should apply a natural sunscreen, or a moisturizer that includes sunscreen (with minimum of SPF 15) every day. Although, it does not mean that you should not go out at all during the day, as if you are like a nocturnal creature. Your skin also needs some sunlight every day. A 10 to 15 exposures at sunrise or sunset will be alright.

In addition to that, a variety of fine skin care products such as an all natural moisturizer is one of the essential components for a vigorous complexity. Keep on moisturizing all through the day to keep your sensitive skin vigorous. Your hands as well as your face is especially vulnerable to everyday dent, and might require it to be moisturized further.

FOOD WITH ORAL CANCER DRUGS?

Are oral oncology drugs being mislabeled? Maybe.
Most oral cancer drugs stipulate that they should be taken in a fasting state, but some actually have better bioavailability when taken with food. This is particularly true for the new prostate cancer drug abiraterone acetate (Zytiga), which has a greater interaction with food than any other marketed drug, yet it is labeled to be taken when fasting.
These points are highlighted in a comment published in the October 20 issue of the Journal of Clinical Oncology by Mark J. Ratain, MD, professor of medicine and director of the Center for Personalized Therapeutics at the University of Chicago, Illinois.
"My major concern is safety," Dr. Ratain told Medscape Medical News. "Very few patients would anticipate that the consequences of taking their medications with food...would be an effective overdose."
In the case of abiraterone acetate, the dose of the drug could be increased 10-fold by eating breakfast half an hour after taking the drug, he writes.
Dr. Ratain notes that food interactions are described in the labeling of many drugs, but are notably absent in the labeling of new oral cancer agents.
Most drugs can be taken either with or without food, he explains, because the effects of food are not clinically significant to drug absorption. There are cases in which absorption is decreased by food; generally, the labeling on those drugs instructs that they be taken on an empty stomach. Similarly, labeling on drugs for which absorption is enhanced by food typically instructs that they be ingested with meals.
"However, a recent study of oral agents approved by the US Food and Drug Administration [FDA] in the last 10 years demonstrated that oral oncology drugs have generally been labeled fasting, despite food effects as large as a 4-fold increase in bioavailability," Dr. Ratain notes.
Bias in Labeling?
This apparent bias for fasting labeling in cancer drugs is exemplified with abiraterone, he notes. Abiraterone, which was approved earlier this year in the United States for the treatment of metastatic prostate cancer, has a greater food interaction than any drug currently on the market. Depending on the fat content, food can increase drug exposure 5- to 10-fold, yet it is labeled to be taken in a fasting state, Dr. Ratain points out.
The effect of a high-fat meal indicates "that absolute bioavailability in the fasting state is no more than 10%," says Dr. Ratain, and is likely due to the low absorption rate under fasting conditions; 77% of the drug is excreted as abiraterone (or its prodrug acetate) in the stool.
"In addition, there is marked interindividual pharmacokinetic variability, with a coefficient of variation in the plasma concentration area under the curve of 59% under labeled conditions," he notes.
It is unclear why this faulty labeling is occurring, or why the FDA has not been more stringent about proper labeling for oral oncology drugs, Dr. Ratain said. He told Medscape Medical Newsthat the FDA has not responded to his inquiries and "essentially stonewalled" him because of the confidentiality of their discussions with sponsors.
"The blame could be assigned to sponsors, the Office of Oncology Drug Products, and/or the Office of Clinical Pharmacology and Biopharmaceutics," he said. "Given that there are multiple sponsors, all of whom who have a different approach to oncology..., the evidence points to an FDA origin."
Oral Drugs Relatively New
Alex Adjei, MD, PhD, who was approached by Medscape Medical News for independent comment, explained that until recently, oncology drugs have generally been given intravenously; for other diseases, oral drugs have been in common use for many years.
Perhaps that is why there has not been that much attention on the food-effect data, Dr. Adjei hypothesized. He is chair of the Department of Medicine at Roswell Park Cancer Institute, in Buffalo, New York.
"In clinical trials, we tend to give the drugs on an empty stomach," he said. "So that was how the drug was tested and that was how it was approved. We don't go back and change the label."
Dr. Adjei pointed out that unlike intravenous drugs, there is considerable variation in the way oral drugs are absorbed. "We try to simplify it by giving them on an empty stomach," he said.
Food-Effect Data Ignored
In a study published last year (Clin Cancer Res. 2010;16:4446-4451), Dr. Ratain and his colleague, Soonmo Peter Kang, MD, also from the University of Chicago, evaluated the effect of food on 99 oral agents that received FDA approval from January 2000 to May 2009. They compared food-labeling patterns between oncology and nononcology drugs using Fisher's exact test.
Food had a significant effect on drug bioavailability in 34 of the 99 drugs evaluated. In cases where food markedly enhanced bioavailability, 8 of 9 nononcology drugs were labeled to be taken with food to take advantage of the food–drug interaction. However, all oncology agents were labeled to be taken in "fasted" states (P = .01).
"The food-labeling pattern of recently approved oral oncology drug products is inconsistent with fundamental principles of oral drug delivery," they write. "The labels of 3 agents (erlotinib, nilotinib, and lapatinib) minimized bioavailability through food restrictions, which is in contrast to the labeling principles used for all other classes of oral agents."
In an editorial that accompanied the study by Drs. Ratain and Kang (Clin Cancer Res. 2010;16:4305-4307), Rajul K. Jain, MD, from the University of Texas M.D. Anderson Cancer Center, Houston, and colleagues explained that the effects of food are complex, and that multiple factors determine final labeling recommendations. "When analyzing the label given to any product or product class, all of the potential influencing factors should be considered," they said.
They also noted that "sponsors are encouraged to conduct food-effect studies early in a product's development so the results can be implemented into larger clinical trials."
In his comment, Dr. Ratain refers back to that editorial, and points out that the agency has "expressed concern about the potential for high intraindividual variability in cancer patients resulting from variability in oral intake secondary to disease or concurrent medications." This appears to indicate a preference for labeling drugs to be used when fasting, even if their bioavailability would be substantially increased when taken with food.
He explains that there isn't any evidence that this concern applies to all oral oncology drugs, and that there is no evidence that intraindividual variability in diet is greater for cancer patients than for those with other life-threatening conditions who also take daily oral drugs.
"If the US Food and Drug Administration were truly concerned about intraindividual variability in diet, why has this never come up in the labeling of nononcology drugs?" he asks.
He notes that the FDA was aware of the food-effect data from early studies of abiraterone and could have required at least 1 randomized study to be conducted to review this, so that it could have been labeled to be taken with food. The FDA has the authority to require such studies as a postmarketing requirement, but chose not to.
With the risk for poor adherence to food-effect labeling, there is a risk for overdose or underdose of a given drug, with the more serious being overdose, Dr. Ratain says.
In addition to this safety issue, there are economic implications, Dr. Ratain notes.
The standard dose of abiraterone for men without liver problems is 1000 mg once daily. But because the bioavailability of the drug is greatly increased when taken with food, it would be interesting to have studies of abiraterone at a dose of 250 mg once daily, administered with a standard breakfast. If this approach is shown to be safe and effective, it could save patients and their payers approximately $3750 per month at current prices.
"It also would send a message to the pharmaceutical industry that flawed drug development has financial consequences," he notes, "along with potential risks of product liability because of defective labeling."
He concludes: "After all, given the high attrition rate for oncology drugs, do we really need to flush our few successful products down the toilet?"
Impracticalities of Dosing and Diet
Lawrence J. Lesko, PhD, FCP, former director of the Office of Clinical Pharmacology at the FDA's Center for Drug Evaluation and Research, and a coauthor of the editorial by Dr. Jain, pointed out that the principal of labeling is consistent safety.
"The most consistent way to take drugs is on an empty stomach," said Dr. Lesko, who is now at the Department of Pharmaceutics at the College of Pharmacy at the University of Florida in Gainesville. "It would be impractical to expect that patients are going to adhere to a specific diet when taking these drugs. And it is often unclear what 'food' may mean to the patient. Is it a glass of juice, breakfast cereal, a cheeseburger?"
The goal is to minimize the variability, he told Medscape Medical News. "Food studies are generally conducted in healthy volunteers and not cancer patients. Labeling can't be done on a theoretical basis; it has to reflect what was done in the study."
Dr. Lesko noted that another problem with tying an oral drug dose to food is that many cancer patients have problems with appetite, nausea and vomiting, and gastrointestinal motility. "Their appetite can change on any given day," he said. "Some days, they may not be able to tolerate a high-fat meal, for example, which raises the bioavailability of abiraterone. It would just be impractical to do this on a day-to-day basis."
The other issue that Dr. Ratain focuses on in his comment is the comparison of oncology and nononcology drugs, Dr. Lesko pointed out. "But you really can't compare them."
For most nononcologic agents, food doesn't matter, so it isn't that important how the product is labeled, he said.
But that is not the case with oral oncologic agents. "Every drug in oncology has a narrow therapeutic index, and taking the drug with food could affect the therapeutic range," he said. "The labels are intended to minimize variability and mimic approval data."

Two Recent Papers by Matt Metzgar

This is just a quick post to highlight two recent papers by the economist and fellow health writer Matt Metzgar.

The first paper is titled "The Feasibility of a Paleolithic Diet for Low-income Consumers", and is co-authored by Dr. Todd C. Rideout, Maelan Fontes-Villalba, and Dr. Remko S. Kuipers (1).  They found that a Paleolithic-type diet that meets all micronutrient requirements except calcium (which probably has an unnecessarily high RDA) costs slightly more money than a non-Paleolithic diet that fulfills the same requirements, but both are possible on a tight budget. 

The second paper is titled "Externalities From Grain Consumption: a Survey", with Matt Metzgar as the sole author (2).  He reviews certain positive and negative externalities due to the effects of grain consumption on health.  The take-home message is that refined grains are unhealthy and therefore costly to society, whole grains are better, but grains in general have certain healthcare-related economic costs that are difficult to deny, such as celiac disease.

There are a lot of ideas floating around on the blogosphere, some good and others questionable.  Composing a manuscript and submitting it to a reputable scientific journal is a good way to demonstrate that your idea holds water, and it's also a good way to communicate it to the scientific community.  The peer review process isn't perfect but it does encourage scientific rigor.  I think Metzgar is a good example of someone who has successfully put his ideas through this process.  Pedro Bastos, who also spoke at the Ancestral Health Symposium, is another example (3).

What Causes Insulin Resistance? Part II

In the last post, I described how cellular energy excess causes insulin resistance, and how this is triggered by whole-body energy imbalance.  In this post, I'll describe another major cause of insulin resistance: inflammation. 

Inflammation

In 1876, a German physician named W Ebstein reported that high doses of sodium salicylate could totally eliminate the signs and symptoms of diabetes in certain patients (Berliner Klinische Wochenschrift. 13:337. 1876). Following up on this work in 1901, the British physician RT Williamson reported that treating diabetic patients with sodium salicylate caused a striking decrease in the amount of glucose contained in the patients' urine, also indicating an apparent improvement in diabetes (2).  This effect was essentially forgotten until 1957, when it was rediscovered.

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CANCER DEATHS OVERTAKE HEART DISEASE IN CANADA

For the first time, cancer has overtaken heart disease as the number-one cause of death across Canada, according to the latest statistics here [1].
According to numbers released yesterday, cancer accounted for 29.6% of deaths (70 558) in 2008--the latest year for which stats have been made available by heath authorities. Heart disease caused 21.3% of deaths (50 722).
Stroke, in third place, caused 5.8% (13 870) of deaths.
Statistics from the previous year had cancer leading heart disease in every province and territory with the exception of Prince Edward Island and the Northwest Territories. In the 2008 statistics, heart disease has now moved into second place in every province/territory, with the exception of Nunavut, where suicide ranks second.
Between 2007 and 2008, cancer deaths climbed 1.4% nationally, continuing a trend seen since 2000. By contrast, heart-disease deaths declined between 2000 and 2006 but actually crept upward between 2007 and 2008.
Preliminary US numbers published by the US Centers for Disease Control and Prevention show that heart disease was still the leading cause of death for both 2008 and 2009, followed by malignant neoplasms, with both diseases declining in this period, although that decline was three times greater for heart disease [2].
In the UK, which has published 2010 causes of death for England and Wales, it is more difficult to draw comparisons, due to how diseases are grouped by statisticians there [3]. "Circulatory diseases" (which include heart disease and stroke, as well as venous and arterial diseases) were the leading cause of death and had declined since 2009. By contrast, deaths due to cancers and neoplasms, in the number-two position, had climbed slightly over the past year.
Commenting on the newly released Canadian statistics for heartwire , Dr Paul Armstrong(University of Calgary, AB) observed that there is both good news and bad in the numbers.
"I guess it's good news that we're making some progress in cardiovascular disease. And obviously if the burden of cardiovascular disease is relieved such that you are living longer, it's more likely that you're going to die of something else," he said.
But before anyone celebrates these numbers, Armstrong points out that despite progress in controlling risk factors such as hypertension and elevated cholesterol, Canada and other countries have not done so well in curbing the upward march of obesity and diabetes. Diabetes, he points out, is the number-six cause of death in Canada, and the number of diabetes deaths has climbed since 2000.
"I worry we could still see a second wave of [increased] heart-disease deaths as a result of the increasing prevalence of diabetes and obesity, although it's too soon to know," Armstrong said.
In response to a poll question on theheart.org this summer, 52% of respondents said they expected cancer to surpass heart disease as the world's number-one killer within the next 10 years.

What Causes Insulin Resistance? Part I

Insulin is an ancient hormone that influences many processes in the body.  Its main role is to manage circulating concentrations of nutrients (principally glucose and fatty acids, the body's two main fuels), keeping them within a fairly narrow range*.  It does this by encouraging the transport of nutrients into cells from the circulation, and discouraging the export of nutrients out of storage sites, in response to an increase in circulating nutrients (glucose or fatty acids). It therefore operates a negative feedback loop that constrains circulating nutrient concentrations.  It also has many other functions that are tissue-specific.

Insulin resistance is a state in which cells lose sensitivity to the effects of insulin, eventually leading to a diminished ability to control circulating nutrients (glucose and fatty acids).  It is a major contributor to diabetes risk, and probably a contributor to the risk of cardiovascular disease, certain cancers and a number of other disorders. 

Why is it important to manage the concentration of circulating nutrients to keep them within a narrow range?  The answer to that question is the crux of this post. 

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Does High Circulating Insulin Drive Body Fat Accumulation? Answers from Genetically Modified Mice

The house mouse Mus musculus is an incredible research tool in the biomedical sciences, due to its ease of care and its ability to be genetically manipulated.  Although mice aren't humans, they resemble us closely in many ways, including how insulin signaling works.  Genetic manipulation of mice allows researchers to identify biological mechanisms and cause-effect relationships in a very precise manner.  One way of doing this is to create "knockout" mice that lack a specific gene, in an attempt to determine that gene's importance in a particular process.  Another way is to create transgenic mice that express a gene of interest, often modified in some way.  A third method is to use an extraordinary (but now common) tool called "Cre-lox" recombination (1), which allows us to delete or add a single gene in a specific tissue or cell type. 

Studying the relationship between obesity and insulin resistance is challenging, because the two typically travel together, confounding efforts to determine which is the cause and which is the effect of the other (or neither).  Some have proposed the hypothesis that high levels of circulating insulin promote body fat accumulation*.  To truly address this question, we need to consider targeted experiments that increase circulating insulin over long periods of time without altering a number of other factors throughout the body.  This is where mice come in.  Scientists are able to perform precise genetic interventions in mice that increase circulating insulin over a long period of time.  These mice should gain fat mass if the hypothesis is correct. 

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The Brain Controls Insulin Action

Insulin regulates blood glucose primarily by two mechanisms:

1. Suppressing glucose production by the liver
2. Enhancing glucose uptake by other tissues, particularly muscle and liver

Since the cells contained in liver, muscle and other tissues respond directly to insulin stimulation, most people don't think about the role of the brain in this process.  An interesting paper just published in Diabetes reminds us of the central role of the brain in glucose metabolism as well as body fat regulation (1).  Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin's ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin's ability to cause muscle to take up glucose is mediated by its effect on the brain. 

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NEW GUIDELINES FOR REIRRADIATION OF HEAD AND NECK CANCER

When head and neck cancer recurs and surgery is not an option, reirradiation provides the only potentially curative option. However, because the tumor often recurs in the same place or very close to tissue that has already been irradiated, this treatment approach represents a "significant challenge."
For this reason, it should be handled at a tertiary-care center, according to a new guideline issued by the American College of Radiology. Specifically, it stipulates that the tertiary center should have a head and neck oncology team that is equipped with the resources and the experience to manage the complexities and toxicities of retreatment.
In the guideline, published in the International Journal of Radiation Oncology, Biology and Physics, a panel of experts outline appropriateness criteria for various clinical scenarios that arise with such patients.
"This is an important document because it is the first set of guidelines for the potentially curative treatment of patients who have regrowth of head and neck tumors. It provides a consensus on how patients should be managed," coauthor Madhur Kumar Garg, MD, said in a statement. Dr. Garg is from the Department of Radiation Oncology at Montefiore Medical Center, in the Bronx, New York, where about a dozen reirradiation procedures are performed annually.
Commitment to Retreatment
Retreatment is justified because clinical trial results have shown that local treatment improves overall survival, the panel of experts notes.
However, they emphasize that, before a commitment to retreatment is made, patients presenting with recurrent or second primary tumors need to undergo careful restaging evaluation. In addition to computed tomography (CT) or magnetic resonance imaging to evaluate the extent of the recurrent tumor, the panel urges that strong consideration be given to positron emission tomography with CT to evaluate for metastatic disease, or "at a minimum, a CT scan of the chest should be performed."
In addition, a detailed history and assessment is needed, which includes documentation of the sequelae of previous treatment, such as fibrosis, carotid stenosis, dysphagia, xerostomia, and osteoradionecrosis.
Retreatment options include surgical resection and palliative chemotherapy — both are regarded as standard of care, the panel writes. But for patients with unresectable disease, reirradiation is the "only potentially curative treatment," they add.
Two phase 2 clinical trials conducted by the Radiation Therapy Oncology Group (RTOG) have shown survival outcomes with reirradiation plus chemotherapy that appear to be superior to those seen with chemotherapy alone in other studies. However, "whether this apparent improvement is the result of selection bias is uncertain," the panel explains. A larger phase 3 comparing reirradiation plus chemotherapy with chemotherapy alone was closed because of poor accrual.
In terms of the dose of radiation delivered in the second treatment course, it appears that at least 50 to 60 Gy is needed, the experts report. Both of the phase 2 studies conducted by the RTOG delivered a total dose of 60 Gy, using an accelerated hyperfractionated regimen delivering 1.4 Gy twice daily in 4 week-on/week-off cycles. Multiple single-institution reports of reirradiation have used once-daily standard fractionation in a planned continuous treatment course with less toxicity, they note. However, differences in study designs and in the chemotherapy regimens make it difficult to discern what independent effect, if any, differences in radiation fractionation had on the toxicity that was seen.

Harvard Food Law Society "Forum on Food Policy" TEDx Conference

Last Friday, it was my pleasure to attended and present at the Harvard Food Law Society's TEDx conference, Forum on Food Policy.  I had never been to Cambridge or Boston before, and I was struck by how European they feel compared to Seattle.  The conference was a great success, thanks to the dedicated efforts of the Food Law Society's presidents Nate Rosenberg, Krista DeBoer, and many other volunteers. 

Dr. Robert Lustig gave a keynote address on Thursday evening, which I unfortunately wasn't able to attend due to my flight schedule.  From what I heard, he focused on practical solutions for reducing national sugar consumption, such as instituting a sugar tax.  Dr. Lustig was a major presence at the conference, and perhaps partially due to his efforts, sugar was a central focus throughout the day.  Nearly everyone agrees that added sugar is harmful to the nation's health at current intakes, so the question kept coming up "how long is it going to take us to do something about it?"  As Dr. David Ludwig said, "...the obesity epidemic can be viewed as a disease of technology with a simple, but politically difficult solution".

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Losing Fat With Simple Food-- Two Reader Anecdotes

Each week, I'm receiving more e-mails and comments from people who are successfully losing fat by eating simple (low reward) food, similar to what I described here.  In some cases, people are breaking through fat loss plateaus that they had reached on conventional low-carbohydrate, low-fat or paleo diets.  This concept can be applied to any type of diet, and I believe it is an important characteristic of ancestral food patterns.

At the Ancestral Health Symposium, I met two Whole Health Source readers, Aravind Balasubramanian and Kamal Patel, who were interested in trying a simple diet to lose fat and improve their health.  In addition, they wanted to break free of certain other high-reward activities in their lives that they felt were not constructive.  They recently embarked on an 8-week low-reward diet and lifestyle to test the effectiveness of the concepts.  Both of them had previously achieved a stable (in Aravind's case, reduced) weight on a paleo-ish diet prior to this experiment, but they still carried more fat than they wanted to.  They offered to write about their experience for WHS, and I thought other readers might find it informative.  Their story is below, followed by a few of my comments.

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The Case for the Food Reward Hypothesis of Obesity, Part II

In this post, I'll explore whether or not the scientific evidence is consistent with the predictions of the food reward hypothesis, as outlined in the last post.

Before diving in, I'd like to address the critique that the food reward concept is a tautology or relies on circular reasoning (or is not testable/falsifiable).  This critique has no logical basis.  The reward and palatability value of a food is not defined by its effect on energy intake or body fatness.  In the research setting, food reward is measured by the ability of food or food-related stimuli to reinforce or motivate behavior (e.g., 1).  In humans, palatability is measured by having a person taste a food and rate its pleasantness in a standardized, quantifiable manner, or sometimes by looking at brain activity by fMRI or related techniques (2).  In rodents, it is measured by observing stereotyped facial responses to palatable and unpalatable foods, which are similar to those seen in human infants.  It is not a tautology or circular reasoning to say that the reinforcing value or pleasantness of food influences food intake and body fatness. These are quantifiable concepts and as I will explain, their relationship with food intake and body fatness can be, and already has been, tested in a controlled manner. 

1.   Increasing the reward/palatability value of the diet should cause fat gain in animals and humans

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CHEMOTHERAPY CAN BE USED SAFELY AFTER FIRST TRIMESTER OF PREGNANCY

A cancer diagnosis can be devastating, but is even more traumatic when the patient is pregnant. A new study offers some reassurance to pregnant patients and their physicians.
The results of the small study, presented during a presidential session here at the 2011 European Multidisciplinary Cancer Congress, show that children who were exposed to chemotherapy in utero did not appear to suffer any detrimental effects in terms of general health and neurologic and cardiac functioning.
Treating cancer in pregnant women is complex. One issue, in particular, is the ethics of treating a woman with chemotherapy, "but there are no good data that describe the ethics," said lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium.
In Europe, there are approximately 2500 to 5000 cases of cancer diagnosed during pregnancy every year; however, it remains unclear how systemic chemotherapy affects the development of the fetus, he said.
This is a common situation, and one that many doctors face, said Michael Baumann, MD, PhD, a radiation oncologist from the University of Technology, Dresden, Germany, and president of the European CanCer Organisation. "That is why this study is so important," he said.
There are a lot of data related to radiotherapy and its use in pregnancy, said Dr. Baumann, who moderated a press briefing during which the highlights of this study were presented. " That there are now good data on chemotherapy.... This is a paradigm shift that we see here."
Neuro and Cardiac Function Normal
In their study, Dr. Amant and colleagues looked at the potential negative effects of in utero exposure to chemotherapy. Participants ranged in age from 18 months to 18 years. Of the 140 children currently in the study, complete data are available for 70.
The children were all evaluated at birth and approximately every 2 years after. Their general health was assessed, and they underwent neuropsychologic testing to assess intelligence, verbal and nonverbal memory, attention, working memory, and behavior.
The mean gestational age at cancer diagnosis was 18.1 weeks, and a total of 236 cycles of chemotherapy were given in the cohort.
About half of the women were diagnosed with breast cancer (51%), and 26% were diagnosed with hematologic cancers. Other diagnoses included cervical cancer, ovarian cancer, and malignancies of the brain, skin, and colorectum. Half of the patients (50%) received chemotherapy, and 38% underwent surgery and received chemotherapy. Treatment was given at a median gestational age of 17 weeks (range, 12 to 37 weeks).
The median gestational age of the children at birth was 35.7 weeks, and intrauterine growth retardation was observed in almost 21% of the children.
Cardiac function was evaluated by electrocardiography and echocardiography. It was necessary to assess for possible cardiac problems because the majority of these women were given anthracyclines, explained Dr. Amant. In breast and gynecologic cancers, "anthracyclines are very important. The majority of children — almost 80% — were exposed to anthracyclines, which can pass through the placenta, so it is very important to assess heart function."
The median follow-up was almost 2 years, although some were followed for up to 18 years.
At birth, no congenital heart defects were observed, and cardiac function was normal. Most of the children had adequate neurologic function and normal cardiac function, explained Dr. Amant; rates were similar to those seen in the general population.
High Rate of Premature Birth
Premature birth was very common in this population, with 47 of the 70 children born before 40 weeks of gestation (66%), and 7 born at 26 to 32 weeks.
Although cognitive development was in the normal range for the majority of the cohort, children who fell below the normal parameters tended to be premature. Because developmental delay is common in children who are premature, Dr. Amant explained, they are unable to tell if these issues are related to chemotherapy exposure.
"We can't exclude the effects of chemotherapy in preterm children," he told Medscape Medical News. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."
Because the majority of the children have done well, Dr. Amant surmised that the cognitive issues in those born premature are not related to the chemotherapy.
Normal findings were observed in 64 children (91.4%), which conforms to the general population.
Developmental Issues in Twins
Two serious problems emerged with a set of twins who were born at 32.5 weeks of gestation. The mother had been treated for leukemia. The male twin was autistic and had other serious neurodevelopmental delays and problems; the female twin also had some degree of neurodevelopmental delay.
Although prenatal exposure to chemotherapeutic agents cannot be completely ruled out, Dr. Amant feels that it was probably not the cause of the severe problems observed in the male twin. Geneticists who studied the data tend to think that the child had some sort of syndrome, he pointed out, which was not related to the chemotherapy. "But we can't rule it out right now," he said.
The high rate of prematurity seen in this study was not caused by chemotherapy, but was most likely related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.
Chemotherapy Should Not Be Feared
"Our message is that we prefer to give chemotherapy until the baby is mature; after the baby is delivered, we continue maternal treatment," said Dr. Amant. "The baby loses 2.5 IQ points for each week that he or she is delivered early."
"We think that the baby has less trauma from chemotherapy than from prematurity," he explained. "In our setting, this changes how we treat patients."
This is not a perfect study, Dr. Amant acknowledged; it was both retrospective and prospective, and had a relatively short follow-up.
"But we think that the fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," Dr. Amant explained.
More Data Needed
"We are quite confident that these children will continue to perform normally, but we need more follow-up and more children," he said. "Right now, the group is too small to make a statement on clinical practice change."
George Pentheroudakis, MD, PhD, who acted as discussant for the paper, agrees that a longer follow-up is needed.
Although the study showed that chemotherapy can be administered with reasonable safety after the first trimester of pregnancy, there are still a number of unanswered questions, noted Dr. Pentheroudakis, who is from the University of Ioannina, Greece.
There are a few children in the study with severe neurocognitive deficits, he pointed out, noting that more careful interpretation of the results is needed. In addition, the "course of these deficits over time" need to be determined.
Undetected cardiac toxicity is a potential problem for these children. Although the electrocardiogram and echocardiogram are good tools, they might not be sensitive enough for the early detection of subclinical cardiac damage, he said.
Also, there was a high incidence of prematurity in the cohort. "What are the causes of prematurity," he wondered. "Is it maternal age, the presence of cancer,...or the cancer treatment that was administered?
Much is still unknown about the long-term effects of chemotherapy exposure, said Dr. Pentheroudakis. "We don't know about fertility or germ cell mutagenesis in the children and their future offspring. More data are needed."
For now, on the basis of these data, the fear of chemotherapy is not a reason to delay treatment that can affect maternal prognosis, he said. "It seems that chemotherapy can be administered with reasonable safety after the first trimester, and there is emerging evidence that the mid- and long-term health of these children is normal."

The Case for the Food Reward Hypothesis of Obesity, Part I

Introduction

When you want to investigate something using the scientific method, first you create a model that you hope describes a natural phenomenon-- this is called a hypothesis.  Then you go about testing that model against reality, under controlled conditions, to see if it has any predictive power.  There is rarely a single experiment, or single study, that can demonstrate that a hypothesis is correct.  Most important hypotheses require many mutually buttressing lines of evidence from multiple research groups before they're widely accepted.  Although it's not necessary, understanding the mechanism by which an effect occurs, and having that mechanism be consistent with the hypothesis, adds substantially to the case.

With that in mind, this post will go into greater detail on the evidence supporting food reward and palatability as major factors in the regulation of food intake and body fatness.  There is a large amount of supportive evidence at this point, which is rapidly expanding due to the efforts of many brilliant researchers, however for the sake of clarity and brevity, so far I've only given a "tip of the iceberg" view of it.  But there are two types of people who want more detail: (1) the skeptics, and (2) scientifically inclined people who want mechanism.  This post is for them.  It will get technical at times, as there is no other way to convey the material effectively.

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Humans on a Cafeteria Diet

In the 1970s, as the modern obesity epidemic was just getting started, investigators were searching for new animal models of diet-induced obesity.  They tried all sorts of things, from sugar to various types of fats, but none of them caused obesity as rapidly and reproducibly as desired*.  1976, Anthony Sclafani tried something new, and disarmingly simple, which he called the "supermarket diet": he gave his rats access to a variety of palatable human foods, in addition to standard rodent chow.  They immediately ignored the chow, instead gorging on the palatable food and rapidly becoming obese (1).  Later renamed the "cafeteria diet", it remains the most rapid and effective way of producing dietary obesity and metabolic syndrome in rodents using solid food (2).

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TWICE DAILY ASPIRIN MAY BE BETTER FOR DIABETICS

Twice-daily aspirin administration, but not a once-daily doubling of the dose, appears to provide good inhibition of platelet cyclooxygenase (COX)-1 in diabetic patients who have rapid recovery of COX-1 activity and might enhance cardiovascular protection, Francesco Zaccardi, MD, a diabetology fellow at Catholic University of Sacred Heart in Rome, Italy, reported here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting.
Aspirin is currently recommended for cardiovascular protection for patients with type 2 diabetes mellitus, regardless of prior vascular events. But primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition. Italian researchers, led by Dr. Zaccardi, investigated glycemic control and other factors as possible reasons for the incomplete inhibition of thromboxane A₂ by low-dose aspirin over 24 hours. Thromboxane A₂, a product of COX-1 activity, is prothrombotic.
The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B₂, the hydrolysis product of thromboxane A₂ and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients underwent 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily (n = 11), 200 mg daily (n = 11), or 100 mg twice daily for 28 days (n = 11). Recovery of COX-1 activity was determined on day 29 during the 12- to 24-hour dosing period.
The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. For the patients in the lowest tertile of recovery of activity, serum thromboxane B₂ increased in the 12- to 24-hour period by 0.02 ng/mL per hour (range, 0.01 to 0.03 ng/mL per hour), compared with an increase of 0.14 ng/mL per hour (range, 0.11 to 0.20 ng/mL per hour) for the tertile with the fastest recovery.
Independent predictors of the slope of thromboxane B₂ recovery were mean platelet volume (MPV) (P < .0001), higher body mass index (BMI) (P = .007), and age (P = .049). None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B₂.
In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. Compared with 100 mg once daily, the once-daily administration of 200 mg of aspirin reduced the slope of the recovery line by 55%, and 100 mg of aspirin twice daily reduced the slope by 88% (P < .05 for each vs 100 mg once daily).
Considering the predictive effect of MPV, Dr. Zaccardi surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Furthermore, BMI might affect the pharmacokinetics after aspirin dosing. He concluded that twice-daily aspirin administration can overcome the inadequate thromboxane B₂ inhibition seen with once-daily dosing. He advised performing larger, randomized clinical trials to test the safety and effectiveness of this approach.
Since it is not feasible to measure COX-1 activity or thromboxane B₂ in routine clinical practice, Dr. Zaccardi told Medscape Medical News that in the future, we will likely "have to focus more attention on BMI, on age, and on MPV, because it's very easy to measure BMI and to obtain the value of MPV from a single blood analysis."
In summary, he said that an important finding of the study is that "one third of type 2 diabetic patients are poor responders to aspirin, and probably they need twice-daily administration of aspirin." He speculated that the one third of patients who are poor responders to aspirin might have diluted out an effect in the other two thirds in primary prevention trials, possibly accounting for the failure of those trials to show efficacy.
With twice-daily dosing, compliance could be a problem. A slow-release formulation of 200 mg of aspirin could be helpful, but does not now exist, Dr. Zaccardi said. Session cochair Michael Cummings, MD, professor of diabetes and endocrinology in Portsmouth, United Kingdom, said he doubts that adding 1 more pill a day for an elderly type 2 diabetic patient on multiple medications already would present much of an additional problem.
He noted that guidelines in the United States and in Europe focus on using once-daily aspirin, so the study is intriguing for its use of twice-daily dosing, which has not been studied previously. "The implications of the study could be that a simple change to the way that we dose aspirin at the moment — [twice-daily] dosing — could lead to different clinical outcomes, and could perhaps have more pronounced cardiovascular benefits than we're seeing with once-daily aspirin," he said, "particularly in patients with type 2 diabetes."
Dr. Cummings noted that it is becoming increasingly apparent that how and when drugs are administered can change outcomes. As an example, he cited recent work showing that nighttime dosing of antihypertension drugs is probably better than taking them in the morning.
Dr. Cummings advised that future trials of aspirin in people with type 2 diabetes will need to look at cardiovascular outcomes, not just mechanisms of platelet inhibition. Dr. Zaccardi agreed, and said that in light of current good regimens for glycemic, cholesterol, and blood pressure control, "what we have to improve is the problem of [platelet] aggregation in diabetic patients. It is probable that this study could represent a solution...[to] the reduced ability of aspirin to block COX-1."

Primal Docs

Chris Armstrong, creator of the website Celiac Handbook, has designed a new non-commercial website called Primal Docs to help people connect with ancestral health-oriented physicians.  It's currently fairly small, but as more physicians join, it will become more useful.  If you are a patient looking for such a physician in your area, or an ancestral health-oriented physician looking for more exposure, it's worth having a look at his site:

Primal Docs

Update 9/22: apparently there is already another website that serves a similar purpose and has many more physicians enrolled: Paleo Physicians Network.

MASTECTOMY OFFERS NO SURVIVAL ADVANTAGE IN YOUNG WOMEN

Lumpectomy with adjuvant radiation and mastectomy provide "equivalent" overall and disease-specific survival in young women with early breast cancer, according to a new study presented at a press conference today in advance of the start of the 2011 Breast Cancer Symposium.
Young women "should not choose a mastectomy based on the assumption of improved survival," said lead investigator Usama Mahmood, MD, who was at the University of Maryland in Baltimore when the study was undertaken.
"Young age alone does not mandate mastectomy," commented Andrew Seidman, MD, from Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press briefing. His comments related to this study and another reported at the briefing, which found similar rates of local recurrence with the 2 competing surgical approaches.
Using the Surveillance, Epidemiology, and End Results (SEER) database, Dr. Mahmood and colleagues reviewed outcomes among 14,760 women aged 20 to 39 years who were diagnosed with early-stage breast cancer (T1-2, N0-1, M0) between 1990 and 2007.
The women underwent breast-conserving therapy (45%; lumpectomy and radiation treatment) or mastectomy (55%). Everyone in the breast conservation group received adjuvant radiation, but only 17% of the mastectomy group received radiation.
A multivariable analysis that included tumor characteristics found that breast-conserving therapy resulted in similar overall survival (hazard ratio [HR], 0.93; P = .16) and breast cancer–specific survival (HR, 0.93; P = .26) as mastectomy, said Dr. Mahmood, who is now a fellow in radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Median follow-up duration was 5.7 years.
A matched-pair analysis involving a subset of 4644 of the patients confirmed no difference in overall survival and disease-specific survival, he also said. The patients were matched according to specific factors such as tumor size, tumor grade, and number of positive nodes.
In this analysis, at 5, 10, and 15 years, the overall survival rates for the breast conservation group were 92.5%, 83.5%, and 77%, respectively. For patients who underwent mastectomy, overall survival rates were 91.9%, 83.6%, and 79.1%, respectively. Breast cancer–specific survival rates were also similar between the 2 groups of women, said Dr. Mahmood.
The study's importance is, in part, due to other research findings, suggested Dr. Mahmood. A series of studies presented in the 1980s comparing breast-conserving therapy and mastectomy found equivalent survival among women with early breast cancer. But the number of young women in those studies was small, he said.
Other research has not encouraged the use of breast-conserving therapy in young women, he suggested.
"Previous studies have shown that young women with breast cancer treated with breast-conservation therapy experience higher local recurrence rates," he said. However, those findings were challenged by another study presented at the press conference. The combination of 2 new studies "should make us question that mastectomy is the only option for young women with breast cancer," said Dr. Seidman, who added the caveat that BRCA status is also a key to decision-making in young women.
The new study "serves as a reminder that women should be counseled appropriately about their treatment options," said Dr. Mahmood.
"The data is the data"
The factors included in the multivariate analysis included year of diagnosis, age, race/ethnicity, tumor grade, progesterone receptor status, tumor size, and lymph node status, noted the study authors. Patients had no more than 3 positive nodes, added Dr. Mahmood.
These are standard factors to consider when assessing breast cancer, suggested Dr. Seidman.
The new analysis did not include a number of factors that might also be used to make treatment decisions in the clinic, he further suggested. For instance, there are biological and luminal subtypes, as well the oncotype recurrence score, all of which may help clinicians and patients in their decision-making, he said.
"But most of us don't think about using that information as a decisive factor in the decision to undergo mastectomy or breast conservation therapy," Dr. Seidman said about these more recently identified breast cancer characteristics and newer tests.
Magnetic resonance imaging (MRI) may or may not have an important role to play in this decision-making process, he suggested. It is used to evaluate breast cancer in the preoperative setting to "better select" patients for the type of surgery, he said.
However, whether or not the use of MRI confers a survival advantage is "not settled," according to Dr. Seidman. "There is an epidemic of breast MRI," he said, quoting his colleague Monica Morrow, MD, from Memorial-Sloan Kettering Cancer Center.
"The data is the data," he said about the study, suggesting that any equivocations about the results and any missing factors in the analysis were not merited.
The investigators have disclosed no relevant financial relationships.

Fat Tissue Insulin Sensitivity and Obesity

In this post, I'll discuss a few more facts pertaining to the idea that elevated insulin promotes the accumulation of fat mass.  

Insulin Action on Fat Cells Over the Course of Fat Gain

The idea that insulin acts on fat cells to promote obesity requires that insulin suppress fat release in people with more fat (or people who are gaining fat) to a greater extent than in lean people.  As I have written before, this is not the case, and in fact the reverse is true.  The fat tissue of obese people fails to normally suppress fatty acid release in response to an increase in insulin caused by a meal or an insulin injection, indicating that insulin's ability to suppress fat release is impaired in obesity (1, 2, 3).  The reason for that is simple: the fat tissue of obese people is insulin resistant.

There has been some question around the blogosphere about when insulin resistance in fat tissue occurs.  Is it only observed in obese people, or does it occur to a lesser extent in people who carry less excess fat mass and are perhaps on a trajectory of fat gain?  To answer this question, let's turn the clocks back to 1968, a year before Neil Armstrong first set foot on the moon. 

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How to Kegel Exercises

The Kegel is the name of a pelvic floor exercise, in honor of Dr. Kegel who discovered the exercise in 1948. I call "invisible year", because you can do when no one can say. Kegels are a series of exercises that can help strengthen the muscles pubococcygeus muscles (PC). They come from your pubic bone, go on their genitals and attach to your coccyx. Men and women have.

After pelvic surgery, pregnancy, or even as we grow older, the muscles lose tone. This can cause loss of bladder control, incontinence, also called loose vagina, (especially after having a child), an inability to control the ejaculation in boys, and reduced sexual pleasure for men and women.

There are several ways to do Kegel exercises. A method requires that you have a full bladder, sit on the toilet and starting to urinate, then suddenly, repress and stop the flow. Start and stop several times in a row. If you cannot shut down the flow of urine, dribble, but you have to start Kegel exercises, for sure. From now on, whenever you urinate start and stop the whole path. This is often called a "tap" and is a good indicator of your progress.

You can also do Kegels right on your desktop, even now. Tighten your PC muscles and hold for a count of eight, then they release slowly and repeat eight times. Yes, you can do these sitting on your computer or your desk at work or school. (But do not be distracted from their teacher or boss). If you can't go to eight or ten at the beginning, use a smaller number and do what you build up to ten.

Another good time to do Kegels is when you are a passenger in a car. Whenever you stop at red lights, a little, but you will.

This not only improve bladder control, but with regular Kegel exercises will improve your sex life. After doing Kegel exercises, a woman will be able to repress and arrest your partner's penis, to increase their sexual pleasures. You men should see an improvement in "intensity" of your erections and ejaculations. These exercises are also recommended for the guys who know the ejaculation. As the penis is not a muscle, increase in muscle tone will improve the blood supply, resulting in firmer erections and also help the man to delay ejaculation. Kegel exercises can also help prevent leakage of urine when sneezing or coughing!

Hyperinsulinemia: Cause or Effect of Obesity?

Is Elevated Insulin the Cause or Effect of Obesity?

The carbohydrate hypothesis, in its most popular current incarnation, states that elevated insulin acts on fat cells to cause fat storage, leading to obesity.  This is due to its ability to increase the activity of lipoprotein lipase and decrease the activity of hormone-sensitive lipase, thus creating a net flux of fat into fat cells.  I'm still not sure why this would be the case, considering that fat tissue becomes more insulin resistant as body fat accumulates, therefore insulin action on it is not necessarily increased.  Total fat release from fat tissue increases with total fat mass (1), demonstrating that insulin is not able to do its job of suppressing fat release as effectively in people who carry excess fat.  But let's put that problem aside for the moment and keep trucking.

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STATINS-A GOOD MEDICINE

Long-term results of the Anglo-Scandinavian Cardiac Outcomes--Lipid-Lowering Arm (ASCOT-LLA) study, eight years after the trial officially stopped, showed that treatment with 10 mg of atorvastatin (Lipitor, Pfizer) reduced all-cause mortality compared with placebo, mainly through a reduction in noncardiovascular deaths [1].
Presenting the results at a hot-line session today at the European Society of Cardiology (ESC) 2011 Congress, investigators observed that reductions in the risk of death from respiratory illness and infection contributed to the overall reduction in all-cause mortality. "The numbers are large, the data are convincing, but we have no definitive explanation to date for the hypothesized legacy effect of atorvastatin on noncardiovascular-death risk reduction," said lead investigator Dr Peter Sever (Imperial College, London, UK).
The study was published online August 28, 2011 in the European Heart Journal to coincide with the ESC presentation.
Chair of the hot-line session, Dr George Parcharidis (Aristotle University of Thessaloniki, Greece), asked, somewhat tongue-in-cheek, whether the data were sufficiently strong to support prescribing all young adults a statin for long-term treatment in the hope of reducing all-cause mortality. "They say that one swallow does not make a summer, and I would never advocate atorvastatin to young people on the basis of these findings," responded Sever. "But what these findings do demand is a prospective study in patients at high risk for infection to determine whether the presence of a statin could reduce serious sepsis or death from serious infectious illness."
ASCOT-LLA and the Long-Term Effects of Atorvastatin
The results of ASCOT-LLA were first presented and simultaneously published online in theLancet in 2003 [2]. As reported by heartwire , lipid lowering with atorvastatin resulted in a significant 36% reduction in the primary end point of fatal coronary heart disease and nonfatal MI after a median follow-up of 3.3 years. At the time the study was stopped, there was a nonsignificant trend toward reduction in all-cause mortality. Upon completion of ASCOT-LLA, investigators continued to collect mortality data and evaluated the mortality outcomes in participants originally randomized to atorvastatin or placebo in the ASCOT-LLA arm for a median of 11 years.
At the end of the extended follow-up, all-cause mortality was significantly reduced by 14% (hazard ratio [HR] 0.86; 95% CI 0.76–0.98), and noncardiovascular mortality was significantly reduced by 15% (HR 0.85; 95% CI 0.73–0.99). There was no difference in death from cardiovascular causes.
Looking more closely at deaths from noncardiovascular causes, investigators found that deaths due to cancer were not statistically significant between those treated with atorvastatin vs placebo. There was, however, a significant 36% reduction in deaths due to infection and respiratory illness (HR 0.64; 95% CI 0.42–0.97), driven primarily by deaths due to infection.
During the session, Sever noted there are emerging data on the effects of statins on infection, with preclinical studies showing statins modulate neutrophil function, reduce proinflammatory cytokine release, improve vascular function, have antithrombotic properties, and improve outcomes from pneumonia and sepsis. Results of other observational studies have suggested that prior statin use reduces mortality from sepsis. Despite these observations, Sever said that there is still the possibility of confounding bias in some of the observational studies that have shown a benefit of statins in pneumonia and sepsis and that caution should be used when interpreting such results until a randomized clinical trial is performed.
Serious Decision for Primary Prevention Patients
Dr Guy De Backer (University Hospital, Ghent, Belgium), the discussant who also wrote an editorial that accompanies the published study [3], said that the introduction of statins into primary prevention is a serious decision considering that asymptomatic patients would be advised to take a drug for the rest of their lives and the only treatment benefit would be that "nothing happens." Moreover, there is little long-term safety data. For these primary-prevention trials, the mean patient age is 55 to 66 years old and the median length of statin use is just under five years, and yet primary-prevention patients would likely be treated with a statin for 15 to 20 years.
For this reason, the long-term ASCOT-LLA study is welcome, said De Backer. In primary-prevention studies, the most important clinical outcome is total mortality and quality of life, he added. One of the reassuring results of ASCOT-LLA is that the results confirm the benefits observed in the Scandinavian Simvastatin Survival Study (4S) and West of Scotland Prevention Study (WOSCOPS). In 4S, WOSCOPS, and ASCOT-LLA, there were significant 15%, 12%, and 14% reductions in all-cause mortality, respectively--all achieving statistical significance. He added that data suggesting a therapeutic role for statins in the management of pneumonia and sepsis are supported by observational studies.
Still, De Backer, like Sever, urges caution in interpreting the findings, especially because there is no explanation for the long-term carryover effect of statins on all-cause mortality but not on cardiovascular mortality. The data are essentially a subgroup analysis, and the reduction in all-cause mortality might be the result of chance, De Backer added. Quoting Dr Peter Sleight (Oxford University, UK), De Backer said, "Subgroup analyses are fun to look at, but don't believe them."

Catered Paleo Dinner with Yours Truly

Gil Butler, organizer of the Western Washington Paleo Enthusiasts group, has organized a catered "paleo" dinner on Sunday, October 9th.  He will be screening the first episode of "Primal Chef", Featuring Robb Wolf and others.  He invited me to give a short (20 minute) presentation, which I accepted.  There are still roughly 30 spots remaining [update 9/21-- the event is full].

The event will be in the Ballard neighborhood of Seattle and the price is $15.76 per person.  I will not be paid for this talk, it's just an opportunity to share ideas and meet people. 

Click here to register.

Book Review: The End of Overeating

The End of Overeating was written based on the personal journey of Dr. David A. Kessler (MD) to understand the obesity epidemic, and treat his own obesity in the process.  Kessler was the FDA commissioner under presidents George HW Bush and Bill Clinton.  He is known for his efforts to regulate cigarettes, and his involvement in modernizing Nutrition Facts labels on packaged food.  He was also the dean of Yale medical school for six years-- a very accomplished person. 

Kessler's book focuses on 1) the ability of food with a high palatability/reward value to cause overeating and obesity, 2) the systematic efforts of the food industry to maximize food palatability/reward to increase sales in a competitive market, and 3) what to do about it.  He has not only done a lot of reading on the subject, but has also participated directly in food reward research himself, so he has real credibility.  The End of Overeating is not the usual diet book baloney. 
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ACTIVE SURVEILLANCE IN LOW RISK PROSTATE CANCER

There is now an "emerging consensus" that supports the use of initial active surveillance in low-risk prostate cancer, according to an essay published online August 8 in the Journal of Clinical Oncology.

At the same time, active surveillance is a "relatively uncommon management strategy," admit the essayists, led by Matthew Cooperberg, MD, from the University of California, San Francisco (UCSF).

Two related challenges have limited the widespread acceptance of active surveillance, say Dr. Cooperberg and his prominent coauthors, Peter Carroll, MD, also from UCSF, and Laurence Klotz, MD, from the University Toronto in Ontario, Canada.

In their essay on the "progress and promise" of active surveillance, the trio identify these 2 big challenges as problems in "defining eligibility" (i.e., who should be followed with active surveillance) and "identifying progression" (i.e., when this strategy should be stopped and replaced with active treatment).

They also introduce a host of other impediments to acceptance of the strategy, including economics. "Active surveillance is labor intensive and reimbursed relatively poorly," they write.

The essayists dramatically cite another retarding factor: patients. For some men, despite all educational efforts of a clinician, "the conversation about surveillance ends at the word cancer," they say.

Dr. Cooperberg and colleagues do not directly say that the practice of urology is at fault for the lack of uptake of active surveillance, but they allude to some responsibility, saying that "cultural biases in favor of aggressive treatment" might be at play.

The behavior of urologists is an important consideration, suggested a medical oncologist not involved with the essay.

"Urologists have been taught that the right way to treat cancer is to take it out," said Richard Lam, MD, from Prostate Oncology Specialists in Marina del Rey, California. This 3-physician practice, which treats about 1500 men with prostate cancer, is headed by medical director Mark Scholz, MD, author of Invasion of the Prostate Snatchers (2010, Other Press), a scathing indictment of the mainstream approach to prostate cancer.

Dr. Lam maintains that urologists "have not been taught to not take out prostate cancer."

"It's almost in their DNA to take it out," he told Medscape Medical News.

"Active surveillance is not a concept that they cannot grasp," said Dr. Lam about urologists. "The question is," he continued, "whether or not the basic principles [of active surveillance] are followed."

"There is very little likelihood that a cancer that is destined to be cured will not be cured if active surveillance is done," Dr. Lam asserts.

However, this is a major concern, as Brantley Thrasher, MD, from the University of Kansas Medical Center in Kansas City, and a spokesperson for the American Urological Association, pointed out in a previous interview with Medscape Medical News.

"Once you know there is a cancer, you have to be very careful," Dr. Thrasher noted. If the patient opts for active surveillance but then is noncompliant with regular follow-up tests, and a metastatic prostate cancer is discovered after a few years, then there is danger — especially in the litigious environment of the United States — of a claim of medical negligence, because there might have been a window of opportunity for curative treatment that was missed, he explained.

Dr. Cooperberg and colleagues also cite "medicolegal" risks as a retardant to the uptake of active surveillance.

But Dr. Lam said that, with a patient who is carefully oriented to active surveillance, "we are not very concerned about lawsuits."

Patient Education Could Change Things

Dr. Lam said that the essay by Dr. Cooperberg and colleagues is "well balanced," and adds that he has admired and followed Dr. Klotz's pioneering work in active surveillance "for years."

But Dr. Lam emphasized the need for patient education about active surveillance, and said that he and his colleagues at Prostate Oncology Specialists work hard to educate patients.

Among the 1500 men with prostate cancer attending their practice, about 400 are on active surveillance.

"It takes a lot of time and empathy to communicate the concept that most prostate cancer is a slow growing disease that doesn't kill people," he said.

"Urologists don't do this," Dr. Lam said.

Education is the key to patient acceptance of active surveillance, he asserted. Foremost, patients need to know that active surveillance is "not a case of writing them off," said Dr. Lam, who provided an example of the kind of simple teaching he uses.

He explains to patients that one of the criteria for judging the appropriateness of active surveillance is the "amount" of cancer. Patients with low-risk cancer are told that as the amount increases, their risk increases. They are asked to think of low-risk prostate cancer as a "marble."

"People don't die of a cancer that is the size of a marble," he explains to patients. If it increases to the size of a "ping pong ball," they will continue to watch and biopsy it. And they take out the cancer that is "like a basketball."

One of the investigators in the Surveillance Therapy Against Radical Treatment (START) trial, the first-ever North American phase 3 trial comparing active surveillance and treatment, also suggested that education can shape patients' attitudes.

When enrolling men for START, Adam Kibel, MD, from the Washington University School of Medicine in St. Louis, Missouri, found that, once educated, "many patients end up being concerned about possibly being randomized to treatment."

Reflecting on "Reflexive" Treatment

Dr. Cooperberg and colleagues make numerous references to the fact that the current approach to the care of men with low-risk prostate cancer is in need of repair.

"In contemporary practice in the United States, diagnosis tends to lead to treatment; thus, as the proportion of prostate cancers diagnosed with low-risk characteristics has grown, overdiagnosis has been associated with high rates of overtreatment," they write.

Overdiagnosis and overtreatment are likely to increase with the American Urological Association's new recommendation to begin screening at age 40 years for most men, they suggest.

Autopsy series have shown that 30% of men in their 30s have histologic evidence of prostate cancer, Dr. Cooperberg and his coauthors point out. Thus, it is especially important that "reflexive treatment should be avoided for young men with low-risk disease, whose period of tumor latency may be prolonged."

In general, urologists need to stop offering surgery to everyone with prostate cancer, suggest the essayists. "Reflexive radical treatment of all new diagnoses is increasingly difficult to justify," they write.

There is evidence now that active surveillance is a sound initial strategy in low-risk prostate cancer. "The data to date are sufficient to conclude that most men with low-risk disease — and likely most with intermediate-risk disease and significant comorbidity — should be offered at least a trial of active surveillance," they write.

Who are the best candidates?

"The obvious candidate for active surveillance is an older man with low-risk prostate cancer," the essayists write. Dr. Lam pointed out that older men with comorbidities such as heart disease, who are less likely to be referred to surgery as a result, are especially obvious candidates.

The essayists concur and further qualify this point. "Cancer risk, comorbidity, and life expectancy should receive greater consideration than chronologic age per se in treatment decision making."

How to define risk progression in this setting is "equally challenging," say the essayists. "Overall, grade progression seems to be the most consistent driver of progression," they write. However, "none" of the end points used to measure progression is "entirely satisfactory."

A Roadmap to Obesity

In this post, I'll explain my current understanding of the factors that promote obesity in humans.  

Heritability

To a large degree, obesity is a heritable condition.  Various studies indicate that roughly two-thirds of the differences in body fatness between individuals is explained by heredity*, although estimates vary greatly (1).  However, we also know that obesity is not genetically determined, because in the US, the obesity rate has more than doubled in the last 30 years, consistent with what has happened to many other cultures (2).  How do we reconcile these two facts?  By understanding that genetic variability determines the degree of susceptibility to obesity-promoting factors.  In other words, in a natural environment with a natural diet, nearly everyone would be relatively lean, but when obesity-promoting factors are introduced, genetic makeup determines how resistant each person will be to fat gain.  As with the diseases of civilization, obesity is caused by a mismatch between our genetic heritage and our current environment.  This idea received experimental support from an interesting recent study (3).

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