New post over at Mother Nature Obeyed:
More Attacks on Vitamin A
Tuesday, March 9, 2010
Wednesday, February 10, 2010
Does Meat Really Leach Calcium From the Bones?
I have a new blog post over at Mother Nature Obeyed on the Weston A. Price Foundation site:
Does Meat Really Leach Calcium From the Bones?
Enjoy!
Does Meat Really Leach Calcium From the Bones?
Enjoy!
Wednesday, January 27, 2010
When the Brain Is Hungry For Cholesterol
Those of you who have spent much time perusing my web site know that cholesterol is the limiting factor for the formation of synapses, connections between neurons that form the basis of learning and memory. In fact, one of the reasons we learn better when we get enough sleep is because the brain ramps up its production of cholesterol when we're getting our shut-eye.
Scientists have long thought that cholesterol in the plasma never enters the brain in significant amounts because its transport is blocked by the blood-brain barrier. In general, the brain produces its own cholesterol and, when that cholesterol's time is up the brain converts it to 24-hydroxy-cholesterol and sends it out with the trash.
An article in February's issue of Current Opinion in Lipidology, however, reviews two recent studies published last year showing that when the brain fails to make enough of its own cholesterol, it does in fact take it from the bloodstream.
In one study, researchers inactivated the gene for squalene synthase, the first enzyme committed to cholesterol synthesis, from the cells in the ventricular zone of the brains of mice. Progenitor cells in this region began producing new blood vessels that allowed them to acquire cholesterol from the bloodstream or from the neural tube.
In the other study, researchers inactivated a cholesterol transporter in glial cells. Glial cells support neurons in a variety of ways — one of them is to produce secretions rich in the cholesterol necessary for synapse formation. The brains of these mice partly made up for the resulting cholesterol deficiency by taking up more cholesterol esters from HDL particles in the bloodstream.
This concept, that when cholesterol made in the brain proves insufficient to meet the brain's needs the brain can compensate by taking cholesterol from the blood, goes a long way in explaining why all of the mental problems suffered by Smith-Lemli-Opitz Syndrome (SLOS) patients improve with dietary cholesterol. In fact, the FDA has even approved a pharmaceutical-grade cholesterol supplement to improve the retardation, hyperactivity, irritability, poor attention span, and tendency toward aggressive and self-injuring behavior seen in these children.
These findings are truly remarkable, because they open up the possibility that cholesterol in the bloodstream may support the brain in much less extreme cases of cholesterol deficiency and in many other undiscovered ways.
Scientists have long thought that cholesterol in the plasma never enters the brain in significant amounts because its transport is blocked by the blood-brain barrier. In general, the brain produces its own cholesterol and, when that cholesterol's time is up the brain converts it to 24-hydroxy-cholesterol and sends it out with the trash.
An article in February's issue of Current Opinion in Lipidology, however, reviews two recent studies published last year showing that when the brain fails to make enough of its own cholesterol, it does in fact take it from the bloodstream.
In one study, researchers inactivated the gene for squalene synthase, the first enzyme committed to cholesterol synthesis, from the cells in the ventricular zone of the brains of mice. Progenitor cells in this region began producing new blood vessels that allowed them to acquire cholesterol from the bloodstream or from the neural tube.
In the other study, researchers inactivated a cholesterol transporter in glial cells. Glial cells support neurons in a variety of ways — one of them is to produce secretions rich in the cholesterol necessary for synapse formation. The brains of these mice partly made up for the resulting cholesterol deficiency by taking up more cholesterol esters from HDL particles in the bloodstream.
This concept, that when cholesterol made in the brain proves insufficient to meet the brain's needs the brain can compensate by taking cholesterol from the blood, goes a long way in explaining why all of the mental problems suffered by Smith-Lemli-Opitz Syndrome (SLOS) patients improve with dietary cholesterol. In fact, the FDA has even approved a pharmaceutical-grade cholesterol supplement to improve the retardation, hyperactivity, irritability, poor attention span, and tendency toward aggressive and self-injuring behavior seen in these children.
These findings are truly remarkable, because they open up the possibility that cholesterol in the bloodstream may support the brain in much less extreme cases of cholesterol deficiency and in many other undiscovered ways.
Monday, January 25, 2010
What to Eat? Check Your Blood Sugar
Dr. William Davis is a practicing cardiologist in Milwaukee, Wisconsin. He publishes interesting thoughts and practical advice on his Heart Scan Blog. Recently, he suggested measuring your blood sugar one hour after meals in order to determine what foods are best for you. Meals that result in a blood sugar under 110 mg/dL one hour after eating are best. You can read the full blog here.
This makes a lot of sense to me, because there is great variation between individuals in the glycemic index of different foods. It could also indentify foods that put your body under stress.
I went to a seminar last year given by someone who had done research contributing to the development of a glycemic index (GI) database, and she concluded that the interindividual variation was so great that the index is almost useless.
The GI compares the rise in blood glucose after eating a food to the rise in blood glucose after consuming pure glucose. Generally, the GI is expressed as some percentage less than 100 because the body takes more time to break starches down into glucose or convert amino acids to glucose than it does to simply transport glucose from the intestines into the blood. However, in one case the researcher presented on, an individual had a much stronger rise in blood glucose after consuming white bread than after consuming glucose! Clearly, this person was not just breaking the bread down into glucose but also releasing stress hormones into his blood that would further rise his glucose levels by breaking down stored glycogen and converting his own protein into sugar. He may have been unaware of his adverse reaction to white bread, but it may have been doing damage to his body all along.
The $20 investment in a blood sugar monitor that Dr. Davis recommends may thus prove a useful investment for helping to determine your ideal diet.
This makes a lot of sense to me, because there is great variation between individuals in the glycemic index of different foods. It could also indentify foods that put your body under stress.
I went to a seminar last year given by someone who had done research contributing to the development of a glycemic index (GI) database, and she concluded that the interindividual variation was so great that the index is almost useless.
The GI compares the rise in blood glucose after eating a food to the rise in blood glucose after consuming pure glucose. Generally, the GI is expressed as some percentage less than 100 because the body takes more time to break starches down into glucose or convert amino acids to glucose than it does to simply transport glucose from the intestines into the blood. However, in one case the researcher presented on, an individual had a much stronger rise in blood glucose after consuming white bread than after consuming glucose! Clearly, this person was not just breaking the bread down into glucose but also releasing stress hormones into his blood that would further rise his glucose levels by breaking down stored glycogen and converting his own protein into sugar. He may have been unaware of his adverse reaction to white bread, but it may have been doing damage to his body all along.
The $20 investment in a blood sugar monitor that Dr. Davis recommends may thus prove a useful investment for helping to determine your ideal diet.
Friday, January 22, 2010
The Importance of Humility in Science -- A Philosophical Musing For the Weekend
Socrates once said, "All I know is that I know nothing." Centuries later, St. Paul, the great expounder of Christian theology, ethics, and mysticism, said that "any man who says he knows something does not yet know as he ought."
A very wise faculty member and department head of a science program I once spoke with told me that the more we learn as scientists the more we learn how little we know, and that he tells all his PhD students when they graduate to never brag about what they know but to go out into the world bragging about how little they know.
This type of humility is essential to science. Not simply to avoid the arrogance that often comes with knowledge, but because our understanding of the world around us often is, in fact, much more limited than we realize or want to believe.
In quantum mechanics, Werner Heisenberg (1901-1976) offered the Heisenberg Uncertainty Principle. Heisenberg showed that we cannot simultaneously determine an electron's position and momentum. The more we study the position, the less able we are to determine the momentum; the more we study the momentum, the less able we are to determine the position.
There is a similar principle that exists in nutrition. The greater the certainty with which we can determine cause and effect, the less certain we can be that our knowledge pertains to the real world. The more certain we are that our knowledge pertains to the real world, the lesser the certainty with which we can determine cause and effect.
Consider for a moment the "gold standard" of evidence for nutritional and medical treatments: the randomized controlled trial. It takes place, at least in part, in a laboratory or hospital setting. The subjects know they are being studied. They know they are receiving some type of treatment or placebo. They are getting their blood drawn. If we really want to understand cause and effect, the subjects may have to be placed in a metabolic ward, where their exercise and food intake is strictly controlled.
If the treatments really need placebos, this alone is a profound admission that every aspect of the study has a psychological impact with physiological consequences. Are the patients thinking the same things? Feeling the same way? Doing the same fun things, the same boring things? No. They may be bothered by blood drawings; they may be hopeful about treatments. They may be analyzing how they eat and exercise more closely. They may be conforming their behavior to the expectations of physicians and scientists.
Is the nutritional or medical treatment that proves effective within this type of setting effective in the real world? Is the one proven ineffective under this model without any effect in the real world? We simply don't know, and can't prove it one way or the other.
If we wish to study with great precision the detailed mechanisms of cause and effect, we turn to studying cells isolated in a petri dish, or we react molecules with molecules in a test tube. We thus establish with great certainty the laws of biochemical reactions but must then begin asking, to what extent does a test tube approximate the living environments within which such biochemicals ordinarily find themselves? To what extent does bathing a cell in a compound approximate the effect of eating it? Do immortalized, usually cancerous, cells behave the same way in a petri dish as normal, healthy cells behave as part of human tissue?
Consider, on the other hand, the observational study. Scientists observe free-living people doing what they would ordinarily do. In some cases the people may be enrolled in a study while in other cases they may not even know they are being studied. In these cases, we can be highly confident that the truths we obtain are applicable to the real world because it is that real world we are studying. Yet at the same time we lose our ability to determine cause and effect.
When all of the different types of evidence agree with each other, we may become more confident that we have discovered a universal truth. But there is always a degree of uncertainty underlying the knowledge we obtain in the field, and the more closely we study a phenomenon, the more we risk distorting it.
The job of the scientist is, of course, to develop models of studying phenomena that produce the least distortion of the real phenomenon. But the scientist also must exercise a healthy dose of humility, and admit that her or his knowledge is but a drop in the ocean of truth.
A very wise faculty member and department head of a science program I once spoke with told me that the more we learn as scientists the more we learn how little we know, and that he tells all his PhD students when they graduate to never brag about what they know but to go out into the world bragging about how little they know.
This type of humility is essential to science. Not simply to avoid the arrogance that often comes with knowledge, but because our understanding of the world around us often is, in fact, much more limited than we realize or want to believe.
In quantum mechanics, Werner Heisenberg (1901-1976) offered the Heisenberg Uncertainty Principle. Heisenberg showed that we cannot simultaneously determine an electron's position and momentum. The more we study the position, the less able we are to determine the momentum; the more we study the momentum, the less able we are to determine the position.
There is a similar principle that exists in nutrition. The greater the certainty with which we can determine cause and effect, the less certain we can be that our knowledge pertains to the real world. The more certain we are that our knowledge pertains to the real world, the lesser the certainty with which we can determine cause and effect.
Consider for a moment the "gold standard" of evidence for nutritional and medical treatments: the randomized controlled trial. It takes place, at least in part, in a laboratory or hospital setting. The subjects know they are being studied. They know they are receiving some type of treatment or placebo. They are getting their blood drawn. If we really want to understand cause and effect, the subjects may have to be placed in a metabolic ward, where their exercise and food intake is strictly controlled.
If the treatments really need placebos, this alone is a profound admission that every aspect of the study has a psychological impact with physiological consequences. Are the patients thinking the same things? Feeling the same way? Doing the same fun things, the same boring things? No. They may be bothered by blood drawings; they may be hopeful about treatments. They may be analyzing how they eat and exercise more closely. They may be conforming their behavior to the expectations of physicians and scientists.
Is the nutritional or medical treatment that proves effective within this type of setting effective in the real world? Is the one proven ineffective under this model without any effect in the real world? We simply don't know, and can't prove it one way or the other.
If we wish to study with great precision the detailed mechanisms of cause and effect, we turn to studying cells isolated in a petri dish, or we react molecules with molecules in a test tube. We thus establish with great certainty the laws of biochemical reactions but must then begin asking, to what extent does a test tube approximate the living environments within which such biochemicals ordinarily find themselves? To what extent does bathing a cell in a compound approximate the effect of eating it? Do immortalized, usually cancerous, cells behave the same way in a petri dish as normal, healthy cells behave as part of human tissue?
Consider, on the other hand, the observational study. Scientists observe free-living people doing what they would ordinarily do. In some cases the people may be enrolled in a study while in other cases they may not even know they are being studied. In these cases, we can be highly confident that the truths we obtain are applicable to the real world because it is that real world we are studying. Yet at the same time we lose our ability to determine cause and effect.
When all of the different types of evidence agree with each other, we may become more confident that we have discovered a universal truth. But there is always a degree of uncertainty underlying the knowledge we obtain in the field, and the more closely we study a phenomenon, the more we risk distorting it.
The job of the scientist is, of course, to develop models of studying phenomena that produce the least distortion of the real phenomenon. But the scientist also must exercise a healthy dose of humility, and admit that her or his knowledge is but a drop in the ocean of truth.
Thursday, January 21, 2010
The Journal of the American Medical Association Finally Questions Whether the FDA Should be Approving Useless No-Evidence Cholesterol-Lowering Drugs
After the Coronary Primary Prevention Trial, fittingly published in 1984, showed that cholestyramine, a drug that lowers cholesterol by causing its conversion to bile acids, could reduce the risk of heart attacks, cholesterol was widely villainized as a killer. From then on, the decades-old campaign of the American Heart Association against eggs and butter was vindicated in the press and the FDA began considering any drug that could effectively reduce cholesterol levels in the blood to be a preventer of heart attacks.
In truth, however, the evidence suggests that cholestyramine, while increasing the risk of dying from other diseases, lowers the risk of heart attacks not by lowering "cholesterol" but by clearing LDL from the bloodstream more quickly and thus reducing its interactions with free radicals that can oxidize, nitrate, and glycate it. Thus, the liver takes up healthy LDL and the immune system does not need to come and clean up the mess made by the toxic, damaged LDL. When the immune system has to come clean up such a mess, it forms arterial plaques.
For more information, see "High Cholesterol and Heart Disease — Myth or Truth?"
Nevertheless, the medical community has gone gung-ho not over reducing damage to LDL particles, but over lowering levels of LDL-associated cholesterol.
Thus when ezetimibe was released, a drug that suppresses absorption of dietary cholesterol, the FDA did not ask whether ezetimibe reduces oxidation, nitration, or glycation of LDL, nor did it ask whether ezetimibe can be proven to prevent heart attacks. Instead, it simply approved the drug as prevention for heart disease based on the sole evidence that it lowers cholesterol.
A recent study in the New England Journal of Medicine, however, strongly suggested that ezetimibe does nothing to prevent heart disease. It compared the use of a statin plus ezetimibe to the use of a statin plus the B vitamin niacin. While the ezetimibe combination was 70% more effective at lowering cholesterol than the niacin combination, the level of atherosclerosis diminished in the niacin group and actually increased in the eztimibe group.
This came on the heels of two studies (SEAS and ENHANCE) published in 2008 showing that combining a statin with ezetimibe instead of a placebo had no effect on atherosclerosis or heart attacks, despite lowering LDL-cholesterol.
Mike Mitka, senior staff writer for the Journal of the American Medical Association (JAMA), finally asked some critical questions in this month's issue of JAMA:
The FDA approved the drug in 2002. In 2005, the first large outcome trial began. Its results will be available in 2015. If its results are anything like the three smaller trials that have been published recently, physicians may stop prescribing it. In the mean time, Merck will make a whole lot of money.
At least writers in the top medical journals are beginning to ask the tough questions. It's a start.
In truth, however, the evidence suggests that cholestyramine, while increasing the risk of dying from other diseases, lowers the risk of heart attacks not by lowering "cholesterol" but by clearing LDL from the bloodstream more quickly and thus reducing its interactions with free radicals that can oxidize, nitrate, and glycate it. Thus, the liver takes up healthy LDL and the immune system does not need to come and clean up the mess made by the toxic, damaged LDL. When the immune system has to come clean up such a mess, it forms arterial plaques.
For more information, see "High Cholesterol and Heart Disease — Myth or Truth?"
Nevertheless, the medical community has gone gung-ho not over reducing damage to LDL particles, but over lowering levels of LDL-associated cholesterol.
Thus when ezetimibe was released, a drug that suppresses absorption of dietary cholesterol, the FDA did not ask whether ezetimibe reduces oxidation, nitration, or glycation of LDL, nor did it ask whether ezetimibe can be proven to prevent heart attacks. Instead, it simply approved the drug as prevention for heart disease based on the sole evidence that it lowers cholesterol.
A recent study in the New England Journal of Medicine, however, strongly suggested that ezetimibe does nothing to prevent heart disease. It compared the use of a statin plus ezetimibe to the use of a statin plus the B vitamin niacin. While the ezetimibe combination was 70% more effective at lowering cholesterol than the niacin combination, the level of atherosclerosis diminished in the niacin group and actually increased in the eztimibe group.
This came on the heels of two studies (SEAS and ENHANCE) published in 2008 showing that combining a statin with ezetimibe instead of a placebo had no effect on atherosclerosis or heart attacks, despite lowering LDL-cholesterol.
Mike Mitka, senior staff writer for the Journal of the American Medical Association (JAMA), finally asked some critical questions in this month's issue of JAMA:
Should the FDA be approving drugs (especially those that represent new classes of medications) that satisfy established surrogate markers without demanding immediate postmarketing studies to prove clinical effectiveness? Why are physicians continuing to prescribe a drug whose clinical effectiveness has yet to be shown? And why are not more patients receiving niacin, with its proven effectiveness as an adjunct therapy to statins?Merck makes $4 billion per year from the 9 million people taking ezetimibe alone or an ezetimibe/statin combination.
The FDA approved the drug in 2002. In 2005, the first large outcome trial began. Its results will be available in 2015. If its results are anything like the three smaller trials that have been published recently, physicians may stop prescribing it. In the mean time, Merck will make a whole lot of money.
At least writers in the top medical journals are beginning to ask the tough questions. It's a start.
Tuesday, January 19, 2010
When Glucose Makes a Mess
In my Cholesterol Podcast on the Livin' La Vida Low-Carb Show with Jimmy Moore, I offered the view that atherosclerosis and many other degenerative diseases can be seen as a process of oxidative damage wherein polyunsaturated fatty acids (PUFAs) get damaged by toxins, heavy metals, and byproducts of normal metabolism, break into pieces, and then continue to damage other molecules. I suggested thinking of this as breaking a glass on the floor — the glass breaks into shards, and then becomes dangerous. Step on the shards, and your foot will bleed. Likewise, when proteins, DNA, and other important molecules come into contact with "the pieces of broken PUFAs" they get seriously hurt.
PUFAs are not the only molecules subject to this type of damage. "Oxidative stress" is very similar to and very related to "nitrative stress" and "carbonyl stress." "Carbonyl stress" involves the breakdown products of sugars.
When our bodies metabolize sugar, we first do two things to it: first, we add some phosphate to it in order to trap it in the cell, target it through a specific series of reactions, and provide some of the energy necessary for those reactions; second, we split it in half. The technical term for this process is "glycolysis."
A small percentage of the resulting half-sugar will spontaneously lose its phosphate and degenerate into a compound called "methylglyoxal."
The next few paragraphs might make your eyes glaze over if you aren't in love with biochemistry. If that happens, you can skip to the last two paragraphs when the plain English will resume.
In the picture of methylglyoxal above, "C" represents carbon, "O" represents oxygen, "H" represents hydrogen, and the lines represent chemical bonds. The carbons double-bonded to oxygens are called "carbonyl groups." These carbonyl groups are highly reactive. They especially love to react with nitrogens from the "amino groups" of other molecules and form what's called an imidazole ring.
In the picture of the imidazole ring above, "N" represents nitrogen and each corner of the ring structure represents a carbon bonded to a hydrogen. The circle in the middle indicates that some of the electrons travel around continuously through the ring rather than sticking with particular atoms. Imidazole rings are naturally present in the amino acid histidine, but methylglyoxal can form them by spontaneously reacting with the free amino groups of the amino acids lysine and arginine. In doing so, it can damage the structure and function of the proteins these amino acids are part of
Every amino acid has a nitrogen-containing amino group, but on most amino acids this amino group would be bound to other amino acids and tucked away safely within a protein. In the two pictures that follow, this "safe" amino group is the one on the far right. The "side chains" of the amino acids are not always tucked away and are thus not always safe. In the two pictures that follow, the side chains proceed to the left.
The side chain of arginine has two nitrogens, and can thus provide the two nitrogens necessary to form an imidazole ring:
The side chain of lysine has only one nitrogen, so two lysines are necessary to form an imidazole ring:
Consequently, methylglyoxal reacts more often with arginine, by simply creating an imidazole ring in its sidechain that does not belong. This deranged form of arginine accumulates in the body with age and has been found in high amounts in human lens tissue.
When methylglyoxal reacts with lysine, however, it does something more dramatic. Since two lysines need to participate to form an imidazole ring, lysines that would ordinarily be distant from each other within a protein, or even lysines from two completely independent proteins, can get stuck together. In the first case the shape of the protein could get damaged and in the second case the protein would get stuck to another protein. Think "bumper cars." It's hard to drive your car when its stuck up against another car — makes a fun game from time to time but if you're playing "bumper cars" on the way to work you're going to get a ticket, your boss isn't going to be happy when you arrive late, and you could get seriously hurt.
As you can see in the following picture, two lysines supply "amino" (NH2) groups that interact with the "carbonyl" (C=O) groups of methylglyoxal. The hydrogens (H) and oxygens (O) leave the scene as water. An imidazole ring is formed, leading to an "imidazolium" crosslink between two lysines, whether of the same protein or of two wholly different proteins. The resulting advance glycation endproduct (AGE) is not so affectionately termed "MOLD," (MethylglyOxal-Lysine Dimer).
And now, returning to plain English...
Like PUFAs, sugars can be broken into harmful pieces, and like shards of glass, they too can damage other molecules. Some authors have suggested that methylglyoxal can, in small amounts, play important physiological functions. Most look at its ability to damage proteins and cause crosslinks within and between proteins and see a molecule running awry, contributing to "carbonyl stress" just like oxidizing compounds contribute to "oxidative stress."
Over the next several months, I will be performing several experiments to determine what type of dietary factors inrease and decrease the formation of methylglyoxal. I will also be reviewing the literature to better understand what kind of harm, and perhaps, what kind of good, it might do in the body. I will be sure to update you here, so stay tuned!
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