My blog is being mercilessly ripped off by cheesy feed aggregators that are using my material for commercial gain, often without attribution. I was able to ignore them when there were only one or two, and when they appeared far down the list on Google searches. But at this point, there are 20+ rip-off sites that ride my coattails under questionable circumstances, and are getting decent Google rankings, so I've had enough. I'm changing my feed settings so that I only partially syndicate my posts, and I'm adding a short plagiarism warning to each post.
What that means is that if you're using an RSS reader, you'll have to click through to my blog to read my material in full. I apologize for the inconvenience, but I don't see any other solution.
Read more »
Selasa, 10 Mei 2011
Minggu, 08 Mei 2011
Ask Me a Question
On May 13th, I'll be recording a podcast with Chris Kresser of The Healthy Skeptic. Chris interviewed me about a year ago, and I thought it went well. Chris is a good host and asks interesting questions.
This time around, we're going to do things a bit differently. I'll start with a little overview of my current thoughts on obesity, then we'll answer reader questions. The show is going to be mostly about obesity and related matters, but I may answer a couple of questions that aren't related to obesity if they're especially interesting. There are two ways to leave questions: either in the comments section of this post, or the comments section of Chris's post. The show will air on May 24th.
Read more »
This time around, we're going to do things a bit differently. I'll start with a little overview of my current thoughts on obesity, then we'll answer reader questions. The show is going to be mostly about obesity and related matters, but I may answer a couple of questions that aren't related to obesity if they're especially interesting. There are two ways to leave questions: either in the comments section of this post, or the comments section of Chris's post. The show will air on May 24th.
Read more »
Jumat, 06 Mei 2011
Food Reward: a Dominant Factor in Obesity, Part II
How to Make a Rat Obese
Rodents are an important model organism for the study of human obesity. To study obesity in rodents, you have to make them fat first. There are many ways to do this, from genetic mutations, to brain lesions, to various diets. However, the most rapid and effective way to make a normal (non-mutant, non-lesioned) rodent obese is the "cafeteria diet." The cafeteria diet first appeared in the medical literature in 1976 (1), and was quickly adopted by other investigators. Here's a description from a recent paper (2):
Investigators have known for decades that the cafeteria diet is a highly effective way of producing obesity in rodents, but what was interesting about this particular study from my perspective is that it compared the cafeteria diet to three other commonly used rodent diets: 1) standard, unpurified chow; 2) a purified/refined high-fat diet; 3) a purified/refined low-fat diet designed as a comparator for the high-fat diet. All three of these diets were given as homogeneous pellets, and the textures range from hard and fibrous (chow) to soft and oily like cookie dough (high-fat). The low-fat diet contains a lot of sugar, the high-fat diet contains a modest amount of sugar, and the chow diet contains virtually none. The particular high-fat diet in this paper (Research Diets D12451, 45% fat, which is high for a rat) is commonly used to produce obesity in rats, although it's not always very effective. The 60% fat version is more effective.
Consistent with previous findings, rats on every diet consumed the same number of calories over time... except the cafeteria diet-fed rats, which ate 30% more than any of the other groups. Rats on every diet gained fat compared to the unpurified chow group, but the cafeteria diet group gained much more than any of the others. There was no difference in fat gain between the purified high-fat and low-fat diets.
So in this paper, they compared two refined diets with vastly different carb:fat ratios and different sugar contents, and yet neither equaled the cafeteria diet in its ability to increase food intake and cause fat gain. The fat, starch and sugar content of the cafeteria diet was not able to fully explain its effect on fat gain. However, each diets' ability to cause fat gain correlated with its respective food reward qualities. Refined diets high in fat or sugar caused fat gain in rats relative to unpurified chow, but were surpassed by a diet containing a combination of fat, sugar, starch, salt, free glutamate (umami), interesting textures and pleasant and invariant aromas.
Although the cafeteria diet is the most effective at causing obesity in rodents, it's not commonly used because it's a lot more work than feeding pellets, and it introduces a lot of variability into experiments because each rat eats a different combination of foods.
How to Make an Obese Human Lean
In 1965, the Annals of the New York Academy of Sciences published a very unusual paper (3). Here is the stated goal of the investigators:
It's a machine that dispenses bland liquid food through a straw, at the push of a button. They don't give any information on the composition of the liquid diet, beyond remarking that "carbohydrate supplied 50 per cent of the calories, protein 20 per cent and fat 30 per cent. the formula contained vitamins and minerals in amount adequate for daily maintenance."
Volunteers were given access to the machine and allowed to consume as much of the liquid diet as they wanted, but no other food. Since they were in a hospital setting, the investigators could be confident that the volunteers ate nothing else.
The first thing they report is what happened when they fed two lean people using the machine, for 16 or 9 days. Both of them maintained their typical calorie intake (~3,075 and ~4,430 kcal per day) and maintained a very stable weight during this period.
Next, the investigators did the same experiment using two "grossly obese" volunteers. Again, they were asked to "obtain food from the machine whenever hungry." Over the course of the first 18 days, the first (male) volunteer consumed a meager 275 calories per day. The second (female) volunteer consumed a ridiculously low 144 calories per day over the course of 12 days, losing 23 pounds. Without showing data, the investigators remarked that an additional three obese volunteers "showed a similar inhibition of calorie intake when fed by machine."
The first volunteer continued eating bland food from the machine for a total of 70 days, losing approximately 70 pounds. After that, he was sent home with the formula and instructed to drink 400 calories of it per day, which he did for an additional 185 days, after which his total weight loss was 200 lbs. The investigators remarked that "during all this time weight was steadily lost and the patient never complained of hunger or gastrointestinal discomfort." This is truly a starvation-level calorie intake, and to eat it continually for 255 days without hunger suggests that something rather interesting was happening in this man's body.
This machine-feeding regimen was nearly as close as one can get to a diet with no rewarding properties whatsoever. Although it contained carbohydrate and fat, it did not contain any flavor or texture to associate them with, and thus the reward value of the diet was minimized. As one would expect if food reward influences the body fat setpoint, lean volunteers maintained starting weight and a normal calorie intake, while their obese counterparts rapidly lost a massive amount of fat and reduced calorie intake dramatically without hunger. This suggests that obesity is not entirely due to a "broken" metabolism (although that may still contribute), but also at least in part to a heightened sensitivity to food reward in susceptible people. This also implies that obesity may not be a disorder, but rather a normal response to the prevailing dietary environment in affluent nations.
A second study by Dr. Michel Cabanac in 1976 confirmed that reducing food reward (by feeding bland food) lowers the fat mass setpoint in humans, using a clever method that I won't discuss for the sake of brevity (4). I learned about both of these studies through the writing of Dr. Seth Roberts, author of The Shangri-La Diet. I'd also like to thank Dr. Stephen Benoit, a researcher in the food reward field, for talking through these ideas with me to make sure I wasn't misinterpreting them.
I'd like to briefly remark that there's an anatomical basis for the idea of two-way communication between brain regions that determine reward and those that control body fatness. It's well known that the latter influence the former (think about your drive to obtain food after you've just eaten a big meal vs. after you've skipped a meal), but there are also connections from the former to the latter via a brain region called the lateral hypothalamus. The point is that it's anatomically plausible that food reward determines in part the amount of body fat a person carries.
Some people may be inclined to think "well, if food tastes bad, you eat less of it; so what!" Although that may be true to some extent, I don't think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently. To me, that implies that highly rewarding food increases the body fat setpoint in susceptible people, and that food with few rewarding properties allows them to return to a lean state.
In the next few posts, I'll describe how food reward explains the effectiveness of many popular fat loss diets, I'll describe how this hypothesis fits in with the diets and health of non-industrial cultures, and I'll outline new dietary strategies for preventing and treating obesity and certain forms of metabolic dysfunction.
Rodents are an important model organism for the study of human obesity. To study obesity in rodents, you have to make them fat first. There are many ways to do this, from genetic mutations, to brain lesions, to various diets. However, the most rapid and effective way to make a normal (non-mutant, non-lesioned) rodent obese is the "cafeteria diet." The cafeteria diet first appeared in the medical literature in 1976 (1), and was quickly adopted by other investigators. Here's a description from a recent paper (2):
In this model, animals are allowed free access to standard chow and water while concurrently offered highly palatable, energy dense, unhealthy human foods ad libitum.In other words, they're given an unlimited amount of human junk food in addition to their whole food-based "standard chow." In this particular paper, the junk foods included Froot Loops, Cocoa Puffs, peanut butter cookies, Reese's Pieces, Hostess Blueberry MiniMuffins, Cheez-its, nacho cheese Doritos, hot dogs, cheese, wedding cake, pork rinds, pepperoni slices and other industrial delicacies. Rats exposed to this food almost completely ignored their healthier, more nutritious and less palatable chow, instead gorging on junk food and rapidly attaining an obese state.
Investigators have known for decades that the cafeteria diet is a highly effective way of producing obesity in rodents, but what was interesting about this particular study from my perspective is that it compared the cafeteria diet to three other commonly used rodent diets: 1) standard, unpurified chow; 2) a purified/refined high-fat diet; 3) a purified/refined low-fat diet designed as a comparator for the high-fat diet. All three of these diets were given as homogeneous pellets, and the textures range from hard and fibrous (chow) to soft and oily like cookie dough (high-fat). The low-fat diet contains a lot of sugar, the high-fat diet contains a modest amount of sugar, and the chow diet contains virtually none. The particular high-fat diet in this paper (Research Diets D12451, 45% fat, which is high for a rat) is commonly used to produce obesity in rats, although it's not always very effective. The 60% fat version is more effective.
Consistent with previous findings, rats on every diet consumed the same number of calories over time... except the cafeteria diet-fed rats, which ate 30% more than any of the other groups. Rats on every diet gained fat compared to the unpurified chow group, but the cafeteria diet group gained much more than any of the others. There was no difference in fat gain between the purified high-fat and low-fat diets.
So in this paper, they compared two refined diets with vastly different carb:fat ratios and different sugar contents, and yet neither equaled the cafeteria diet in its ability to increase food intake and cause fat gain. The fat, starch and sugar content of the cafeteria diet was not able to fully explain its effect on fat gain. However, each diets' ability to cause fat gain correlated with its respective food reward qualities. Refined diets high in fat or sugar caused fat gain in rats relative to unpurified chow, but were surpassed by a diet containing a combination of fat, sugar, starch, salt, free glutamate (umami), interesting textures and pleasant and invariant aromas.
Although the cafeteria diet is the most effective at causing obesity in rodents, it's not commonly used because it's a lot more work than feeding pellets, and it introduces a lot of variability into experiments because each rat eats a different combination of foods.
How to Make an Obese Human Lean
In 1965, the Annals of the New York Academy of Sciences published a very unusual paper (3). Here is the stated goal of the investigators:
The study of food intake in man is fraught with difficulties which result from the enormously complex nature of human eating behavior. In man, in contrast to lower animals, the eating process involves an intricate mixture of physiologic, psychologic, cultural and esthetic considerations. People eat not only to assuage hunger, but because of the enjoyment of the meal ceremony, the pleasures of the palate and often to gratify unconscious needs that are hard to identify. Because of inherent difficulties in studying human food intake in the usual setting, we have attempted to develop a system that would minimize the variables involved and thereby improve the chances of obtaining more reliable and reproducible data.Here's a photo of their "system":
It's a machine that dispenses bland liquid food through a straw, at the push of a button. They don't give any information on the composition of the liquid diet, beyond remarking that "carbohydrate supplied 50 per cent of the calories, protein 20 per cent and fat 30 per cent. the formula contained vitamins and minerals in amount adequate for daily maintenance."Volunteers were given access to the machine and allowed to consume as much of the liquid diet as they wanted, but no other food. Since they were in a hospital setting, the investigators could be confident that the volunteers ate nothing else.
The first thing they report is what happened when they fed two lean people using the machine, for 16 or 9 days. Both of them maintained their typical calorie intake (~3,075 and ~4,430 kcal per day) and maintained a very stable weight during this period.
Next, the investigators did the same experiment using two "grossly obese" volunteers. Again, they were asked to "obtain food from the machine whenever hungry." Over the course of the first 18 days, the first (male) volunteer consumed a meager 275 calories per day. The second (female) volunteer consumed a ridiculously low 144 calories per day over the course of 12 days, losing 23 pounds. Without showing data, the investigators remarked that an additional three obese volunteers "showed a similar inhibition of calorie intake when fed by machine."
The first volunteer continued eating bland food from the machine for a total of 70 days, losing approximately 70 pounds. After that, he was sent home with the formula and instructed to drink 400 calories of it per day, which he did for an additional 185 days, after which his total weight loss was 200 lbs. The investigators remarked that "during all this time weight was steadily lost and the patient never complained of hunger or gastrointestinal discomfort." This is truly a starvation-level calorie intake, and to eat it continually for 255 days without hunger suggests that something rather interesting was happening in this man's body.
This machine-feeding regimen was nearly as close as one can get to a diet with no rewarding properties whatsoever. Although it contained carbohydrate and fat, it did not contain any flavor or texture to associate them with, and thus the reward value of the diet was minimized. As one would expect if food reward influences the body fat setpoint, lean volunteers maintained starting weight and a normal calorie intake, while their obese counterparts rapidly lost a massive amount of fat and reduced calorie intake dramatically without hunger. This suggests that obesity is not entirely due to a "broken" metabolism (although that may still contribute), but also at least in part to a heightened sensitivity to food reward in susceptible people. This also implies that obesity may not be a disorder, but rather a normal response to the prevailing dietary environment in affluent nations.
A second study by Dr. Michel Cabanac in 1976 confirmed that reducing food reward (by feeding bland food) lowers the fat mass setpoint in humans, using a clever method that I won't discuss for the sake of brevity (4). I learned about both of these studies through the writing of Dr. Seth Roberts, author of The Shangri-La Diet. I'd also like to thank Dr. Stephen Benoit, a researcher in the food reward field, for talking through these ideas with me to make sure I wasn't misinterpreting them.
I'd like to briefly remark that there's an anatomical basis for the idea of two-way communication between brain regions that determine reward and those that control body fatness. It's well known that the latter influence the former (think about your drive to obtain food after you've just eaten a big meal vs. after you've skipped a meal), but there are also connections from the former to the latter via a brain region called the lateral hypothalamus. The point is that it's anatomically plausible that food reward determines in part the amount of body fat a person carries.
Some people may be inclined to think "well, if food tastes bad, you eat less of it; so what!" Although that may be true to some extent, I don't think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently. To me, that implies that highly rewarding food increases the body fat setpoint in susceptible people, and that food with few rewarding properties allows them to return to a lean state.
In the next few posts, I'll describe how food reward explains the effectiveness of many popular fat loss diets, I'll describe how this hypothesis fits in with the diets and health of non-industrial cultures, and I'll outline new dietary strategies for preventing and treating obesity and certain forms of metabolic dysfunction.
Kamis, 28 April 2011
Food Reward: a Dominant Factor in Obesity, Part I
A Curious Finding
It all started with one little sentence buried in a paper about obese rats. I was reading about how rats become obese when they're given chocolate Ensure, the "meal replacement drink", when I came across this:
As I explained in previous posts, the human (and rodent) brain regulates the amount of fat the body carries, in a manner similar to how the brain regulates blood pressure, body temperature, blood oxygenation and blood pH (2). That fact, in addition to several other lines of evidence, suggests that obesity probably results from a change in this regulatory system. I refer to the amount of body fat that the brain defends as the "body fat setpoint", however it's clear that the setpoint is dependent on diet and lifestyle factors. The implication of this paper that I could not escape is that a food's flavor influences body fatness and probably the body fat setpoint.
An Introduction to Food Reward
The brain contains a sophisticated system that assigns a value judgment to everything we experience, integrating a vast amount of information into a one-dimensional rating system that labels things from awesome to terrible. This is the system that decides whether we should seek out a particular experience, or avoid it. For example, if you burn yourself each time you touch the burner on your stove, your brain will label that action as bad and it will discourage you from touching it again. On the other hand, if you feel good every time you're cold and put on a sweater, your brain will encourage that behavior. In the psychology literature, this phenomenon is called "reward," and it's critical to survival.
The brain assigns reward to, and seeks out, experiences that it perceives as positive, and discourages behaviors that it views as threatening. Drugs of abuse plug directly into reward pathways, bypassing the external routes that would typically trigger reward. Although this system has been studied most in the context of drug addiction, it evolved to deal with natural environmental stimuli, not drugs.
As food is one of the most important elements of survival, the brain's reward system is highly attuned to food's rewarding properties. The brain uses input from smell, taste, touch, social cues, and numerous signals from the digestive tract* to assign a reward value to foods. Experiments in rats and humans have outlined some of the qualities of food that are inherently rewarding:
The human brain evolved to deal with a certain range of rewarding experiences. It didn't evolve to constructively manage strong drugs of abuse such as heroin and crack cocaine, which overstimulate reward pathways, leading to the pathological drug seeking behaviors that characterize addiction. These drugs are "superstimuli" that exceed our reward system's normal operating parameters. Over the next few posts, I'll try to convince you that in a similar manner, industrially processed food, which has been professionally crafted to maximize its rewarding properties, is a superstimulus that exceeds the brain's normal operating parameters, leading to an increase in body fatness and other negative consequences.
* Nerves measure stomach distension. A number of of gut-derived paracrine and endocrine signals, including CCK, PYY, ghrelin, GLP-1 and many others potentially participate in food reward sensing, some by acting directly on the brain via the circulation, and others by signaling indirectly via the vagus nerve. More on this later.
It all started with one little sentence buried in a paper about obese rats. I was reading about how rats become obese when they're given chocolate Ensure, the "meal replacement drink", when I came across this:
...neither [obesity-prone] nor [obesity-resistant] rats will overeat on either vanilla- or strawberry-flavored Ensure.The only meaningful difference between chocolate, vanilla and strawberry Ensure is the flavor, yet rats eating the chocolate variety overate, rapidly gained fat and became metabolically ill, while rats eating the other flavors didn't (1). Furthermore, the study suggested that the food's flavor determined, in part, what amount of fatness the rats' bodies "defended."
As I explained in previous posts, the human (and rodent) brain regulates the amount of fat the body carries, in a manner similar to how the brain regulates blood pressure, body temperature, blood oxygenation and blood pH (2). That fact, in addition to several other lines of evidence, suggests that obesity probably results from a change in this regulatory system. I refer to the amount of body fat that the brain defends as the "body fat setpoint", however it's clear that the setpoint is dependent on diet and lifestyle factors. The implication of this paper that I could not escape is that a food's flavor influences body fatness and probably the body fat setpoint.
An Introduction to Food Reward
The brain contains a sophisticated system that assigns a value judgment to everything we experience, integrating a vast amount of information into a one-dimensional rating system that labels things from awesome to terrible. This is the system that decides whether we should seek out a particular experience, or avoid it. For example, if you burn yourself each time you touch the burner on your stove, your brain will label that action as bad and it will discourage you from touching it again. On the other hand, if you feel good every time you're cold and put on a sweater, your brain will encourage that behavior. In the psychology literature, this phenomenon is called "reward," and it's critical to survival.
The brain assigns reward to, and seeks out, experiences that it perceives as positive, and discourages behaviors that it views as threatening. Drugs of abuse plug directly into reward pathways, bypassing the external routes that would typically trigger reward. Although this system has been studied most in the context of drug addiction, it evolved to deal with natural environmental stimuli, not drugs.
As food is one of the most important elements of survival, the brain's reward system is highly attuned to food's rewarding properties. The brain uses input from smell, taste, touch, social cues, and numerous signals from the digestive tract* to assign a reward value to foods. Experiments in rats and humans have outlined some of the qualities of food that are inherently rewarding:
- Fat
- Starch
- Sugar
- Salt
- Meatiness (glutamate)
- The absence of bitterness
- Certain textures (e.g., soft or liquid calories, crunchy foods)
- Certain aromas (e.g., esters found in many fruits)
- Calorie density ("heavy" food)
The human brain evolved to deal with a certain range of rewarding experiences. It didn't evolve to constructively manage strong drugs of abuse such as heroin and crack cocaine, which overstimulate reward pathways, leading to the pathological drug seeking behaviors that characterize addiction. These drugs are "superstimuli" that exceed our reward system's normal operating parameters. Over the next few posts, I'll try to convince you that in a similar manner, industrially processed food, which has been professionally crafted to maximize its rewarding properties, is a superstimulus that exceeds the brain's normal operating parameters, leading to an increase in body fatness and other negative consequences.
* Nerves measure stomach distension. A number of of gut-derived paracrine and endocrine signals, including CCK, PYY, ghrelin, GLP-1 and many others potentially participate in food reward sensing, some by acting directly on the brain via the circulation, and others by signaling indirectly via the vagus nerve. More on this later.
Senin, 25 April 2011
PROBIOTIC REDUCES RECURRENT URINARY TRACT INFECTION
In a randomized, double-blind phase 2 study, an intravaginal probiotic composed of Lactobacillus crispatus CTV-05 (Lactin-V, Osel Inc) reduced the rate of recurrent urinary tract infection (rUTI) in UTI-prone women by roughly one half, which compares favorably with historical data on antimicrobial prophylaxis, the researchers say.
They add that larger trials are warranted to see whether use of vaginal Lactobacillus could replace long-term antimicrobial preventive treatments in women susceptible to rUTI.
The study was published online April 15 and in the May 15 print issue of Clinical Infectious Diseases.
UTIs are common in women and frequently recur, Ann Stapleton, MD, from the University of Washington in Seattle, and colleagues note in their report. It has been shown, they add, that women with rUTIs often have alterations in vaginal microbiota, including depletion of lactobacilli.
A phase 1 study of Lactobacillus crispatus CTV-05 showed that the probiotic can be given as a vaginal suppository with minimal adverse effects to healthy women with a history of rUTI. In the phase 2 study, 100 premenopausal women (median age, 21 years) with a history of rUTI received antimicrobials for acute UTI and then were randomly assigned to receive eitherLactobacillus crispatus CTV-05 or placebo vaginal suppository gelatin capsules administered once daily for 5 days, followed by once weekly for 10 weeks.
"We found that Lactin-V reduced the risk of rUTI approximately as effectively as antimicrobial prophylaxis, achieved high-level vaginal colonization in most women, and was well tolerated," Dr. Stapleton and colleagues report.
According to the investigators, culture-confirmed rUTI occurred in 7 (15%) of 48 of women who received Lactobacillus crispatus CTV-05 compared with 13 (27%) of 48 women who received placebo (relative risk [RR], .5; 95% confidence interval [CI], .2 - 1.2).
A high level of vaginal colonization with L crispatus throughout follow-up was associated with a significant reduction in rUTI only among women receiving Lactobacillus crispatus CTV-05 (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01).
The safety profile of the probiotic mirrored that seen in the phase 1 study. Adverse effects were reported by 56% of women receiving Lactobacillus crispatus CTV-05 and 50% of those receiving placebo. The most common adverse effects included vaginal discharge or itching or moderate abdominal discomfort.
A novel aspect of this study, the authors say, is the application of quantitative polymerase chain reaction to assess vaginal microbiota after UTI. This enabled them to define sentinel changes in vaginal microbiota with or without the Lactobacillus crispatus CTV-05 probiotic.
Using quantitative polymerase chain reaction to assess L crispatus colonization in women in both study groups, the researchers say, allowed them to distinguish the natural recovery of the vaginal microbiota after UTI, as may have potentially occurred in the placebo group, from specific effects attributable to the probiotic.
What was "striking," the investigators add, was that placebo-treated women often had high concentrations of vaginal L crispatus during follow-up, yet this failed to protect them from rUTI (RR, 1.1; 95% CI, .4 - 3.1). In contrast, women who received Lactobacillus crispatus CTV-05 and achieved high colonization were protected from rUTI (RR, .07; 95% CI, .02 - .3; P < .01).
"Lactin-V after treatment for acute UTI," they conclude, "confers a significant advantage over repopulation of the vaginal microbiota with endogenous L. crispatus."
"Ongoing studies in our group are directed at understanding the mechanisms of protection in vivo and optimizing this prophylactic regimen," they note.
They add that larger trials are warranted to see whether use of vaginal Lactobacillus could replace long-term antimicrobial preventive treatments in women susceptible to rUTI.
The study was published online April 15 and in the May 15 print issue of Clinical Infectious Diseases.
UTIs are common in women and frequently recur, Ann Stapleton, MD, from the University of Washington in Seattle, and colleagues note in their report. It has been shown, they add, that women with rUTIs often have alterations in vaginal microbiota, including depletion of lactobacilli.
A phase 1 study of Lactobacillus crispatus CTV-05 showed that the probiotic can be given as a vaginal suppository with minimal adverse effects to healthy women with a history of rUTI. In the phase 2 study, 100 premenopausal women (median age, 21 years) with a history of rUTI received antimicrobials for acute UTI and then were randomly assigned to receive eitherLactobacillus crispatus CTV-05 or placebo vaginal suppository gelatin capsules administered once daily for 5 days, followed by once weekly for 10 weeks.
"We found that Lactin-V reduced the risk of rUTI approximately as effectively as antimicrobial prophylaxis, achieved high-level vaginal colonization in most women, and was well tolerated," Dr. Stapleton and colleagues report.
According to the investigators, culture-confirmed rUTI occurred in 7 (15%) of 48 of women who received Lactobacillus crispatus CTV-05 compared with 13 (27%) of 48 women who received placebo (relative risk [RR], .5; 95% confidence interval [CI], .2 - 1.2).
A high level of vaginal colonization with L crispatus throughout follow-up was associated with a significant reduction in rUTI only among women receiving Lactobacillus crispatus CTV-05 (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01).
The safety profile of the probiotic mirrored that seen in the phase 1 study. Adverse effects were reported by 56% of women receiving Lactobacillus crispatus CTV-05 and 50% of those receiving placebo. The most common adverse effects included vaginal discharge or itching or moderate abdominal discomfort.
A novel aspect of this study, the authors say, is the application of quantitative polymerase chain reaction to assess vaginal microbiota after UTI. This enabled them to define sentinel changes in vaginal microbiota with or without the Lactobacillus crispatus CTV-05 probiotic.
Using quantitative polymerase chain reaction to assess L crispatus colonization in women in both study groups, the researchers say, allowed them to distinguish the natural recovery of the vaginal microbiota after UTI, as may have potentially occurred in the placebo group, from specific effects attributable to the probiotic.
What was "striking," the investigators add, was that placebo-treated women often had high concentrations of vaginal L crispatus during follow-up, yet this failed to protect them from rUTI (RR, 1.1; 95% CI, .4 - 3.1). In contrast, women who received Lactobacillus crispatus CTV-05 and achieved high colonization were protected from rUTI (RR, .07; 95% CI, .02 - .3; P < .01).
"Lactin-V after treatment for acute UTI," they conclude, "confers a significant advantage over repopulation of the vaginal microbiota with endogenous L. crispatus."
"Ongoing studies in our group are directed at understanding the mechanisms of protection in vivo and optimizing this prophylactic regimen," they note.
Rabu, 20 April 2011
BRCA2 MUTATION LINKED TO BETTER SURVIVAL IN OVARIAN CANCER PATIENTS
Ovarian cancer patients with the BRCA2 gene mutation are more likely to survive their disease than those with the BRCA1 mutation and those without either mutation.
After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).
The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.
"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.
"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.
The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 andBRCA2 carriers and noncarriers that are driving this association."
Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.
Possible Treatment Implications
Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."
"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.
This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.
It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.
"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.
"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."
Survival Advantage for BRCA2 Carriers
In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 andBRCA2 mutations on ovarian cancer survival.
The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.
BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).
In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.
The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.
After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).
The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.
"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.
"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.
The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 andBRCA2 carriers and noncarriers that are driving this association."
Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.
Possible Treatment Implications
Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."
"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.
This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.
It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.
"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.
"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."
Survival Advantage for BRCA2 Carriers
In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 andBRCA2 mutations on ovarian cancer survival.
The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.
BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).
In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.
The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.
Senin, 18 April 2011
Upcoming Talks
I'll be giving at least two talks at conferences this year:Ancestral Health Symposium; "The Human Ecological Niche and Modern Health"; August 5-6 in Los Angeles. This is going to be a great conference. Many of my favorite health/nutrition writers will be presenting. Organizer Brent Pottenger and I collaborated on designing the symposium's name so I hope you like it.
My talk will be titled "Obesity; Old Solutions to a New Problem." I'll be presenting some of my emerging thoughts on obesity. I expect to ruffle some feathers!
Tickets are going fast so reserve one today! I doubt there will be any left two weeks from now.
TEDx Harvard Law; "Food Policy and Public Health"; Oct 21 at Harvard. My talk is tentatively titled "The American Diet: a Historical Perspective." This topic interests me because it helps us frame the discussion on why chronic disease is so prevalent today, and what are the appropriate public health measures to combat it. This should also be a great conference.
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