Buying a Multivitamin? Buyer Beware
by John Neustadt, ND
President, NBI
Medical Director, Montana Integrative Medicine
Dietary supplements are big business. Not only can you buy them almost anywhere -- supermarkets, big box stores, drug stores, gas stations -- everyone seems to be popping capsules or tablets of one kind of another. According to Nutraceuticals World, an industry publication, Americans spend $24-25 billion a year on supplements. And global sales are projected to reach $187 billion by 2010.
Every week patients show me their dietary supplements and ask me what I think. Most of the time they're inexpensive, one-a-day type brand. They're convenient and cheap. They're also very poor quality.
The industry is poorly regulated and it’s buyer beware. New FDA regulations are taking effect. These define Good Manufacturing Practices (GMP) and require manufacturing procedures that eliminate instances of contamination, mix-ups, and errors.
GMP is important for protecting the public. But GMP doesn't mandate the quality of the finished product. Manufacturers can still use poorly absorbed nutrients and in amounts that have never been shown in the research to actually help. In fact, to save money most manufacturers today use inexpensive, poor-quality raw materials.
There are three simple questions you can ask to make smart buying decisions. Is it a tablet or capsule? Is it one a day or do you take it multiple times a day? Are there "oxide" forms of minerals in the product? I'll explain each question.
Is it a tablet or capsule?
Tablets are generally more difficult to break apart in your stomach because they contain binders that hold it together. These pills can go right through you without being dissolved or absorbed. While not all tablets have this problem, it would be extremely difficult for the general consumer to know if any one tablet is good or not. But capsules don't have this problem. They are superior to tablets, and why NBI’s Supreme Multivitamin comes in vegetarian cellulose capsules. Always buy capsules if you can.
Is it a one-a-day multivitamin?
If it is, then you're pretty much guaranteed it's garbage. This is because companies have to squeeze and bind all the nutrients together in the tablet. To do so they tend to use forms of minerals that are poorly absorbed, which is a good lead into the next question. This is why NBI’s Supreme Multivitamin requires people take multiple capsules each day.
Does it contain highly-absorbable nutrients?
Companies use poorly absorbed nutrients because they are less expensive. They also know that they can get away with it because most consumers shop just on price. They don't understand that most of what they're buying is likely not even being absorbed.
If it's a once-daily tablet then the product likely contains nutrients that can't be absorbed. Simply look at the Supplements Facts label on the bottle. This is where each ingredient is listed in detail. Find magnesium, calcium, zinc and copper. If calcium is calcium carbonate, or if any of the other minerals are "oxides" (e.g., magnesium oxide, copper oxide), then it's a poor quality formula and not worth your money.
The oxide forms of these minerals are poorly absorbed. In fact, you can only absorb about two percent of magnesium when it's in the oxide form. So if the bottle lists one hundred milligrams magnesium (as magnesium oxide), then you're actually only absorbing about two milligrams. The remaining ninety eight milligrams just pass right through you. Magnesium in an oxide form is so poorly absorbed that in higher doses it's a laxative.
Companies use the oxide form of minerals because they're cheap. But you'd be better off eating a few spinach leaves than wasting your money on a dietary supplement that contains minerals in their oxide forms.
Instead, the most absorbable form of minerals are the amino acid chelated forms. A chelate is a mineral combined with an amino acid such as citrate, malate or aspartate. Amino acid chelated minerals are easier for the body to absorb and can increase absorption to 75%. If you really want your money’s worth, only buy products that contain all their minerals as amino acid chelates (eg, magnesium amino acid chelate).
Calcium, found in all multivitamins and calcium supplements, is a little different. It doesn't come in an oxide form. Instead, most products contain calcium carbonate (this includes coral calcium). It's a large molecule with a lot of elemental calcium. But its size makes it difficult to absorb and can be constipating.
Stomach acid is required to absorb calcium carbonate. But as people age they tend to produce less stomach acid. Up to twenty-one percent of people sixty to sixty-nine years old, thirty-one percent of those seventy to seventy-nine years old, and thirty-seven percent of those above the age of eighty have hypochlorhydria (low stomach acid) or achlorhydria (no stomach acid).
Just when people need the calcium most as they age and take osteoporosis supplements to protect their bones they're absorbing lessand less of this essential mineral.
In contrast, calcium citrate or malate is smaller, easier to absorb and doesn't require stomach acid. The most absorbable forms of minerals are listed as an "amino acid chelate," or as citrate, malate, aspartate or asporotate. Only buy supplements that contain these forms of minerals.
The dietary supplement aisle is confusing for most people, and manufacturers know this. That's why people largely shop just on price. They buy the least expensive bottle possible. In doing so they're flushing their money down the toilet. Be a savvy consumer. Look at your dietary supplement and ask these questions. You'll be getting a better value for your money by buying quality. This is why NBI’s Supreme Multivitamin contains only amino acid chelated minerals and calcium citrate.
How does Supreme Multivitamin compare?
Supreme Mulitivitamin is manufactured to the highest industry standards. It comes in capsules, contains no binders and only the most absorbable forms of minerals. As important, it contains the highest amounts vitamin D, vitamin C, B-complex vitamins, minerals and additional nutrients available in one product.
NBI also ensures each nutrient is tested for contaminants and shown to exceed FDA standards. Additionally, all NBI products are manufactured at a GMP-certified, FDA registered manufacturing company that also manufactures pharmaceuticals. This ensures that NBI products actually conform to pharmaceutical grade manufacturing standards.
Finally, NBI stands behind every one of its products with an unconditional money-back guarantee. No other company provides this level of quality and assurance.
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not, and is not intended to replace actual medical advice from a qualified doctor.
To receive your free 'Manna Goods Health Bulletin' via email, send an email to: the.manna.goods@gmail.com (Put 'Subscribe' in the subject line.)
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Wednesday, June 26, 2013
Saturday, June 22, 2013
SAFE ALTERNATIVES TO BYPASS SURGERY
SAFE ALTERNATIVES TO BYPASS SURGERY
by: Whitaker, Julian, M.D.
Julian Whitaker is a graduate of Emory University Medical School and a member of the American Medical Association. In 1976 he began working with Nathan Pritikin and this changed the direction of his professional career. In 1979 he opened the Whitaker Wellness Institute in Newport Beach, California where he uses preventive medicine with low-fat nutrition, exercise and lifestyle changes as the primary treatment for patients with heart disease, high blood pressure, diabetes and obesity. Along with Nobel Prize-winning Dr. Linus Pauling, Dr. Whitaker founded the California Orthomolecular Medical Society. He is the author of Reversing Heart Disease, Reversing Diabetes, The Heart Surgery Trap, and Dr. Whitaker's Guide to Natural Healing. He is the publisher of Health and Healing, the nation's leading health newsletter with a circulation of nearly 700,000.
HEART DISEASE
I am of the very strong opinion that the whole premise of the invasive treatment of heart disease today is just plain wrong and has been disproven. The premise of doing catheterization to find blockages and the premise that you can't treat people unless you have an angiogram are wrong. We have this big debate that using chelation therapy and vitamins and minerals for heart problems is not backed up by scientific evidence. And all of that is just not true. I will present some studies to show you that the premise of the technical approach to cardiovascular disease of running in and trying to do replumbing, whether the replumbing is an operation or a catheter or a balloon simply doesn't get the job done and actually makes people worse. Most of these studies are listed in my two books on heart disease and my Guide to Natural Healing. Reversing Heart Disease, discusses diet and reducing risk factors, and the later book, The Heart Surgery Trap, discusses getting a second opinion when you are faced with a bypass operation or even catheterization.
SCIENTIFIC STUDIES ON BYPASS SURGERY
If we believe that surgical alteration of the arteries is beneficial, then there should be some proof in the scientific literature. In the United States there have been only two truly controlled trials of the values of bypass surgery. Heart disease is a fatal disease - its primary effect is a fatal heart attack. Therefore if you have a therapy which improves that disease you should improve mortality rates. However, scientific studies of bypass surgery have demonstrated that people die at the same rate with or without the surgery. The first study, the Veteran's Administration Hospital Study, published in 1977, was a highly sophisticated five year study with about 600 patients, all of whom had blockages. Half of them had had heart attacks and were typical bypass candidates. They randomized the people into two groups of 300. Three hundred had the operation and 300 didn't. At three, four and five years later, they found no difference whatsoever in the death rates between the two groups. The three year death rate was about 4% per year for both groups.
They did another study. Usually if a surgical procedure is not validated by a scientifically controlled trial, they abandon the procedure. But this industry was already ongoing, so they decided to do another study with 800 patients, all of whom had blockages. This was the CASS study, published in 1984 in the New England Journal of Medicine. Again, the survival rates turned out to be identical between the surgical and non-surgical groups. The death rate in both groups was 1.6% per year which means the survival rate is 98.4% on a yearly basis. They also found that there was no difference in the death rate whether the patient had one, two or three blockages. If there is no difference, why are we operating on them? Subsequently they looked at the five and ten-year follow-up. At five and ten years there was no difference in death rates between the two groups or in any other statistics for that matter. At 16 years, they found that there was no difference at all, and in fact that those who had the surgery were doing worse because the operation actually alters the blood flow in such a way that it begins to weaken the heart, so that having a bypass makes the next heart attack more dangerous.
BYPASS SURGERY WEAKENS THE HEART
The nationwide death rate from bypass surgery is 4%, but the nationwide death rate from the disease without the surgery is 1%, so the surgery is four times more deadly than the disease and actually increases it down the line because people have further problems. Once you get tied into the aggressive approach to heart disease, it is hard to get out because you are always having problems, and they always have to do another procedure, another angiogram or something else. Forty percent of the grafts are blocked up after five years, and 75% are blocked after 10 years. The side effects like memory loss and personality disorders are significant.
WALKING TIMB BOMBS
Yet, when a person is confronted by a cardiologist or heart surgeon about whether or not they should have surgery, they are told they are a walking time bomb, that they can go any moment, "but if we operate on you we can save your life". Both statements are a lie. This is not just my opinion. It's not that I have an axe to grind. It has been proven to be untrue in the CASS study which showed that whether they were operated on or not, the death rate was the same. That means that time bomb doesn't go off 98.4% of the time.
THE EJECTION FACTOR
The most important factor we consider is the ejection factor. This has nothing to do with blocked arteries; it is a measure of the efficiency of the pumping of the heart. The heart fills with blood; let's say it fills with 100 cc's, and then it pumps out 50 cc's. If the heart pumps out 50% that is called a 50% ejection fraction which means the heart is functioning well. This is the only measurement which will give you a prognostic indication about what is going to happen to that individual in the future. When the ejection fraction is 50% or greater, it doesn't matter how many blockages you have, even if it is the left main artery or triple vessel disease, the studies clearly show that surgery does not help you. It is when the ejection factor is low that you might have some benefit.
ESTIMATING THE EJECTION FACTOR
You do not have to have an angiogram to get the ejection fraction. You can estimate the ejection fraction on the function of the heart over the telephone. I had a patient who was a lawyer in his mid-forties. He had been skiing out west and all of a sudden he had some chest pains, so he went to the cardiologist, and they did a stress test and an angiogram, and found a couple of blockages and scheduled him for surgery. He was lying in Johns Hopkins shaved and ready for surgery when someone gave him my book. He called me up and I asked him some questions to find out how his heart was functioning: "Do you get short of breath; do your feet swell; do you have to sleep on two pillows; do you wake up at night short of breath; do you get really short of breath going up stairs?" He answered no to all the questions, so I told him he better get out of the hospital. He came to see me, and he was so healthy I didn't even recommend chelation therapy. But he was about to undergo a $70,000 operation that was putting him in jeopardy. When you undergo bypass surgery, you are subjected to the pump, and that will cause brain damage. It causes brain damage to everyone. So all of his professional and social life was being put into jeopardy for an operation he obviously did not need, could not benefit from, and could only be hurt by. I have hundreds of patients who have been told they had to have bypass surgery when they just didn't need it.
ANGIOGRAPHY
The only information you get from an angiogram is where the surgeon may or may not operate. It has nothing to do with treatment. Treatment depends on how much pain the individual has, the level of their blood pressure and cholesterol, the function of the heart and their exercise tolerance, whether they have cardiac arrhythmias. Eighty percent of angiograms go on to some kind of operation like a bypass or an angioplasty. So where you really stop it is with the angiogram. In 1987 and in 1992, Dr. T.D. Graboys and his group in Boston published studies in the Journal of the American Medical Association in which he gave his protocol for second opinions for patients who were told to have an angiogram. Most cardiologists tell you they can't treat you unless they have an angiogram to look at the blood vessels. I believe treatment of the patient with heart disease is usually best done without an angiogram. I am a nutritionally oriented physician. That is what you would expect me to say, and this is the way I treat my patients. But Thomas Graboys is a teaching cardiologist at Harvard. Of 168 patients referred to him who had been told by other board certified cardiologists to have an angiogram, he agreed with only six of them. If this Harvard board certified very conservative cardiologist feels comfortable in treating these 162 patients, why is it that they were told by other cardiologists they needed an angiogram or they couldn't be treated? Because it's a business. The increase in the numbers of bypass surgery reflects only one thing, and that is the number of surgeons in the community. Since that is what they have to do to survive in their profession, we are going to have more and more of this kind of thing. Get a second opinion. Dr. Graboys study concluded that bypass surgery could be reduced by 50% to 80%.
THE HEART INDUSTRY
Eugene Brunwald published an article in the New England Journal of Medicine in 1977 which claimed that an industry was being built around an operation that had been disproven, and it was continuing to grow. It was a money machine. And that is still going on. In 1977, there were only about 70,000 bypass procedures per year. Now there are 500,000 bypass surgeries per year plus an additional 400,000 angioplasties, which also have never been validated scientifically.
ANGIOPLASTY
Angioplasty will never be researched in a scientific study, and no one has ever mounted a scientific study on the benefits of angioplasty. The death rate of the procedure is roughly four times the expected death rate of the disease.
LOW FAT VEGETARIAN DIET When I worked with Pritikin I saw people on the Pritikin low fat diet get well. I saw diseases melt away. We were always able to take the patients off drugs. The Lifestyle Heart Trial conducted by Dean Ornish, published in the Lancet, 1990, demonstrated that atherosclerosis can be reversed by changing the diet. The control group received regular medical care and followed the standard American Heart Association diet. The experimental group was asked to eat a low-fat vegetarian diet for at least one year. The diet included fruits, vegetables, grains, legumes and soybean products, but no animal products were allowed except egg white and one cup per day of nonfat yogurt. Although margarine has been promoted by the American Heart Association, studies show that margarine and other hydrogenated foods are very damaging foods to heart patients and probably carcinogenic. They were also asked to perform stress-reduction techniques such as breathing exercises, stretching exercises, meditation, and other relaxation techniques for an hour each day and to exercise at least three hours a week. At the end of the year, the experimental group showed significant regression of atherosclerosis of the coronary blood vessels. In contrast, subjects in the control group showed progression of their disease.
VITAMINS AND MINERALS Research has shown that 300 mg. of vitamin C or more daily reduces heart attack rates by 50% and increases life span by about six years. Beta carotene, vitamin E and the other anti-oxidants have a similar effect. Doctors prescribe Mevacor to lower cholesterol presumably to lower heart attacks. The side effects of Mevacor are cataracts, liver failure, hepatitis or gall bladder disease. Why don't you just take some vitamin C which has no side effects whatsoever. Folic acid, vitamin B6 and B12 are essential for eliminating homocysteine build-up in the blood which reduces the conversion of LDL and the deposition of cholesterol in the arteries. This has been published in many journals including the New England Journal of Medicine and the Journal of the American Medical Association. You need to take B complex vitamins every day, at least 400 mg of folic acid, 50-100 mg of B6, and 400 or more mcg of B12. B vitamins alone can reduce heart disease dramatically. We use magnesium I.V.'s for heart disease, arrhythmias, high blood pressure, angina and asthma. It's a natural calcium channel blocker which works in a similar way to calcium channel blocker medications with none of the side effects.
COENZYME Q10 AND CARNITINE
If you have heart disease, you definitely need to be taking coenzyme Q10 and carnitine. I use coenzyme Q10 for every single heart patient, particularly when your ejection level is low. Take 30 to 100 mg three times daily. Carnitine also helps the ejection factor. Take 500 mg of carnitine two times daily.
AMINO ACIDS
L-arginine at about 6 g per day will increase nitric oxide which relaxes the arteries, lowers the blood pressure and smooths out the blood flow. In a study done at Stanford, it was shown that L-lysine when given with vitamin C can actually carve out arterial blockages.
CHELATION THERAPY
Most of you know about this. Dr. Cutler is now doing it at Stoneybrook. There is better research on chelation therapy than there is on bypass surgery, and it has to be better than bypass surgery because it doesn't hurt anyone. Chelation results in a 93% improvement. There are plenty of scientific studies on this subject. I don't think chelation therapy is a cure all, but I think used along with everything else, it is extremely powerful.
ENHANCED EXTERNAL CALIPULSATION
This is a new very powerful therapy for heart disease. There has been a large study done on it in Stoneybrook in New York. People don't have to suffer with angina with this kind of therapy available. I have seen some excellent results. Of the patients I have treated, 16 out of 18 had complete relief of angina.
SUMMARY:
The best that can be said about bypass surgery and balloon angioplasty is that they are irrelevant to the course of the disease in all but the most serious cases. Bypass does not increase blood flow to the heart in most cases and may even reduce blood flow. The cardiopulmonary pump used during bypass surgery can cause brain damage. This damage can lead to memory loss, paralysis and personality changes. The need for bypass surgery is determined mainly by how well the left ventricular pump is working, not the number of blood vessels blocked. Bypass surgery or angioplasty are not curative; they do not address the reasons why the plaque developed in the first place. The section upstream of the graft has accelerated plaque formation at a rate ten times higher than the ungrafted coronary artery. This is probably way patients do poorly over time. Up to 90% of bypass procedures are done when the ejection fraction is greater than 50% which indicates a healthy heart.
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
by: Whitaker, Julian, M.D.
Julian Whitaker is a graduate of Emory University Medical School and a member of the American Medical Association. In 1976 he began working with Nathan Pritikin and this changed the direction of his professional career. In 1979 he opened the Whitaker Wellness Institute in Newport Beach, California where he uses preventive medicine with low-fat nutrition, exercise and lifestyle changes as the primary treatment for patients with heart disease, high blood pressure, diabetes and obesity. Along with Nobel Prize-winning Dr. Linus Pauling, Dr. Whitaker founded the California Orthomolecular Medical Society. He is the author of Reversing Heart Disease, Reversing Diabetes, The Heart Surgery Trap, and Dr. Whitaker's Guide to Natural Healing. He is the publisher of Health and Healing, the nation's leading health newsletter with a circulation of nearly 700,000.
HEART DISEASE
I am of the very strong opinion that the whole premise of the invasive treatment of heart disease today is just plain wrong and has been disproven. The premise of doing catheterization to find blockages and the premise that you can't treat people unless you have an angiogram are wrong. We have this big debate that using chelation therapy and vitamins and minerals for heart problems is not backed up by scientific evidence. And all of that is just not true. I will present some studies to show you that the premise of the technical approach to cardiovascular disease of running in and trying to do replumbing, whether the replumbing is an operation or a catheter or a balloon simply doesn't get the job done and actually makes people worse. Most of these studies are listed in my two books on heart disease and my Guide to Natural Healing. Reversing Heart Disease, discusses diet and reducing risk factors, and the later book, The Heart Surgery Trap, discusses getting a second opinion when you are faced with a bypass operation or even catheterization.
SCIENTIFIC STUDIES ON BYPASS SURGERY
If we believe that surgical alteration of the arteries is beneficial, then there should be some proof in the scientific literature. In the United States there have been only two truly controlled trials of the values of bypass surgery. Heart disease is a fatal disease - its primary effect is a fatal heart attack. Therefore if you have a therapy which improves that disease you should improve mortality rates. However, scientific studies of bypass surgery have demonstrated that people die at the same rate with or without the surgery. The first study, the Veteran's Administration Hospital Study, published in 1977, was a highly sophisticated five year study with about 600 patients, all of whom had blockages. Half of them had had heart attacks and were typical bypass candidates. They randomized the people into two groups of 300. Three hundred had the operation and 300 didn't. At three, four and five years later, they found no difference whatsoever in the death rates between the two groups. The three year death rate was about 4% per year for both groups.
They did another study. Usually if a surgical procedure is not validated by a scientifically controlled trial, they abandon the procedure. But this industry was already ongoing, so they decided to do another study with 800 patients, all of whom had blockages. This was the CASS study, published in 1984 in the New England Journal of Medicine. Again, the survival rates turned out to be identical between the surgical and non-surgical groups. The death rate in both groups was 1.6% per year which means the survival rate is 98.4% on a yearly basis. They also found that there was no difference in the death rate whether the patient had one, two or three blockages. If there is no difference, why are we operating on them? Subsequently they looked at the five and ten-year follow-up. At five and ten years there was no difference in death rates between the two groups or in any other statistics for that matter. At 16 years, they found that there was no difference at all, and in fact that those who had the surgery were doing worse because the operation actually alters the blood flow in such a way that it begins to weaken the heart, so that having a bypass makes the next heart attack more dangerous.
BYPASS SURGERY WEAKENS THE HEART
The nationwide death rate from bypass surgery is 4%, but the nationwide death rate from the disease without the surgery is 1%, so the surgery is four times more deadly than the disease and actually increases it down the line because people have further problems. Once you get tied into the aggressive approach to heart disease, it is hard to get out because you are always having problems, and they always have to do another procedure, another angiogram or something else. Forty percent of the grafts are blocked up after five years, and 75% are blocked after 10 years. The side effects like memory loss and personality disorders are significant.
WALKING TIMB BOMBS
Yet, when a person is confronted by a cardiologist or heart surgeon about whether or not they should have surgery, they are told they are a walking time bomb, that they can go any moment, "but if we operate on you we can save your life". Both statements are a lie. This is not just my opinion. It's not that I have an axe to grind. It has been proven to be untrue in the CASS study which showed that whether they were operated on or not, the death rate was the same. That means that time bomb doesn't go off 98.4% of the time.
THE EJECTION FACTOR
The most important factor we consider is the ejection factor. This has nothing to do with blocked arteries; it is a measure of the efficiency of the pumping of the heart. The heart fills with blood; let's say it fills with 100 cc's, and then it pumps out 50 cc's. If the heart pumps out 50% that is called a 50% ejection fraction which means the heart is functioning well. This is the only measurement which will give you a prognostic indication about what is going to happen to that individual in the future. When the ejection fraction is 50% or greater, it doesn't matter how many blockages you have, even if it is the left main artery or triple vessel disease, the studies clearly show that surgery does not help you. It is when the ejection factor is low that you might have some benefit.
ESTIMATING THE EJECTION FACTOR
You do not have to have an angiogram to get the ejection fraction. You can estimate the ejection fraction on the function of the heart over the telephone. I had a patient who was a lawyer in his mid-forties. He had been skiing out west and all of a sudden he had some chest pains, so he went to the cardiologist, and they did a stress test and an angiogram, and found a couple of blockages and scheduled him for surgery. He was lying in Johns Hopkins shaved and ready for surgery when someone gave him my book. He called me up and I asked him some questions to find out how his heart was functioning: "Do you get short of breath; do your feet swell; do you have to sleep on two pillows; do you wake up at night short of breath; do you get really short of breath going up stairs?" He answered no to all the questions, so I told him he better get out of the hospital. He came to see me, and he was so healthy I didn't even recommend chelation therapy. But he was about to undergo a $70,000 operation that was putting him in jeopardy. When you undergo bypass surgery, you are subjected to the pump, and that will cause brain damage. It causes brain damage to everyone. So all of his professional and social life was being put into jeopardy for an operation he obviously did not need, could not benefit from, and could only be hurt by. I have hundreds of patients who have been told they had to have bypass surgery when they just didn't need it.
ANGIOGRAPHY
The only information you get from an angiogram is where the surgeon may or may not operate. It has nothing to do with treatment. Treatment depends on how much pain the individual has, the level of their blood pressure and cholesterol, the function of the heart and their exercise tolerance, whether they have cardiac arrhythmias. Eighty percent of angiograms go on to some kind of operation like a bypass or an angioplasty. So where you really stop it is with the angiogram. In 1987 and in 1992, Dr. T.D. Graboys and his group in Boston published studies in the Journal of the American Medical Association in which he gave his protocol for second opinions for patients who were told to have an angiogram. Most cardiologists tell you they can't treat you unless they have an angiogram to look at the blood vessels. I believe treatment of the patient with heart disease is usually best done without an angiogram. I am a nutritionally oriented physician. That is what you would expect me to say, and this is the way I treat my patients. But Thomas Graboys is a teaching cardiologist at Harvard. Of 168 patients referred to him who had been told by other board certified cardiologists to have an angiogram, he agreed with only six of them. If this Harvard board certified very conservative cardiologist feels comfortable in treating these 162 patients, why is it that they were told by other cardiologists they needed an angiogram or they couldn't be treated? Because it's a business. The increase in the numbers of bypass surgery reflects only one thing, and that is the number of surgeons in the community. Since that is what they have to do to survive in their profession, we are going to have more and more of this kind of thing. Get a second opinion. Dr. Graboys study concluded that bypass surgery could be reduced by 50% to 80%.
THE HEART INDUSTRY
Eugene Brunwald published an article in the New England Journal of Medicine in 1977 which claimed that an industry was being built around an operation that had been disproven, and it was continuing to grow. It was a money machine. And that is still going on. In 1977, there were only about 70,000 bypass procedures per year. Now there are 500,000 bypass surgeries per year plus an additional 400,000 angioplasties, which also have never been validated scientifically.
ANGIOPLASTY
Angioplasty will never be researched in a scientific study, and no one has ever mounted a scientific study on the benefits of angioplasty. The death rate of the procedure is roughly four times the expected death rate of the disease.
LOW FAT VEGETARIAN DIET When I worked with Pritikin I saw people on the Pritikin low fat diet get well. I saw diseases melt away. We were always able to take the patients off drugs. The Lifestyle Heart Trial conducted by Dean Ornish, published in the Lancet, 1990, demonstrated that atherosclerosis can be reversed by changing the diet. The control group received regular medical care and followed the standard American Heart Association diet. The experimental group was asked to eat a low-fat vegetarian diet for at least one year. The diet included fruits, vegetables, grains, legumes and soybean products, but no animal products were allowed except egg white and one cup per day of nonfat yogurt. Although margarine has been promoted by the American Heart Association, studies show that margarine and other hydrogenated foods are very damaging foods to heart patients and probably carcinogenic. They were also asked to perform stress-reduction techniques such as breathing exercises, stretching exercises, meditation, and other relaxation techniques for an hour each day and to exercise at least three hours a week. At the end of the year, the experimental group showed significant regression of atherosclerosis of the coronary blood vessels. In contrast, subjects in the control group showed progression of their disease.
VITAMINS AND MINERALS Research has shown that 300 mg. of vitamin C or more daily reduces heart attack rates by 50% and increases life span by about six years. Beta carotene, vitamin E and the other anti-oxidants have a similar effect. Doctors prescribe Mevacor to lower cholesterol presumably to lower heart attacks. The side effects of Mevacor are cataracts, liver failure, hepatitis or gall bladder disease. Why don't you just take some vitamin C which has no side effects whatsoever. Folic acid, vitamin B6 and B12 are essential for eliminating homocysteine build-up in the blood which reduces the conversion of LDL and the deposition of cholesterol in the arteries. This has been published in many journals including the New England Journal of Medicine and the Journal of the American Medical Association. You need to take B complex vitamins every day, at least 400 mg of folic acid, 50-100 mg of B6, and 400 or more mcg of B12. B vitamins alone can reduce heart disease dramatically. We use magnesium I.V.'s for heart disease, arrhythmias, high blood pressure, angina and asthma. It's a natural calcium channel blocker which works in a similar way to calcium channel blocker medications with none of the side effects.
COENZYME Q10 AND CARNITINE
If you have heart disease, you definitely need to be taking coenzyme Q10 and carnitine. I use coenzyme Q10 for every single heart patient, particularly when your ejection level is low. Take 30 to 100 mg three times daily. Carnitine also helps the ejection factor. Take 500 mg of carnitine two times daily.
AMINO ACIDS
L-arginine at about 6 g per day will increase nitric oxide which relaxes the arteries, lowers the blood pressure and smooths out the blood flow. In a study done at Stanford, it was shown that L-lysine when given with vitamin C can actually carve out arterial blockages.
CHELATION THERAPY
Most of you know about this. Dr. Cutler is now doing it at Stoneybrook. There is better research on chelation therapy than there is on bypass surgery, and it has to be better than bypass surgery because it doesn't hurt anyone. Chelation results in a 93% improvement. There are plenty of scientific studies on this subject. I don't think chelation therapy is a cure all, but I think used along with everything else, it is extremely powerful.
ENHANCED EXTERNAL CALIPULSATION
This is a new very powerful therapy for heart disease. There has been a large study done on it in Stoneybrook in New York. People don't have to suffer with angina with this kind of therapy available. I have seen some excellent results. Of the patients I have treated, 16 out of 18 had complete relief of angina.
SUMMARY:
The best that can be said about bypass surgery and balloon angioplasty is that they are irrelevant to the course of the disease in all but the most serious cases. Bypass does not increase blood flow to the heart in most cases and may even reduce blood flow. The cardiopulmonary pump used during bypass surgery can cause brain damage. This damage can lead to memory loss, paralysis and personality changes. The need for bypass surgery is determined mainly by how well the left ventricular pump is working, not the number of blood vessels blocked. Bypass surgery or angioplasty are not curative; they do not address the reasons why the plaque developed in the first place. The section upstream of the graft has accelerated plaque formation at a rate ten times higher than the ungrafted coronary artery. This is probably way patients do poorly over time. Up to 90% of bypass procedures are done when the ejection fraction is greater than 50% which indicates a healthy heart.
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
Sunday, June 16, 2013
Comedian Says Doctor Botched Bypass Surgery
Comedian Says Doctor Botched Bypass Surgery
By, Harriet Chiang, Chronicle Legal Affairs Writer
Published 4:00 am, Friday, May 19, 2000
2000-05-19 04:00:00 PDT San Francisco -- Comedian Dana Carvey said it was a somber day when he learned that a doctor had operated on the wrong artery during Carvey's double bypass surgery in 1998.
Carvey, who has a family history of high cholesterol, had the surgery to clear a blocked artery. Because of the surgical mishap, the blockage in the diseased artery remained. He has since made a complete recovery. But yesterday he was in court to testify in his $7.5 million lawsuit against the San Francisco surgeon who made the mistake.
After he learned of the botched surgery, he said, he was devastated. "I remember just lying in my bed just sobbing," Carvey told the jury in San Francisco Superior Court. "I can't believe they connected it to the wrong artery," he kept saying to himself.
"I was absolutely just terrified that I was going to have another open heart surgery," he said. That turned out to be unnecessary. But he did require a subsequent angioplasty to clear the blocked artery.
Last year, Carvey, a resident of Marin County, filed suit against the surgeon, Elias Hanna, to recover damages for the six months in 1998 the entertainer spent recovering from the angioplasty. During that time, he said, he had to turn down offers to do commercials, a television series and a spot on the "Hollywood Squares" game show.
In the doctor's defense, Hanna's lawyer has said that Carvey, 44, has an "unusual anatomy" and that his blood vessels were positioned in an atypical way.
While Hanna sat in the front row of the courtroom, Carvey, wearing a blue shirt and black suit, testified how he anguished over making the decision to have open heart surgery in the first place.
But after three unsuccessful angioplasties in 1997, he said that the doctors convinced him that surgery was an effective way to resolve the recurring blockage of his arteries.
"Let's bite the bullet and do this horrific thing, this open heart surgery so I can get on with my life, my career," he recalled thinking to himself.
He had the operation at Marin General Hospital in March 1998. He was "euphoric" when he went home, believing that the potentially life-threatening blockage was finally cleared.
But soon after the surgery, he began to have the same discomfort he experienced before. Hanna assured him it was the effects of the operation. But in May, Carvey was tested by his regular doctors in Los Angeles, who discovered the mistake. They called it a "goof-up" and a case of "gross negligence," Carvey said.
He was told there was a high risk of the artery closing up again. "We all knew I was back to square one again," he said quietly.
He had another angioplasty and then went through six months of recuperation. He recalled being weak and pale and dreading the prospect of having to undergo another open heart surgery if the angioplasty was unsuccessful.
For the first four months, he said, he was so sapped of strength that he could only work three days of stand- up comedy performances.
By the fall, he was beginning to regain his strength and picked up his work schedule.
During his daylong testimony, Carvey mostly maintained a serious demeanor, often taking deep breaths to relieve the tension. But occasionally he drew chuckles from the jury.
After he came out of the surgery at Marin General Hospital, he recalled how he was given morphine to relieve the postoperative pain. "They tell you it's going to run out," he said with a smile, refering to the patient-regulated morphine pump. "But I kept hitting it."
When Hanna's lawyer, Dane Jones, asked him about his accounting and business affairs, he shook his head and talked vaguely about "that stuff."
"I'm just a comedian," he told the lawyer.
A year later, Carvey said that he is on a low-fat diet as well as medication to maintain a low cholesterol level.
"Is your health otherwise good?" his lawyer, David Baum asked him.
"Perfect," Carvey responded.
The trial is expected to last through next week.
Read more: http://www.sfgate.com/health/article/Comedian-Says-Doctor-Botched-Bypass-Surgery-2759026.php#ixzz2PS5IHYbi
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
By, Harriet Chiang, Chronicle Legal Affairs Writer
Published 4:00 am, Friday, May 19, 2000
2000-05-19 04:00:00 PDT San Francisco -- Comedian Dana Carvey said it was a somber day when he learned that a doctor had operated on the wrong artery during Carvey's double bypass surgery in 1998.
Carvey, who has a family history of high cholesterol, had the surgery to clear a blocked artery. Because of the surgical mishap, the blockage in the diseased artery remained. He has since made a complete recovery. But yesterday he was in court to testify in his $7.5 million lawsuit against the San Francisco surgeon who made the mistake.
After he learned of the botched surgery, he said, he was devastated. "I remember just lying in my bed just sobbing," Carvey told the jury in San Francisco Superior Court. "I can't believe they connected it to the wrong artery," he kept saying to himself.
"I was absolutely just terrified that I was going to have another open heart surgery," he said. That turned out to be unnecessary. But he did require a subsequent angioplasty to clear the blocked artery.
Last year, Carvey, a resident of Marin County, filed suit against the surgeon, Elias Hanna, to recover damages for the six months in 1998 the entertainer spent recovering from the angioplasty. During that time, he said, he had to turn down offers to do commercials, a television series and a spot on the "Hollywood Squares" game show.
In the doctor's defense, Hanna's lawyer has said that Carvey, 44, has an "unusual anatomy" and that his blood vessels were positioned in an atypical way.
While Hanna sat in the front row of the courtroom, Carvey, wearing a blue shirt and black suit, testified how he anguished over making the decision to have open heart surgery in the first place.
But after three unsuccessful angioplasties in 1997, he said that the doctors convinced him that surgery was an effective way to resolve the recurring blockage of his arteries.
"Let's bite the bullet and do this horrific thing, this open heart surgery so I can get on with my life, my career," he recalled thinking to himself.
He had the operation at Marin General Hospital in March 1998. He was "euphoric" when he went home, believing that the potentially life-threatening blockage was finally cleared.
But soon after the surgery, he began to have the same discomfort he experienced before. Hanna assured him it was the effects of the operation. But in May, Carvey was tested by his regular doctors in Los Angeles, who discovered the mistake. They called it a "goof-up" and a case of "gross negligence," Carvey said.
He was told there was a high risk of the artery closing up again. "We all knew I was back to square one again," he said quietly.
He had another angioplasty and then went through six months of recuperation. He recalled being weak and pale and dreading the prospect of having to undergo another open heart surgery if the angioplasty was unsuccessful.
For the first four months, he said, he was so sapped of strength that he could only work three days of stand- up comedy performances.
By the fall, he was beginning to regain his strength and picked up his work schedule.
During his daylong testimony, Carvey mostly maintained a serious demeanor, often taking deep breaths to relieve the tension. But occasionally he drew chuckles from the jury.
After he came out of the surgery at Marin General Hospital, he recalled how he was given morphine to relieve the postoperative pain. "They tell you it's going to run out," he said with a smile, refering to the patient-regulated morphine pump. "But I kept hitting it."
When Hanna's lawyer, Dane Jones, asked him about his accounting and business affairs, he shook his head and talked vaguely about "that stuff."
"I'm just a comedian," he told the lawyer.
A year later, Carvey said that he is on a low-fat diet as well as medication to maintain a low cholesterol level.
"Is your health otherwise good?" his lawyer, David Baum asked him.
"Perfect," Carvey responded.
The trial is expected to last through next week.
Read more: http://www.sfgate.com/health/article/Comedian-Says-Doctor-Botched-Bypass-Surgery-2759026.php#ixzz2PS5IHYbi
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Wednesday, May 29, 2013
Benefits of Drinking Coffee
Benefits of Drinking Coffee
Benefits
All-cause mortality:
In women, coffee consumption significantly decreases all-cause mortality, apparently decreasing somewhat linearly to a relative risk of approximately 0.85 for those drinking 3 cups per day compared to those who consume no coffee, but the relative risk then remains almost the same for up to 6 cups per day, according to a large prospective cohort study in 1993. In men, these beneficial effects were not as great, in fact with an increased risk for those drinking approximately one cup every other day compared to those drinking none, but yet having a significant trend towards less mortality for those who drink more than 2 cups per day compared to those who drink none. Results were similar for decaffeinated coffee. An inverse association between coffee consumption and total and cause-specific mortality was also found in a 2012 analysis of data from the National Institutes of Health–AARP Diet and Health Study.
Reduced risk of Alzheimer's disease and Dementia:
Several studies comparing moderate coffee drinkers (defined as 3–5 cups per day) with light coffee drinkers (defined as 0–2 cups per day) found that those who drank more coffee were significantly less likely to develop Alzheimer's disease later in life.
A longitudinal study in 2009 found that moderate coffee drinkers had reduced risk of developing dementia in addition to Alzheimer's disease.
Reduced risk of gallstone disease:
Drinking caffeinated coffee has been correlated with a lower incidence of gallstones and gallbladder disease in both men and women in two studies performed by the Harvard School of Public Health. A lessened risk was not seen in those who drank decaffeinated coffee.
Reduced risk of Parkinson's disease:
A study comparing heavy coffee drinkers (3.5 cups a day) with non-drinkers found that the coffee drinkers were significantly less likely to develop Parkinson's disease later in life. Likewise, a second study found an inverse relationship between the amount of coffee regularly drunk and the likelihood of developing Parkinson's disease.
Cognitive performance:
Many people drink coffee for its ability to increase short term recall.
Likewise, in tests of simple reaction time, choice reaction time, incidental verbal memory, and visuospatial reasoning, participants who regularly drank coffee were found to perform better on all tests, with a positive relationship between test scores and the amount of coffee regularly drunk. Elderly participants were found to have the largest effect associated with regular coffee drinking. Another study found that women over the age of 80 performed significantly better on cognitive tests if they had regularly drunk coffee over their lifetimes. A recent study showed that roast coffee protected primary neuronal cells against hydrogen peroxide-induced cell death.
Caffeine and analgesics:
Coffee contains caffeine, which may increase the effectiveness of gastrointestinal uptake of some pain killers, especially in patients with migraine and headache medications. For this reason, many over-the-counter headache drugs include caffeine in their formula. Caffeine itself does not have analgesic properties. In some patients with migraine, caffeine can alleviate pain by acting on the cerebral blood vessels. A 2012 study suggested caffeinated coffee reduced pain in an office environment.
Antidiabetic:
Coffee intake may reduce one's risk of diabetes mellitus type 2 by up to half. While this was originally noticed in patients who consumed high amounts (7 cups a day), the relationship was later shown to be linear. This effect has been attributed to the compounds caffeic acid and chlorogenic acid, which are thought to suppress the formation of human islet amyloid polypeptide (hlAPP).
Liver protection:
Coffee can also reduce the incidence of cirrhosis of the liver and has been linked to a reduced risk of hepatocellular carcinoma, a primary liver cancer that usually arises in patients with preexisting cirrhosis. The exact mechanism and the amount of coffee needed to achieve a beneficial effect have long been unclear. The cytokine transforming growth factor (TGF) beta has long been recognized for promoting fibrosis ability acting through the Smad family of transcription factors. In a report published in the Journal of Hepatology, Gressner and colleagues provide the first mechanistic context for the epidemiological studies on coffee drinkers by showing that caffeine may have potent anti-fibrotic capabilities through its ability to antagonize the Smad pathway.
Cancer:
Coffee consumption is also correlated in Africa to a reduced risk of oral, esophageal, and pharyngeal cancer. In ovarian cancer, no benefit was found. In the Nurses' Health Study and a 2011 Swedish study, a modest reduction in breast cancer was observed in postmenopausal women only, which was not confirmed in decaffeinated coffee, and a reduction in endometrial cancer was observed in people who drank either caffeinated or decaffeinated coffee. The Harvard Medical School reported in 2006 that researchers found that coffee drinkers were 50% less likely to get liver cancer than nondrinkers. Another study found a correlation between coffee consumption (both regular and decaffinated) and a lower risk of aggressive prostate cancer.
Instant coffee contains a much higher level of acrylamide than brewed coffee.
Cardioprotective:
Coffee moderately reduces the incidence of dying from cardiovascular disease, according to a large prospective cohort study published in 2008.
A 2009 prospective study in Japan following nearly 77,000 individuals aged 40 to 79 found that coffee consumption, along with caffeine intake, was associated with a reduced risk of dying from cardiovascular disease.
A 2012 meta-analysis concluded that people who drank moderate amounts of coffee had a lower rate of heart failure, with the biggest effect found for those who drank more than four cups a day.
Laxative / diuretic:
Coffee is also a powerful stimulant for peristalsis and is sometimes considered to prevent constipation. However, coffee can also cause excessively loose bowel movements. The stimulative effect of coffee consumption on the colon is found in both caffeinated and decaffeinated coffee.
Contrary to popular belief, caffeine does not act as a diuretic when consumed in moderation (less than five cups a day or 500 to 600 milligrams), and does not lead to dehydration or to a water-electrolyte imbalance; current evidence suggests that caffeinated beverages contribute to the body's daily fluid requirements no differently from pure water.
Antioxidant:
Coffee contains polyphenols such as flavan-3-ols (monomers and procyanidins), hydroxycinnamic acids, flavonols and anthocyanidins. These compounds have antioxidative effect and potentially reduce oxidative cell damage. One particular substance with putative anticarcinogenic effect is methylpyridinium. This compound is not present in significant amounts in other foods. Methylpyridinium is not present in raw coffee beans but is formed during the roasting process from trigonelline, which is common in raw coffee beans. It is present in both caffeinated and decaffeinated coffee, and even in instant coffee. Research funded by Kraft Foods shows that roast coffee contains more lipophilic antioxidants and chlorogenic acid lactones and is more protective against hydrogen peroxide-induced cell death in primary neuronal cells than green coffee. The espresso method of extraction yields higher antioxidant activity than other brewing methods.
Prevention of dental cavities:
The tannins in coffee may reduce the cariogenic potential of foods. In vitro experiments have shown that these polyphenolic compounds may interfere with glucosyltransferase activity of mutans streptococci, which may reduce plaque formation.
Gout:
Coffee consumption contributes to a decreased risk of gout in men over age 40. In a large study of over 45,000 men over a 12-year period, the risk for developing gout in men over 40 was inversely proportional with the amount of coffee consumed.
Blood pressure:
A 2011 study showed that moderate (≤4 cups per day) coffee consumption was inversely associated with high blood pressure and high triglyceride level in Japanese men. However, the study showed no significant association between coffee consumption and prevalence of metabolic syndrome for Japanese women.
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Benefits
All-cause mortality:
In women, coffee consumption significantly decreases all-cause mortality, apparently decreasing somewhat linearly to a relative risk of approximately 0.85 for those drinking 3 cups per day compared to those who consume no coffee, but the relative risk then remains almost the same for up to 6 cups per day, according to a large prospective cohort study in 1993. In men, these beneficial effects were not as great, in fact with an increased risk for those drinking approximately one cup every other day compared to those drinking none, but yet having a significant trend towards less mortality for those who drink more than 2 cups per day compared to those who drink none. Results were similar for decaffeinated coffee. An inverse association between coffee consumption and total and cause-specific mortality was also found in a 2012 analysis of data from the National Institutes of Health–AARP Diet and Health Study.
Reduced risk of Alzheimer's disease and Dementia:
Several studies comparing moderate coffee drinkers (defined as 3–5 cups per day) with light coffee drinkers (defined as 0–2 cups per day) found that those who drank more coffee were significantly less likely to develop Alzheimer's disease later in life.
A longitudinal study in 2009 found that moderate coffee drinkers had reduced risk of developing dementia in addition to Alzheimer's disease.
Reduced risk of gallstone disease:
Drinking caffeinated coffee has been correlated with a lower incidence of gallstones and gallbladder disease in both men and women in two studies performed by the Harvard School of Public Health. A lessened risk was not seen in those who drank decaffeinated coffee.
Reduced risk of Parkinson's disease:
A study comparing heavy coffee drinkers (3.5 cups a day) with non-drinkers found that the coffee drinkers were significantly less likely to develop Parkinson's disease later in life. Likewise, a second study found an inverse relationship between the amount of coffee regularly drunk and the likelihood of developing Parkinson's disease.
Cognitive performance:
Many people drink coffee for its ability to increase short term recall.
Likewise, in tests of simple reaction time, choice reaction time, incidental verbal memory, and visuospatial reasoning, participants who regularly drank coffee were found to perform better on all tests, with a positive relationship between test scores and the amount of coffee regularly drunk. Elderly participants were found to have the largest effect associated with regular coffee drinking. Another study found that women over the age of 80 performed significantly better on cognitive tests if they had regularly drunk coffee over their lifetimes. A recent study showed that roast coffee protected primary neuronal cells against hydrogen peroxide-induced cell death.
Caffeine and analgesics:
Coffee contains caffeine, which may increase the effectiveness of gastrointestinal uptake of some pain killers, especially in patients with migraine and headache medications. For this reason, many over-the-counter headache drugs include caffeine in their formula. Caffeine itself does not have analgesic properties. In some patients with migraine, caffeine can alleviate pain by acting on the cerebral blood vessels. A 2012 study suggested caffeinated coffee reduced pain in an office environment.
Antidiabetic:
Coffee intake may reduce one's risk of diabetes mellitus type 2 by up to half. While this was originally noticed in patients who consumed high amounts (7 cups a day), the relationship was later shown to be linear. This effect has been attributed to the compounds caffeic acid and chlorogenic acid, which are thought to suppress the formation of human islet amyloid polypeptide (hlAPP).
Liver protection:
Coffee can also reduce the incidence of cirrhosis of the liver and has been linked to a reduced risk of hepatocellular carcinoma, a primary liver cancer that usually arises in patients with preexisting cirrhosis. The exact mechanism and the amount of coffee needed to achieve a beneficial effect have long been unclear. The cytokine transforming growth factor (TGF) beta has long been recognized for promoting fibrosis ability acting through the Smad family of transcription factors. In a report published in the Journal of Hepatology, Gressner and colleagues provide the first mechanistic context for the epidemiological studies on coffee drinkers by showing that caffeine may have potent anti-fibrotic capabilities through its ability to antagonize the Smad pathway.
Cancer:
Coffee consumption is also correlated in Africa to a reduced risk of oral, esophageal, and pharyngeal cancer. In ovarian cancer, no benefit was found. In the Nurses' Health Study and a 2011 Swedish study, a modest reduction in breast cancer was observed in postmenopausal women only, which was not confirmed in decaffeinated coffee, and a reduction in endometrial cancer was observed in people who drank either caffeinated or decaffeinated coffee. The Harvard Medical School reported in 2006 that researchers found that coffee drinkers were 50% less likely to get liver cancer than nondrinkers. Another study found a correlation between coffee consumption (both regular and decaffinated) and a lower risk of aggressive prostate cancer.
Instant coffee contains a much higher level of acrylamide than brewed coffee.
Cardioprotective:
Coffee moderately reduces the incidence of dying from cardiovascular disease, according to a large prospective cohort study published in 2008.
A 2009 prospective study in Japan following nearly 77,000 individuals aged 40 to 79 found that coffee consumption, along with caffeine intake, was associated with a reduced risk of dying from cardiovascular disease.
A 2012 meta-analysis concluded that people who drank moderate amounts of coffee had a lower rate of heart failure, with the biggest effect found for those who drank more than four cups a day.
Laxative / diuretic:
Coffee is also a powerful stimulant for peristalsis and is sometimes considered to prevent constipation. However, coffee can also cause excessively loose bowel movements. The stimulative effect of coffee consumption on the colon is found in both caffeinated and decaffeinated coffee.
Contrary to popular belief, caffeine does not act as a diuretic when consumed in moderation (less than five cups a day or 500 to 600 milligrams), and does not lead to dehydration or to a water-electrolyte imbalance; current evidence suggests that caffeinated beverages contribute to the body's daily fluid requirements no differently from pure water.
Antioxidant:
Coffee contains polyphenols such as flavan-3-ols (monomers and procyanidins), hydroxycinnamic acids, flavonols and anthocyanidins. These compounds have antioxidative effect and potentially reduce oxidative cell damage. One particular substance with putative anticarcinogenic effect is methylpyridinium. This compound is not present in significant amounts in other foods. Methylpyridinium is not present in raw coffee beans but is formed during the roasting process from trigonelline, which is common in raw coffee beans. It is present in both caffeinated and decaffeinated coffee, and even in instant coffee. Research funded by Kraft Foods shows that roast coffee contains more lipophilic antioxidants and chlorogenic acid lactones and is more protective against hydrogen peroxide-induced cell death in primary neuronal cells than green coffee. The espresso method of extraction yields higher antioxidant activity than other brewing methods.
Prevention of dental cavities:
The tannins in coffee may reduce the cariogenic potential of foods. In vitro experiments have shown that these polyphenolic compounds may interfere with glucosyltransferase activity of mutans streptococci, which may reduce plaque formation.
Gout:
Coffee consumption contributes to a decreased risk of gout in men over age 40. In a large study of over 45,000 men over a 12-year period, the risk for developing gout in men over 40 was inversely proportional with the amount of coffee consumed.
Blood pressure:
A 2011 study showed that moderate (≤4 cups per day) coffee consumption was inversely associated with high blood pressure and high triglyceride level in Japanese men. However, the study showed no significant association between coffee consumption and prevalence of metabolic syndrome for Japanese women.
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Saturday, May 18, 2013
Indoor Air Pollution
Indoor Air Pollution
Is Your Home A Healthy Home? http://ow.ly/1z7GnH
Air pollution is the introduction into the atmosphere of chemicals, particulate matter, or biological materials that cause discomfort, disease, or death to humans, damage other living organisms or damage the natural environment or built environment.
In this context, we often think of our outside environment, but air pollution takes place inside our homes as well.
Indoor air pollution and urban air quality are listed as two of the World’s Worst Toxic Pollution Problems in the 2008 Blacksmith Institute World's Worst Polluted Places report.[1]
A lack of ventilation indoors concentrates air pollution where people often spend the majority of their time. Radon (Rn) gas, a carcinogen, is exuded from the Earth in certain locations and trapped inside houses. Building materials including carpeting and plywood emit formaldehyde (H2CO) gas. Paint and solvents give off volatile organic compounds (VOCs) as they dry. Lead paint can degenerate into dust and be inhaled. Intentional air pollution is introduced with the use of air fresheners, incense, and other scented items. Controlled wood fires in stoves and fireplaces can add significant amounts of smoke particulates into the air, inside and out.[2] Indoor pollution fatalities may be caused by using pesticides and other chemical sprays indoors without proper ventilation.
Carbon monoxide (CO) poisoning and fatalities are often caused by faulty vents and chimneys, or by the burning of charcoal indoors. Chronic carbon monoxide poisoning can result even from poorly adjusted pilot lights. Traps are built into all domestic plumbing to keep sewer gas, hydrogen sulfide, out of interiors. Clothing emits tetrachloroethylene, or other dry cleaning fluids, for days after dry cleaning.
Though its use has now been banned in many countries, the extensive use of asbestos in industrial and domestic environments in the past has left a potentially very dangerous material in many localities. Asbestosis is a chronic inflammatory medical condition affecting the tissue of the lungs. It occurs after long-term, heavy exposure to asbestos from asbestos-containing materials in structures. Sufferers have severe dyspnea (shortness of breath) and are at an increased risk regarding several different types of lung cancer. As clear explanations are not always stressed in non-technical literature, care should be taken to distinguish between several forms of relevant diseases. According to the World Health Organisation (WHO), these may defined as; asbestosis, lung cancer, and Peritoneal Mesothelioma (generally a very rare form of cancer, when more widespread it is almost always associated with prolonged exposure to asbestos).
Biological sources of air pollution are also found indoors, as gases and airborne particulates. Pets produce dander, people produce dust from minute skin flakes and decomposed hair, dust mites in bedding, carpeting and furniture produce enzymes and micrometre-sized fecal droppings, inhabitants emit methane, mold forms in walls and generates mycotoxins and spores, air conditioning systems can incubate Legionnaires' disease and mold, and houseplants, soil and surrounding gardens can produce pollen, dust, and mold. Indoors, the lack of air circulation allows these airborne pollutants to accumulate more than they would otherwise occur in nature.
-----
[1] "Reports". WorstPolluted.org. Archived from the original on 11 August 2010. Retrieved 2010-08-29.
close
[2] "Duflo, E., Greenstone, M., and Hanna, R. (2008) "Indoor air pollution, health and economic well-being". ''S.A.P.I.EN.S.'' '''1''' (1)". Sapiens.revues.org. Retrieved 2010-08-29.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not, and is not intended to replace actual medical advice from a qualified doctor.
To receive your free 'Manna Goods Health Bulletin' via email, send an email to: the.manna.goods@gmail.com (Put 'Subscribe' in the subject line.)
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Is Your Home A Healthy Home? http://ow.ly/1z7GnH
Air pollution is the introduction into the atmosphere of chemicals, particulate matter, or biological materials that cause discomfort, disease, or death to humans, damage other living organisms or damage the natural environment or built environment.
In this context, we often think of our outside environment, but air pollution takes place inside our homes as well.
Indoor air pollution and urban air quality are listed as two of the World’s Worst Toxic Pollution Problems in the 2008 Blacksmith Institute World's Worst Polluted Places report.[1]
A lack of ventilation indoors concentrates air pollution where people often spend the majority of their time. Radon (Rn) gas, a carcinogen, is exuded from the Earth in certain locations and trapped inside houses. Building materials including carpeting and plywood emit formaldehyde (H2CO) gas. Paint and solvents give off volatile organic compounds (VOCs) as they dry. Lead paint can degenerate into dust and be inhaled. Intentional air pollution is introduced with the use of air fresheners, incense, and other scented items. Controlled wood fires in stoves and fireplaces can add significant amounts of smoke particulates into the air, inside and out.[2] Indoor pollution fatalities may be caused by using pesticides and other chemical sprays indoors without proper ventilation.
Carbon monoxide (CO) poisoning and fatalities are often caused by faulty vents and chimneys, or by the burning of charcoal indoors. Chronic carbon monoxide poisoning can result even from poorly adjusted pilot lights. Traps are built into all domestic plumbing to keep sewer gas, hydrogen sulfide, out of interiors. Clothing emits tetrachloroethylene, or other dry cleaning fluids, for days after dry cleaning.
Though its use has now been banned in many countries, the extensive use of asbestos in industrial and domestic environments in the past has left a potentially very dangerous material in many localities. Asbestosis is a chronic inflammatory medical condition affecting the tissue of the lungs. It occurs after long-term, heavy exposure to asbestos from asbestos-containing materials in structures. Sufferers have severe dyspnea (shortness of breath) and are at an increased risk regarding several different types of lung cancer. As clear explanations are not always stressed in non-technical literature, care should be taken to distinguish between several forms of relevant diseases. According to the World Health Organisation (WHO), these may defined as; asbestosis, lung cancer, and Peritoneal Mesothelioma (generally a very rare form of cancer, when more widespread it is almost always associated with prolonged exposure to asbestos).
Biological sources of air pollution are also found indoors, as gases and airborne particulates. Pets produce dander, people produce dust from minute skin flakes and decomposed hair, dust mites in bedding, carpeting and furniture produce enzymes and micrometre-sized fecal droppings, inhabitants emit methane, mold forms in walls and generates mycotoxins and spores, air conditioning systems can incubate Legionnaires' disease and mold, and houseplants, soil and surrounding gardens can produce pollen, dust, and mold. Indoors, the lack of air circulation allows these airborne pollutants to accumulate more than they would otherwise occur in nature.
-----
[1] "Reports". WorstPolluted.org. Archived from the original on 11 August 2010. Retrieved 2010-08-29.
close
[2] "Duflo, E., Greenstone, M., and Hanna, R. (2008) "Indoor air pollution, health and economic well-being". ''S.A.P.I.EN.S.'' '''1''' (1)". Sapiens.revues.org. Retrieved 2010-08-29.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not, and is not intended to replace actual medical advice from a qualified doctor.
To receive your free 'Manna Goods Health Bulletin' via email, send an email to: the.manna.goods@gmail.com (Put 'Subscribe' in the subject line.)
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Friday, May 17, 2013
Re-occlusion
In-Stent Restenosis
(Also Called 'Re-occlusion')
Dr. Ellis, head of Invasive and Interventional Cardiology and Director of the Cleveland Clinic’s Sones Cardiac Catheterization Laboratories, responds to this question that his patients often ask him:
"What are the treatment options for restenosis that occurs at the site of a previously implanted stent?”
There are many treatment options for blockages that occur at the site where a stent was placed. The first step is to meet with an experienced cardiac interventionalist who can tailor a treatment approach based on the location of the blocked stent, extent of the blockage, the patient’s age, type of cardiovascular disease and coexisting medical conditions. A number of things need to be considered.
Is the artery totally blocked?
First, the interventionalist should determine whether or not angioplasty equipment can even be placed across the blockage, depending on the location and severity of the blockage. If the stent is not totally blocked, the interventionalist is often able to access the blockage using traditional percutaneous techniques.
What are options for totally blocked arteries (total coronary occlusion)?
If the stent is totally blocked, alternate percutaneous techniques may be used by experienced interventionalists to access the blockage and considerably improve the success rate of this treatment approach. Special guide wires and catheters can be gently steered across the total blockages. The fine movement of new guide wire tips is much easier to control than previous guide wire tips. Success rates approach 80%. In addition, Cleveland Clinic interventionalists can use the "retrograde" approach, in which total coronary blockages are accessed from collateral blood vessels. Collateral blood vessels are new blood vessels that form to reroute blood flow around a blockage, and develop when the blockage becomes severely narrowed.
In some cases when the blockage cannot be accessed surgery may be recommended.
Has the blockage occurred where a bare metal stent was placed?
To treat a blockage that has occurred at the site of an uncoated, bare metal stent, placement of a drug-eluting stent (for eligible patients) often provides a very satisfactory long-term outcome.
If the blockage is short, sometimes balloon angioplasty or cutting balloon angioplasty are enough to effectively treat the blockage.
Balloon angioplasty is a procedure in which a small balloon at the tip of the catheter is inserted near the blocked or narrowed area of the coronary artery. When the balloon is inflated, the scar tissue of the blockage is compressed against the artery walls and the diameter of the blood vessel is widened (dilated) to increase blood flow to the heart.
The cutting balloon catheter has a balloon tip with small blades. When the balloon is inflated, the blades are activated. The small blades score the plaque, and the balloon expands the previously placed stent .
Has the blockage occurred where a drug-eluting stent was placed?
Determine proper placement. First, it is important to know if the stent was actually placed and expanded properly. An intravascular ultrasound examination can help determine if the stent was properly deployed. If the stent wasn't properly placed, sometimes simply re-expanding it is all that is needed. If the stent was well-expanded and tissue regrowth has occurred within the stent, using a different type of drug-eluting stent is generally the best option.
Review the type of drug eluting stent used. If a Sirolimus – type (Cypher, Xience, Endeavor) drug eluting stent was used, the physician will consider a Taxus stent (delivers paclitaxel). If a Taxus stent was used, the physician will consider a Sirolimus analog delivering stent.
Long-term anticoagulation therapy.
Almost all coronary interventional procedures involve the use of stents. Until the artery around the stent has healed there is a risk of blood clots forming on the metal. With bare metal stents, clopidigrel needs to be taken for at least 4 weeks and with DES, at least a year. Randomized trials are ongoing to better clarify the optimal duration of clopidigrel and related medications. In addition, in some patients prasugrel may be a better choice than clopidogrel. Talk to your doctor about the latest information about this choice. Aspirin is known to reduce the risk of heart attack in anybody with coronary artery disease bad enough to require a stent and should be taken indefinitely.
Consider bypass surgery as treatment options.
Coronary artery bypass graft surgery is a treatment in which one or more blocked coronary arteries are bypassed by a blood vessel graft to restore normal blood flow to the heart. These grafts usually come from the patient’s own arteries and veins located in the chest, leg or arm. The graft goes around the blocked artery (or arteries) to create new pathways for oxygen-rich blood to flow to the heart.
An experienced team of cardiologists and surgeons can evaluate your cardiac catheterization and medical history to determine the best option to treat restenosis.
In Summary
While restenosis that occurs at the site of a previously implanted stent can be a challenging condition to treat, experienced interventionalists who are familiar with multiple treatment options can often provide you with a treatment option that has a high likelihood of success.
For more information:
-Total Coronary Occlusions: Treatment for a totally blocked coronary artery
-Cardiac Catheterization and Coronary Interventional Procedures (angioplasty and stent)
-Bifurcation Blockage
-Live Web Chat Transcripts - see Coronary Artery Disease and Interventional Procedures
References:
-Holmes, DR, et al. Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal Stents. JAMA. 2006;295:1264-1273.
-Smith, SC, Jr, et al. “Management Strategies for Restenosis After PTCA,” from ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions. Circulation. 2006;113:156-75. http://circ.ahajournals.org/cgi/content/full/113/1/156
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. A prospective, multicenter, randomized trial evaluating the TAXUS paclitaxel-eluting coronary stent versus vascular brachytherapy for the treatment of bare metal stent in-stent restenosis: the TAXUS-V ISR trial. Program and abstracts from the Innovation in Intervention i2 Summit 2006; March 11-14, 2006; Atlanta, Georgia. Abstract 2402-9.
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA. 2006;295:1253-1263
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
(Also Called 'Re-occlusion')
Dr. Ellis, head of Invasive and Interventional Cardiology and Director of the Cleveland Clinic’s Sones Cardiac Catheterization Laboratories, responds to this question that his patients often ask him:
"What are the treatment options for restenosis that occurs at the site of a previously implanted stent?”
There are many treatment options for blockages that occur at the site where a stent was placed. The first step is to meet with an experienced cardiac interventionalist who can tailor a treatment approach based on the location of the blocked stent, extent of the blockage, the patient’s age, type of cardiovascular disease and coexisting medical conditions. A number of things need to be considered.
Is the artery totally blocked?
First, the interventionalist should determine whether or not angioplasty equipment can even be placed across the blockage, depending on the location and severity of the blockage. If the stent is not totally blocked, the interventionalist is often able to access the blockage using traditional percutaneous techniques.
What are options for totally blocked arteries (total coronary occlusion)?
If the stent is totally blocked, alternate percutaneous techniques may be used by experienced interventionalists to access the blockage and considerably improve the success rate of this treatment approach. Special guide wires and catheters can be gently steered across the total blockages. The fine movement of new guide wire tips is much easier to control than previous guide wire tips. Success rates approach 80%. In addition, Cleveland Clinic interventionalists can use the "retrograde" approach, in which total coronary blockages are accessed from collateral blood vessels. Collateral blood vessels are new blood vessels that form to reroute blood flow around a blockage, and develop when the blockage becomes severely narrowed.
In some cases when the blockage cannot be accessed surgery may be recommended.
Has the blockage occurred where a bare metal stent was placed?
To treat a blockage that has occurred at the site of an uncoated, bare metal stent, placement of a drug-eluting stent (for eligible patients) often provides a very satisfactory long-term outcome.
If the blockage is short, sometimes balloon angioplasty or cutting balloon angioplasty are enough to effectively treat the blockage.
Balloon angioplasty is a procedure in which a small balloon at the tip of the catheter is inserted near the blocked or narrowed area of the coronary artery. When the balloon is inflated, the scar tissue of the blockage is compressed against the artery walls and the diameter of the blood vessel is widened (dilated) to increase blood flow to the heart.
The cutting balloon catheter has a balloon tip with small blades. When the balloon is inflated, the blades are activated. The small blades score the plaque, and the balloon expands the previously placed stent .
Has the blockage occurred where a drug-eluting stent was placed?
Determine proper placement. First, it is important to know if the stent was actually placed and expanded properly. An intravascular ultrasound examination can help determine if the stent was properly deployed. If the stent wasn't properly placed, sometimes simply re-expanding it is all that is needed. If the stent was well-expanded and tissue regrowth has occurred within the stent, using a different type of drug-eluting stent is generally the best option.
Review the type of drug eluting stent used. If a Sirolimus – type (Cypher, Xience, Endeavor) drug eluting stent was used, the physician will consider a Taxus stent (delivers paclitaxel). If a Taxus stent was used, the physician will consider a Sirolimus analog delivering stent.
Long-term anticoagulation therapy.
Almost all coronary interventional procedures involve the use of stents. Until the artery around the stent has healed there is a risk of blood clots forming on the metal. With bare metal stents, clopidigrel needs to be taken for at least 4 weeks and with DES, at least a year. Randomized trials are ongoing to better clarify the optimal duration of clopidigrel and related medications. In addition, in some patients prasugrel may be a better choice than clopidogrel. Talk to your doctor about the latest information about this choice. Aspirin is known to reduce the risk of heart attack in anybody with coronary artery disease bad enough to require a stent and should be taken indefinitely.
Consider bypass surgery as treatment options.
Coronary artery bypass graft surgery is a treatment in which one or more blocked coronary arteries are bypassed by a blood vessel graft to restore normal blood flow to the heart. These grafts usually come from the patient’s own arteries and veins located in the chest, leg or arm. The graft goes around the blocked artery (or arteries) to create new pathways for oxygen-rich blood to flow to the heart.
An experienced team of cardiologists and surgeons can evaluate your cardiac catheterization and medical history to determine the best option to treat restenosis.
In Summary
While restenosis that occurs at the site of a previously implanted stent can be a challenging condition to treat, experienced interventionalists who are familiar with multiple treatment options can often provide you with a treatment option that has a high likelihood of success.
For more information:
-Total Coronary Occlusions: Treatment for a totally blocked coronary artery
-Cardiac Catheterization and Coronary Interventional Procedures (angioplasty and stent)
-Bifurcation Blockage
-Live Web Chat Transcripts - see Coronary Artery Disease and Interventional Procedures
References:
-Holmes, DR, et al. Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal Stents. JAMA. 2006;295:1264-1273.
-Smith, SC, Jr, et al. “Management Strategies for Restenosis After PTCA,” from ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions. Circulation. 2006;113:156-75. http://circ.ahajournals.org/cgi/content/full/113/1/156
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. A prospective, multicenter, randomized trial evaluating the TAXUS paclitaxel-eluting coronary stent versus vascular brachytherapy for the treatment of bare metal stent in-stent restenosis: the TAXUS-V ISR trial. Program and abstracts from the Innovation in Intervention i2 Summit 2006; March 11-14, 2006; Atlanta, Georgia. Abstract 2402-9.
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA. 2006;295:1253-1263
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
Thursday, May 9, 2013
Stress, Serotonin Receptors, and the Neurobiology of Depression
Stress, Serotonin Receptors, and the Neurobiology of Depression
http://www.cyberounds.com
Juan F. López, M.D.
Department of Psychiatry and Mental Health Research Institute
University of Michigan, Ann Arbor
Introduction
Major Depressive Disorder (MDD), also known as Major Depression, is a psychiatric syndrome characterized by pervasive disturbances in mood, sleep, appetite, energy, motivation, hedonic capacity, and thinking. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a depressive episode must be diagnosed if a patient has had depressed mood, or has lost interest or pleasure in most activities, for a duration of at least two weeks. However, depressive episodes often last months, sometimes years, and they carry a significant impairment in social and occupational functioning. Depressive episodes also tend to be recurrent, and if left untreated, most patients will have multiple episodes during their lifetime. The episodes tend to become more frequent, and/or more severe as the disease progresses (Post 1992). This is known as the "kindling" or "sensitization" hypothesis of mood disorders.
MDD is a common medical disorder, with a lifetime prevalence of 17.1%, and a 12 month prevalence of 10.3%, in the general population (Kessler et al., 1994). However, the prevalence of MDD in medical populations is even higher, with rates ranging from 30% to 50%, depending on the specific medical condition. This psychiatric disorder also carries a significant morbidity and mortality, with a negative impact not only for the patient itself, but also for the family, and for society in general. About two thirds of severely depressed patients exhibit suicidal ideation, and 10% to 15% commit suicide (Kaplan and Sadock, 1991).
The specific pathogenetic cause of depression is unknown, but it is widely accepted that its etiology, course, and long-term prognosis are influenced by genetic, environmental and neurobiological factors. A greater understanding of the neurobiology of this disorder is leading us to better treatment strategies that can prevent or decrease the impact of this disease. Although many neurotransmitters and neurohormones have been linked to the pathophysiolgy of depression, (e.g. norepinephrine, dopamine, thyroid hormones), research studies have implicated disturbances in the serotonin (5-HT) system and the Hypothalamic-Pituitary-Adrenal (HPA) axis as two of the neurobiological alterations most consistently associated with affective illness (Gold et al., 1988; Meltzer, 1988; Kathol et al., 1989; Nemeroff, 1998). Therefore, this presentation will focus on the regulation of these two systems, as they relate to depression.
Historically, the role of each of these two biological systems in mood disorders have been studied independently, but more recently, their interaction in the brain, as it relates to the pathophysiology of depression, has received increased attention. In this presentation, we will review recent animal and human findings, from the perspective of the 5-HT and HPA axis, which shed new light into the neurobiology of MDD. We will discuss some of the ways in which adrenal glucocorticoids and 5-HT receptors interact during conditions of chronic stress, or severe "allostatic load". We will also discuss what is the potential significance of these findings for the pathophysiology and treatment of mood disorders.
That disturbances in the Hypothalamic-Pituitary-Adrenal axis and in serotonin may share a common pathophysiological mechanism is not surprising, since we know from animal studies that they interact extensively and that they are related in a variety of ways (McEwen, 1987; Chalmers et al., 1993; López et al., 1999). The hippocampus, and the paraventricular nucleus of the hypothalamus (PVN), in particular, are anatomical regions in which components of the Hypothalamic-Pituitary-Adrenal axis and the 5-HT systems have a rich representation (see Figure 1 for an illustration of how serotonin neurons from the raphe nucleus project to the PVN and hippocampus). These regions are also part of the limbic system, an area implicated in the regulation of several vegetative functions (arousal, sleep, appetite and hedonic capacity) as well as in the control of mood. The hippocampus has also been implicated in memory and cognitive function. The recognition that the hippocampus is an integral component of the Hypothalamic-Pituitary-Adrenal axis has led some investigators (including our laboratory) to refer to this neuroendocrine system as the "Limbic"-Hypothalamic-Pituitary-Adrenal (LHPA) axis. We will therefore, for the purpose of this presentation, use the term "LHPA", instead of the more commonly used term "HPA", when referring to this system.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis and Stress
The LHPA is the classic neuroendocrine system that responds to stress. Perception of stress by an organism results in a series of events, the final result of which is the secretion of glucocorticoids (cortisol in humans, corticosterone in rats) from the adrenal cortex (Dallman et al., 1987). Activation and termination of the adrenocortical stress response is critical for adaptation and survival. Inhibition of stress responsiveness is partly achieved by the binding of circulating glucocorticoids to specific cytoplasmic receptors in hypothalamus, where they inhibit corticotropin releasing hormone (CRH) and consequently pituitary adrenocorticotropin (ACTH) secretion. Additional modulation of the system is apparently achieved in limbic structures, especially the hippocampus, a structure that is linked to the hypothalamus through neuronal connections that converge on the paraventricular nucleus of the hypothalamus (PVN), where the stress responsive CRH and vasopressin (AVP) neurons reside (López et al., 1991).
There are several lines of evidence that highlight the importance of the hippocampus for LHPA feedback mechanisms (McEwen, 1991). Pioneer work by McEwen demonstrated that the hippocampus contains a high abundance of two types of glucocorticoid receptors which are thought to control negative feedback: Type I (also known as Mineralocorticoid Receptor, or "MR") and Type II (also known as Glucocorticoid receptors or "GR"). Type I (or MR) resembles the kidney mineralocorticoid receptor and has stringent specificity, binding selectively corticosterone, the main glucocorticoid of the rat. In the rodent brain, MR is most densely localized in hippocampal and septal neurons. Type II or GR receptors are widely distributed in rat brain, including hippocampus, hypothalamus, and prefrontal cortex. However, they bind corticosterone with a lower affinity compared to the Type I (or MR) receptor. Their highest affinity is for potent synthetic glucocorticoids, such as dexamethasone (McEwen, 1991). These receptor characteristics complement each other and put the MR and GR in a position to modulate LHPA responses (see DeKloet et al., 1998, for a recent excellent review on the neurobiology of GR and MR). The MR receptors appear to be operative at low corticosterone concentrations and may offer tonic inhibition to the axis during the nadir of the circadian rhythm (De Kloet et al., 1988; McEwen 1991). When high concentrations are present, MR receptors saturate, and the GR receptors ensure the return of homeostasis. As stated above, it is also well established that the hippocampus is a central component of limbic circuitry and is fundamental in controlling aspects of cognitive and behavioral functions, putting these receptors in a position to modulate simultaneously the neuroendocrine and cognitive response of the organism to stress.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis in Depression
Hyperactivity of the LHPA axis is a well documented phenomena in MDD. This dysregulation is manifested, among other things, by cortisol hypersecretion, failure to suppress cortisol secretion after dexamethasone administration, exaggerated adrenal responses to endocrine challenges, and blunted ACTH response to CRH administration (Carroll et al., 1976; Kalin et al., 1987; López et al., 1987; Gold et al., 1988; Kathol et al., 1989b). This last observation has been interpreted as evidence of pituitary downregulation of CRH receptors secondary to an increase in secretion of CRH. There is indeed good evidence of increased central drive, based on increased activity at the nadir of the circadian rhythm (Young et al., 1995) as well as more direct findings of elevated CRH in the CSF of depressed patients (Nemeroff et al., 1984), and increased CRH immunoreactivity and mRNA levels in the PVN (Raadsheer et al., 1994, 1995). Interestingly, post-mortem studies have also found evidence of chronic LHPA activation in suicide victims, such as adrenal hyperplasia (Dorovini-Zis and Zis, 1987), downregulation of CRH receptors (Nemeroff et al., 1988), and increases in proopiomelanocortin mRNA, the precursor for ACTH, in the pituitary (López et al., 1992). It is not known whether these LHPA changes in suicide are due to the fact that a significant subset of suicide victims are patients with depressive disorders, to the stress surrounding the suicide itself, or to a neurobiological "abnormality" common to all suicides irrespective of diagnosis.
We have found, in a group of suicide victims with a history of depression, decreases in hippocampal MR mRNA levels (López et al., 1998), and more recently, a decrease in GR mRNA levels in prefrontal cortex (unpublished observation) an area of the brain which is associated with higher cognitive, and executive function. We don't know whether these changes represent a genetic, or developmental, vulnerability "marker" for suicide, or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress and/or to high peripheral glucocorticoid levels (Herman and Watson, 1994; Herman et al., 1995).
Historically, the presence of LHPA overactivity in patients with depression was believed by many to be a "secondary" phenomena of the illness, reflecting either a central monoaminergic disturbance, the stress of the illness, or both. However, over the past few years, it has become clearer that the LHPA abnormalities in MDD are intimately linked to the pathohysiology of the disease. This change in perspective was stimulated in part by the increased awareness that glucocorticoids, the final products of the LHPA axis have been shown to have profound effects on mood and behavior (McEwen 1987). For example, a high incidence of depression is linked to pathologies involving elevated corticosteroid levels, such as Cushing's syndrome. This corticosteroid-induced depression usually disappears when corticosteroid levels return to normal (Kathol 1985; Murphy 1991). In fact, it has become increasingly clear, from both animal and clinical studies, that circulating glucocorticoid levels provide important hormonal control of affect, which may be mediated by steroid-induced modulation of central limbic circuitry (McEwen 1987). The precise mechanism by which corticosteroids exert this influence on affect is not well understood. However, this mechanism is likely to involve interactions with brain neurotransmitters, since we know that central control of affect is intimately associated with the actions of the monoamines serotonin, norepinephrine and dopamine.
Serotonin Receptors and Depression
The serotonin system has been widely investigated as a key element in the pathophysiology of Depression (Meltzer, 1989), and of suicide (Mann et al., 1989), and as a mediator of the therapeutic action of antidepressants (Berendsen, 1995). Although the 5-HT system has many components, the three 5-HT molecules believed to be most closely associated with the neurobiology of mood are the serotonin transporter (5-HTt), the serotonin 1a receptor (5-HT1a), and the serotonin 2a receptor (5-HT2a, formerly 5-HT2). Most new (as well as older) antidepressants inhibit the re-uptake of serotonin from the synapse, and alter 5-HTt protein and mRNA levels (López et al., 1994; Owens and Nemeroff, 1998). Animal studies have also demonstrated that chronic antidepressant administration affects the function and number of the 5-HT1a and 2a receptors. Many electrophysiological studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a function in the hippocampus, while at the same time they "down-regulate" or "desensitize" 5-HT1a function in the raphe, where it acts as an inhibitory somatodendritic receptor (Blier and de Montigny, 1994). Some studies have also reported a modest increase in 5-HT1a receptor number in hippocampus following antidepressant administration to rodents (Welner et al., 1989; Klimek et al., 1994). We have found that suicide victims with a history of depression have decreases in 5-HT1a gene expression in hippocampus (López et al., 1998). These changes are in the opposite direction of what is observed with antidepressant treatment in rat hippocampus.
The 5-HT2a receptor has also been shown to be affected by chronic antidepressant treatment. Most, but not all, studies have reported decreases in 5-HT2a binding in the prefrontal cortex after chronic antidepressant administration (Peroutka and Snyder, 1980; Bourin and Baker, 1996). The opposite changes (5-HT2a upregulation) are found in the prefrontal cortex of suicide victims (Mann et al., 1986; Arango et al., 1990; Hrdina et al., 1993), although these findings are not universal (Stockmeier, 1997). In addition, subjects with a history of MDD dying of natural causes have increases in 5-HT2a binding in the prefrontal cortex (Yates et al., 1990).
These findings have led several investigators to propose that postsynaptic 5-HT1a and 5-HT2a receptors have functionally opposing effects (Schreiber and De Vry, 1993), that a disturbed balance of these receptors may be contributing to the pathophysiology of Depression (Berendsen, 1995), and that restoring this balance is necessary for antidepressant action (Borsini, 1994).
Interaction Between the LHPA axis and Serotonin
Another level of complexity is added by the fact that 5-HT and the LHPA axis interact at multiple levels. For example, it is known that some of the 5-HT neurons arising from the nucleus raphe dorsalis and nucleus raphe magnus project to the PVN and synapse onto CRH neurons (Fuller, 1992). 5-HT neurons also project to other brain areas, such as the amygdala and the suprachiasmatic nucleus, which are thought to modulate the function of the PVN (Törk, 1990). Pharmacological stimulation with 5-HT agents can activate ACTH and cortisol release (Fuller, 1992). Many brain areas that express 5-HT receptors also have abundant concentrations of corticosteroid receptors. In the limbic system in particular, the hippocampus has high concentrations of 5-HT1a in the same neurons that contain abundant GR and MR receptor levels, and the prefrontal cortex is rich in 5-HT2a receptors (Pazos and Palacios, 1987), as well as GR receptors.
Interestingly, unlike rodents, human prefrontal cortex also has significant amounts of MR mRNA. This constitutes anatomical evidence suggesting that MR may have a more expanded role in modulating brain function in humans than in rodents. Furthermore, the co-localization of MR and GR in prefrontal cortex suggest that both of these receptors are capable of modulating higher brain functions, such as mood, social behavior, and cognitive processing, perhaps by interacting with 5-HT receptors.
Serotonin and corticosteroid receptors not only interact anatomically, but also functionally. It has been reported that administration of serotonin can up-regulate GR in the hippocampus, and that conversely, pharmacological destruction of serotonergic projections decreases GR and MR mRNA levels in the hippocampus (Betitto et al., 1990; Seckl et al., 1990). Regulation in the other direction, i.e. glucocorticoid regulation of 5-HT receptors, has also been reported. Animal studies have demonstrated that adrenalectomy and corticosteroid administration powerfully regulate 5-HT1a receptor number and mRNA in the hippocampus (Chalmers et al., 1992, 1994; Kuroda et al., 1994). This effect of glucocorticoids seems to be specific for the postsynaptic 5-HT1a receptor, since the somatodendritic 5-HT1a is not affected by these manipulations (Chalmers et al., 1992).
The 5-HT2a receptor is also sensitive to changes in peripheral glucocorticoid levels. Upregulation of 5-HT2a in rat neocortex cortex has been reported following ten days of exogenous administration of ACTH (Kuroda et al., 1992). This effect is abolished by adrenalectomy and mimicked by corticosterone administration for ten days. Dexamethasone treatment for the same amount of time also causes a dose dependent increase in 5-HT2a binding in cortex (Kuroda et al., 1993), suggesting that this effect is mediated by GR, since dexamethasone is a potent GR agonist. Interestingly, the effect of corticosteroids on 5-HT2a receptor number seems to be specific for the cortex. Dexamethasone did not alter 5-HT2a binding in rat hippocampus. Given the relatively equal abundance of MR and GR in the hippocampus, and the preponderance of GR in rat frontal cortex, it is plausible that 5-HT receptor regulation in the cortex is mediated through different mechanisms than in the hippocampus.
Stress, Serotonin and the LHPA axis
In reviewing the clinical, psychological and biological literature on depressive illness, one factor that emerges as being closely associated with depression is stress. Stress and depression have been linked in a variety of ways: For example, both physical and psychological stressors have been shown to be temporally (and perhaps causally) related to the onset of depressive episodes (Post 1992). Some studies have suggested that, at least for recurrent depression, stressful life events are more common in "non-endogenous depression" (Frank et al., 1994). Other studies have found that stressful life events are significantly correlated even with the first episode of psychotic/endogenous depression (Brown et al., 1994). This is not to say that stress "causes" depression in people. Rather, stress is very likely interacting with an endogenous genetic predisposition, such that in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e. vulnerability + stress = depression). In fact, studies in twins by Kendler et al have demonstrated a clear interaction between genetic substrate and a recent stressful life event in the precipitation of a depressive episode: the more the genetic "loading" for depression, the more likely than a stressful event will trigger an episode. There are of course cases in which the genetic "loading" or predisposition is so high, that an episode of depression can occur in the absence of any apparent precipitating factors.
Another important link between depression and stress is the fact that both the LHPA and 5-HT systems, in addition to been involved in the pathophysiology of depression, are also, as we have discussed above, critical contributors to the neurobiology of stress (McEwen 1987) . Therefore, studying the neurobiology of stress by focusing on these two systems has given us important clues into the pathophysiology of affective illness, shed light on the actions of antidepressants, and begin to reveal how stress and mood disorders are related.
We have used chronic unpredictable stress, a postulated animal model of depression (Katz and Sibell, 1982; Armario et al., 1988) to investigate the parallel changes in 5-HT and LHPA related molecules, and to study how chronic stress and circulating glucocorticoids influence the 5-HT receptor system (López et al., 1997, 1998,1999b). In this paradigm, rats are exposed to different mild to moderate stressors everyday, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity, and increases in peripheral glucocorticoids, very similar to those found in MDD (Chapel et al., 1996; Armario et al., 1988). We found that rats subjected to this paradigm show a significant decrease in 5-HT1a mRNA and binding in the hippocampus, as well as decreases in MR mRNA levels in this same region (López et al., 1998). Chronic unpredictable stress also causes a significant increase in 5-HT2a receptor and mRNA levels in the prefrontal cortex (López et al, submitted). As stated above, these "opposite" effects (hippocampal 5-HT1a downregulation, cortical 5-HT2a upregulation) are also found in suicide victims with a history of depression (Mann et al., 1989; López et al., 1997). It is not clear if these 5-HT receptor changes are due to a direct effect of corticosteroids on the receptor themselves, or if they are secondary to corticosteroid induced changes in serotonin synthesis and turnover. However, the effects of chronic stress on these 5-HT receptors are prevented if the stress-related glucocorticoid increase is abolished. No changes are found in the presynaptic 5-HT transporter sites after chronic stress, suggesting that the effects are mainly in the postsynaptic receptors (López et al., 1997, 1998).
Antidepressant Medications, the LHPA Axis and 5-HT Receptors
The LHPA overactivity observed with chronic unpredictable stress can also be prevented by the chronic administration of either imipramine or desipramine, two tricyclic antidepressants (López et al., 1998). Both desipramine and imipramine also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in cortex. On the other hand, zimelidine and fluoxetine, two specific serotonin reuptake inhibitors, are unable to prevent the stress-induced elevation in corticosterone levels. This failure to prevent the LHPA overactivity is associated with a failure to restore the 5-HT receptor changes to baseline levels. This suggests that failure of an antidepressant to reverse the LHPA hypersecretion is associated with a failure to prevent the 5-HT receptor "dysregulation" secondary to chronic stress. We have proposed that this may be one of the neurobiological mechanisms underlying "treatment resistance" in patients with severe depression (López et al., 1997).
There is some clinical evidence that these mechanisms may be operating in depressive disorders. Persistence of hypercortisolemia after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome (Greden et al., 1983; Ribeiro et al., 1995). In addition, some clinical studies have found that tricyclics are more effective than SSRIs in the treatment of melancholia (Danish University Antidepressant Group, 1986, 1990; Roose et al., 1994), Venlafaxine, an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported to be more effective than fluoxetine in treating melancholic depression (Clerc et al., 1994), and in comorbid depression and anxiety (Silverstone et al., 1999). Since melancholia and severity of depression are associated with a higher incidence of hypercortisolemia (Kathol et al., 1989; Meador-Woodruff et al., 1990), it is possible that the presence of a severely disturbed LHPA axis in this population may be contributing to the relative resistance to SSRI treatment. Interestingly, many augmentation strategies in treatment resistant patients are in effect attempts to broaden the biochemical profile of the pharmacological treatment, which may be more effective in reversing LHPA overactivity than a treatment whose main impact is in a single neurotransmitter system.
Interplay Between Stress, the LHPA Axis, Serotonin, and Antidepressants
Based on the animal and human studies reviewed here, we can generate a working model of the interplay between stress, the LHPA axis, 5-HT receptors, and their potential interactions in suicide and depression. Figure 2 illustrates this model (solid arrows represent known effects, dashed arrows represent possible effects).
While it is possible that some monoamine receptor changes are due to antecedent changes in their endogenous ligands, we propose that many of the receptor changes observed may be a result of the LHPA overactivity present in at least some suicide victims, in particular those with a history of affective disorders. The rationale for this hypothesis derives from the above evidence, which can be summarized as follows:
1) Depressed patients, as well as suicide victims, show evidence of overactivity of the LHPA axis.
2) Chronic stress and/or high steroid levels in rats result in an alteration of specific 5-HT receptors (e.g. increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a).
3) Many human studies show the same receptor changes in the brain of suicide victims (increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a) as found in hypercorticoid states.
4) Chronic antidepressant administration causes opposite 5-HT receptor changes to those seen with chronic stress
5) Antidepressant administration reverses the overactivity of the LHPA axis.
If indeed the 5-HT1a and 5-HT2a receptors have at least a partial role in controlling affective states (either directly or secondarily through other systems), then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. This of course does not exclude the possibility that stress can be simultaneously acting through other systems, such as the CRH receptors, thereby synergistically affecting mood and behavior. Antidepressants can counteract this phenomenon by affecting 5-HT receptor function directly and by simultaneously regulating stress induced corticosteroid secretion.
Conclusion
Corticosteroid modulation of 5-HT receptors has important implications for the pathophysiology and treatment of mood disorders, and perhaps suicide. This may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and or precipitate suicidal behavior. Another implication is that altered 5-HT levels or metabolism do not necessarily have to be present for 5-HT receptor abnormalities to occur. Based on the animal data, it is apparent that specific 5-HT receptors may be directly regulated in response to alterations of corticosteroid levels. Thus, in depressed patients normal levels of serotonin and its metabolites may not necessarily reflect normal central 5-HT activity.
An important therapeutic implication of this model is the prediction that agents that can reduce the stress response, and/or decrease LHPA activation, will be useful in the pharmacological treatment of anxiety, depression and perhaps suicidal behavior. In fact, patients with MDD who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole (Murphy et al 1991; Wolkowitz et al 1993). However, these agents have many side effects, and are often difficult for patients to tolerate. In this respect, CRH receptor antagonists, which are currently under development, may provide us with a new therapeutic weapon to treat these patients (De Souza 1995, Chalmers et al., 1996). These compounds could be used in conjunction with antidepressants, as adjuvants or augmenting agents, and may decrease treatment resistance. This agents may also be useful in monotherapy, since preventing hypercortisolemia may be translated into an improvement of monoaminergic receptor function. The use of modern biochemical and pharmacological tools, coupled with our increased understanding of the neurobiology of depression, should allow us to test these hypotheses, first in animal models and then directly in patients with affective illness.
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Juan F. López, M.D.
Department of Psychiatry and Mental Health Research Institute
University of Michigan, Ann Arbor
Introduction
Major Depressive Disorder (MDD), also known as Major Depression, is a psychiatric syndrome characterized by pervasive disturbances in mood, sleep, appetite, energy, motivation, hedonic capacity, and thinking. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a depressive episode must be diagnosed if a patient has had depressed mood, or has lost interest or pleasure in most activities, for a duration of at least two weeks. However, depressive episodes often last months, sometimes years, and they carry a significant impairment in social and occupational functioning. Depressive episodes also tend to be recurrent, and if left untreated, most patients will have multiple episodes during their lifetime. The episodes tend to become more frequent, and/or more severe as the disease progresses (Post 1992). This is known as the "kindling" or "sensitization" hypothesis of mood disorders.
MDD is a common medical disorder, with a lifetime prevalence of 17.1%, and a 12 month prevalence of 10.3%, in the general population (Kessler et al., 1994). However, the prevalence of MDD in medical populations is even higher, with rates ranging from 30% to 50%, depending on the specific medical condition. This psychiatric disorder also carries a significant morbidity and mortality, with a negative impact not only for the patient itself, but also for the family, and for society in general. About two thirds of severely depressed patients exhibit suicidal ideation, and 10% to 15% commit suicide (Kaplan and Sadock, 1991).
The specific pathogenetic cause of depression is unknown, but it is widely accepted that its etiology, course, and long-term prognosis are influenced by genetic, environmental and neurobiological factors. A greater understanding of the neurobiology of this disorder is leading us to better treatment strategies that can prevent or decrease the impact of this disease. Although many neurotransmitters and neurohormones have been linked to the pathophysiolgy of depression, (e.g. norepinephrine, dopamine, thyroid hormones), research studies have implicated disturbances in the serotonin (5-HT) system and the Hypothalamic-Pituitary-Adrenal (HPA) axis as two of the neurobiological alterations most consistently associated with affective illness (Gold et al., 1988; Meltzer, 1988; Kathol et al., 1989; Nemeroff, 1998). Therefore, this presentation will focus on the regulation of these two systems, as they relate to depression.
Historically, the role of each of these two biological systems in mood disorders have been studied independently, but more recently, their interaction in the brain, as it relates to the pathophysiology of depression, has received increased attention. In this presentation, we will review recent animal and human findings, from the perspective of the 5-HT and HPA axis, which shed new light into the neurobiology of MDD. We will discuss some of the ways in which adrenal glucocorticoids and 5-HT receptors interact during conditions of chronic stress, or severe "allostatic load". We will also discuss what is the potential significance of these findings for the pathophysiology and treatment of mood disorders.
That disturbances in the Hypothalamic-Pituitary-Adrenal axis and in serotonin may share a common pathophysiological mechanism is not surprising, since we know from animal studies that they interact extensively and that they are related in a variety of ways (McEwen, 1987; Chalmers et al., 1993; López et al., 1999). The hippocampus, and the paraventricular nucleus of the hypothalamus (PVN), in particular, are anatomical regions in which components of the Hypothalamic-Pituitary-Adrenal axis and the 5-HT systems have a rich representation (see Figure 1 for an illustration of how serotonin neurons from the raphe nucleus project to the PVN and hippocampus). These regions are also part of the limbic system, an area implicated in the regulation of several vegetative functions (arousal, sleep, appetite and hedonic capacity) as well as in the control of mood. The hippocampus has also been implicated in memory and cognitive function. The recognition that the hippocampus is an integral component of the Hypothalamic-Pituitary-Adrenal axis has led some investigators (including our laboratory) to refer to this neuroendocrine system as the "Limbic"-Hypothalamic-Pituitary-Adrenal (LHPA) axis. We will therefore, for the purpose of this presentation, use the term "LHPA", instead of the more commonly used term "HPA", when referring to this system.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis and Stress
The LHPA is the classic neuroendocrine system that responds to stress. Perception of stress by an organism results in a series of events, the final result of which is the secretion of glucocorticoids (cortisol in humans, corticosterone in rats) from the adrenal cortex (Dallman et al., 1987). Activation and termination of the adrenocortical stress response is critical for adaptation and survival. Inhibition of stress responsiveness is partly achieved by the binding of circulating glucocorticoids to specific cytoplasmic receptors in hypothalamus, where they inhibit corticotropin releasing hormone (CRH) and consequently pituitary adrenocorticotropin (ACTH) secretion. Additional modulation of the system is apparently achieved in limbic structures, especially the hippocampus, a structure that is linked to the hypothalamus through neuronal connections that converge on the paraventricular nucleus of the hypothalamus (PVN), where the stress responsive CRH and vasopressin (AVP) neurons reside (López et al., 1991).
There are several lines of evidence that highlight the importance of the hippocampus for LHPA feedback mechanisms (McEwen, 1991). Pioneer work by McEwen demonstrated that the hippocampus contains a high abundance of two types of glucocorticoid receptors which are thought to control negative feedback: Type I (also known as Mineralocorticoid Receptor, or "MR") and Type II (also known as Glucocorticoid receptors or "GR"). Type I (or MR) resembles the kidney mineralocorticoid receptor and has stringent specificity, binding selectively corticosterone, the main glucocorticoid of the rat. In the rodent brain, MR is most densely localized in hippocampal and septal neurons. Type II or GR receptors are widely distributed in rat brain, including hippocampus, hypothalamus, and prefrontal cortex. However, they bind corticosterone with a lower affinity compared to the Type I (or MR) receptor. Their highest affinity is for potent synthetic glucocorticoids, such as dexamethasone (McEwen, 1991). These receptor characteristics complement each other and put the MR and GR in a position to modulate LHPA responses (see DeKloet et al., 1998, for a recent excellent review on the neurobiology of GR and MR). The MR receptors appear to be operative at low corticosterone concentrations and may offer tonic inhibition to the axis during the nadir of the circadian rhythm (De Kloet et al., 1988; McEwen 1991). When high concentrations are present, MR receptors saturate, and the GR receptors ensure the return of homeostasis. As stated above, it is also well established that the hippocampus is a central component of limbic circuitry and is fundamental in controlling aspects of cognitive and behavioral functions, putting these receptors in a position to modulate simultaneously the neuroendocrine and cognitive response of the organism to stress.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis in Depression
Hyperactivity of the LHPA axis is a well documented phenomena in MDD. This dysregulation is manifested, among other things, by cortisol hypersecretion, failure to suppress cortisol secretion after dexamethasone administration, exaggerated adrenal responses to endocrine challenges, and blunted ACTH response to CRH administration (Carroll et al., 1976; Kalin et al., 1987; López et al., 1987; Gold et al., 1988; Kathol et al., 1989b). This last observation has been interpreted as evidence of pituitary downregulation of CRH receptors secondary to an increase in secretion of CRH. There is indeed good evidence of increased central drive, based on increased activity at the nadir of the circadian rhythm (Young et al., 1995) as well as more direct findings of elevated CRH in the CSF of depressed patients (Nemeroff et al., 1984), and increased CRH immunoreactivity and mRNA levels in the PVN (Raadsheer et al., 1994, 1995). Interestingly, post-mortem studies have also found evidence of chronic LHPA activation in suicide victims, such as adrenal hyperplasia (Dorovini-Zis and Zis, 1987), downregulation of CRH receptors (Nemeroff et al., 1988), and increases in proopiomelanocortin mRNA, the precursor for ACTH, in the pituitary (López et al., 1992). It is not known whether these LHPA changes in suicide are due to the fact that a significant subset of suicide victims are patients with depressive disorders, to the stress surrounding the suicide itself, or to a neurobiological "abnormality" common to all suicides irrespective of diagnosis.
We have found, in a group of suicide victims with a history of depression, decreases in hippocampal MR mRNA levels (López et al., 1998), and more recently, a decrease in GR mRNA levels in prefrontal cortex (unpublished observation) an area of the brain which is associated with higher cognitive, and executive function. We don't know whether these changes represent a genetic, or developmental, vulnerability "marker" for suicide, or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress and/or to high peripheral glucocorticoid levels (Herman and Watson, 1994; Herman et al., 1995).
Historically, the presence of LHPA overactivity in patients with depression was believed by many to be a "secondary" phenomena of the illness, reflecting either a central monoaminergic disturbance, the stress of the illness, or both. However, over the past few years, it has become clearer that the LHPA abnormalities in MDD are intimately linked to the pathohysiology of the disease. This change in perspective was stimulated in part by the increased awareness that glucocorticoids, the final products of the LHPA axis have been shown to have profound effects on mood and behavior (McEwen 1987). For example, a high incidence of depression is linked to pathologies involving elevated corticosteroid levels, such as Cushing's syndrome. This corticosteroid-induced depression usually disappears when corticosteroid levels return to normal (Kathol 1985; Murphy 1991). In fact, it has become increasingly clear, from both animal and clinical studies, that circulating glucocorticoid levels provide important hormonal control of affect, which may be mediated by steroid-induced modulation of central limbic circuitry (McEwen 1987). The precise mechanism by which corticosteroids exert this influence on affect is not well understood. However, this mechanism is likely to involve interactions with brain neurotransmitters, since we know that central control of affect is intimately associated with the actions of the monoamines serotonin, norepinephrine and dopamine.
Serotonin Receptors and Depression
The serotonin system has been widely investigated as a key element in the pathophysiology of Depression (Meltzer, 1989), and of suicide (Mann et al., 1989), and as a mediator of the therapeutic action of antidepressants (Berendsen, 1995). Although the 5-HT system has many components, the three 5-HT molecules believed to be most closely associated with the neurobiology of mood are the serotonin transporter (5-HTt), the serotonin 1a receptor (5-HT1a), and the serotonin 2a receptor (5-HT2a, formerly 5-HT2). Most new (as well as older) antidepressants inhibit the re-uptake of serotonin from the synapse, and alter 5-HTt protein and mRNA levels (López et al., 1994; Owens and Nemeroff, 1998). Animal studies have also demonstrated that chronic antidepressant administration affects the function and number of the 5-HT1a and 2a receptors. Many electrophysiological studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a function in the hippocampus, while at the same time they "down-regulate" or "desensitize" 5-HT1a function in the raphe, where it acts as an inhibitory somatodendritic receptor (Blier and de Montigny, 1994). Some studies have also reported a modest increase in 5-HT1a receptor number in hippocampus following antidepressant administration to rodents (Welner et al., 1989; Klimek et al., 1994). We have found that suicide victims with a history of depression have decreases in 5-HT1a gene expression in hippocampus (López et al., 1998). These changes are in the opposite direction of what is observed with antidepressant treatment in rat hippocampus.
The 5-HT2a receptor has also been shown to be affected by chronic antidepressant treatment. Most, but not all, studies have reported decreases in 5-HT2a binding in the prefrontal cortex after chronic antidepressant administration (Peroutka and Snyder, 1980; Bourin and Baker, 1996). The opposite changes (5-HT2a upregulation) are found in the prefrontal cortex of suicide victims (Mann et al., 1986; Arango et al., 1990; Hrdina et al., 1993), although these findings are not universal (Stockmeier, 1997). In addition, subjects with a history of MDD dying of natural causes have increases in 5-HT2a binding in the prefrontal cortex (Yates et al., 1990).
These findings have led several investigators to propose that postsynaptic 5-HT1a and 5-HT2a receptors have functionally opposing effects (Schreiber and De Vry, 1993), that a disturbed balance of these receptors may be contributing to the pathophysiology of Depression (Berendsen, 1995), and that restoring this balance is necessary for antidepressant action (Borsini, 1994).
Interaction Between the LHPA axis and Serotonin
Another level of complexity is added by the fact that 5-HT and the LHPA axis interact at multiple levels. For example, it is known that some of the 5-HT neurons arising from the nucleus raphe dorsalis and nucleus raphe magnus project to the PVN and synapse onto CRH neurons (Fuller, 1992). 5-HT neurons also project to other brain areas, such as the amygdala and the suprachiasmatic nucleus, which are thought to modulate the function of the PVN (Törk, 1990). Pharmacological stimulation with 5-HT agents can activate ACTH and cortisol release (Fuller, 1992). Many brain areas that express 5-HT receptors also have abundant concentrations of corticosteroid receptors. In the limbic system in particular, the hippocampus has high concentrations of 5-HT1a in the same neurons that contain abundant GR and MR receptor levels, and the prefrontal cortex is rich in 5-HT2a receptors (Pazos and Palacios, 1987), as well as GR receptors.
Interestingly, unlike rodents, human prefrontal cortex also has significant amounts of MR mRNA. This constitutes anatomical evidence suggesting that MR may have a more expanded role in modulating brain function in humans than in rodents. Furthermore, the co-localization of MR and GR in prefrontal cortex suggest that both of these receptors are capable of modulating higher brain functions, such as mood, social behavior, and cognitive processing, perhaps by interacting with 5-HT receptors.
Serotonin and corticosteroid receptors not only interact anatomically, but also functionally. It has been reported that administration of serotonin can up-regulate GR in the hippocampus, and that conversely, pharmacological destruction of serotonergic projections decreases GR and MR mRNA levels in the hippocampus (Betitto et al., 1990; Seckl et al., 1990). Regulation in the other direction, i.e. glucocorticoid regulation of 5-HT receptors, has also been reported. Animal studies have demonstrated that adrenalectomy and corticosteroid administration powerfully regulate 5-HT1a receptor number and mRNA in the hippocampus (Chalmers et al., 1992, 1994; Kuroda et al., 1994). This effect of glucocorticoids seems to be specific for the postsynaptic 5-HT1a receptor, since the somatodendritic 5-HT1a is not affected by these manipulations (Chalmers et al., 1992).
The 5-HT2a receptor is also sensitive to changes in peripheral glucocorticoid levels. Upregulation of 5-HT2a in rat neocortex cortex has been reported following ten days of exogenous administration of ACTH (Kuroda et al., 1992). This effect is abolished by adrenalectomy and mimicked by corticosterone administration for ten days. Dexamethasone treatment for the same amount of time also causes a dose dependent increase in 5-HT2a binding in cortex (Kuroda et al., 1993), suggesting that this effect is mediated by GR, since dexamethasone is a potent GR agonist. Interestingly, the effect of corticosteroids on 5-HT2a receptor number seems to be specific for the cortex. Dexamethasone did not alter 5-HT2a binding in rat hippocampus. Given the relatively equal abundance of MR and GR in the hippocampus, and the preponderance of GR in rat frontal cortex, it is plausible that 5-HT receptor regulation in the cortex is mediated through different mechanisms than in the hippocampus.
Stress, Serotonin and the LHPA axis
In reviewing the clinical, psychological and biological literature on depressive illness, one factor that emerges as being closely associated with depression is stress. Stress and depression have been linked in a variety of ways: For example, both physical and psychological stressors have been shown to be temporally (and perhaps causally) related to the onset of depressive episodes (Post 1992). Some studies have suggested that, at least for recurrent depression, stressful life events are more common in "non-endogenous depression" (Frank et al., 1994). Other studies have found that stressful life events are significantly correlated even with the first episode of psychotic/endogenous depression (Brown et al., 1994). This is not to say that stress "causes" depression in people. Rather, stress is very likely interacting with an endogenous genetic predisposition, such that in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e. vulnerability + stress = depression). In fact, studies in twins by Kendler et al have demonstrated a clear interaction between genetic substrate and a recent stressful life event in the precipitation of a depressive episode: the more the genetic "loading" for depression, the more likely than a stressful event will trigger an episode. There are of course cases in which the genetic "loading" or predisposition is so high, that an episode of depression can occur in the absence of any apparent precipitating factors.
Another important link between depression and stress is the fact that both the LHPA and 5-HT systems, in addition to been involved in the pathophysiology of depression, are also, as we have discussed above, critical contributors to the neurobiology of stress (McEwen 1987) . Therefore, studying the neurobiology of stress by focusing on these two systems has given us important clues into the pathophysiology of affective illness, shed light on the actions of antidepressants, and begin to reveal how stress and mood disorders are related.
We have used chronic unpredictable stress, a postulated animal model of depression (Katz and Sibell, 1982; Armario et al., 1988) to investigate the parallel changes in 5-HT and LHPA related molecules, and to study how chronic stress and circulating glucocorticoids influence the 5-HT receptor system (López et al., 1997, 1998,1999b). In this paradigm, rats are exposed to different mild to moderate stressors everyday, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity, and increases in peripheral glucocorticoids, very similar to those found in MDD (Chapel et al., 1996; Armario et al., 1988). We found that rats subjected to this paradigm show a significant decrease in 5-HT1a mRNA and binding in the hippocampus, as well as decreases in MR mRNA levels in this same region (López et al., 1998). Chronic unpredictable stress also causes a significant increase in 5-HT2a receptor and mRNA levels in the prefrontal cortex (López et al, submitted). As stated above, these "opposite" effects (hippocampal 5-HT1a downregulation, cortical 5-HT2a upregulation) are also found in suicide victims with a history of depression (Mann et al., 1989; López et al., 1997). It is not clear if these 5-HT receptor changes are due to a direct effect of corticosteroids on the receptor themselves, or if they are secondary to corticosteroid induced changes in serotonin synthesis and turnover. However, the effects of chronic stress on these 5-HT receptors are prevented if the stress-related glucocorticoid increase is abolished. No changes are found in the presynaptic 5-HT transporter sites after chronic stress, suggesting that the effects are mainly in the postsynaptic receptors (López et al., 1997, 1998).
Antidepressant Medications, the LHPA Axis and 5-HT Receptors
The LHPA overactivity observed with chronic unpredictable stress can also be prevented by the chronic administration of either imipramine or desipramine, two tricyclic antidepressants (López et al., 1998). Both desipramine and imipramine also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in cortex. On the other hand, zimelidine and fluoxetine, two specific serotonin reuptake inhibitors, are unable to prevent the stress-induced elevation in corticosterone levels. This failure to prevent the LHPA overactivity is associated with a failure to restore the 5-HT receptor changes to baseline levels. This suggests that failure of an antidepressant to reverse the LHPA hypersecretion is associated with a failure to prevent the 5-HT receptor "dysregulation" secondary to chronic stress. We have proposed that this may be one of the neurobiological mechanisms underlying "treatment resistance" in patients with severe depression (López et al., 1997).
There is some clinical evidence that these mechanisms may be operating in depressive disorders. Persistence of hypercortisolemia after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome (Greden et al., 1983; Ribeiro et al., 1995). In addition, some clinical studies have found that tricyclics are more effective than SSRIs in the treatment of melancholia (Danish University Antidepressant Group, 1986, 1990; Roose et al., 1994), Venlafaxine, an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported to be more effective than fluoxetine in treating melancholic depression (Clerc et al., 1994), and in comorbid depression and anxiety (Silverstone et al., 1999). Since melancholia and severity of depression are associated with a higher incidence of hypercortisolemia (Kathol et al., 1989; Meador-Woodruff et al., 1990), it is possible that the presence of a severely disturbed LHPA axis in this population may be contributing to the relative resistance to SSRI treatment. Interestingly, many augmentation strategies in treatment resistant patients are in effect attempts to broaden the biochemical profile of the pharmacological treatment, which may be more effective in reversing LHPA overactivity than a treatment whose main impact is in a single neurotransmitter system.
Interplay Between Stress, the LHPA Axis, Serotonin, and Antidepressants
Based on the animal and human studies reviewed here, we can generate a working model of the interplay between stress, the LHPA axis, 5-HT receptors, and their potential interactions in suicide and depression. Figure 2 illustrates this model (solid arrows represent known effects, dashed arrows represent possible effects).
While it is possible that some monoamine receptor changes are due to antecedent changes in their endogenous ligands, we propose that many of the receptor changes observed may be a result of the LHPA overactivity present in at least some suicide victims, in particular those with a history of affective disorders. The rationale for this hypothesis derives from the above evidence, which can be summarized as follows:
1) Depressed patients, as well as suicide victims, show evidence of overactivity of the LHPA axis.
2) Chronic stress and/or high steroid levels in rats result in an alteration of specific 5-HT receptors (e.g. increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a).
3) Many human studies show the same receptor changes in the brain of suicide victims (increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a) as found in hypercorticoid states.
4) Chronic antidepressant administration causes opposite 5-HT receptor changes to those seen with chronic stress
5) Antidepressant administration reverses the overactivity of the LHPA axis.
If indeed the 5-HT1a and 5-HT2a receptors have at least a partial role in controlling affective states (either directly or secondarily through other systems), then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. This of course does not exclude the possibility that stress can be simultaneously acting through other systems, such as the CRH receptors, thereby synergistically affecting mood and behavior. Antidepressants can counteract this phenomenon by affecting 5-HT receptor function directly and by simultaneously regulating stress induced corticosteroid secretion.
Conclusion
Corticosteroid modulation of 5-HT receptors has important implications for the pathophysiology and treatment of mood disorders, and perhaps suicide. This may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and or precipitate suicidal behavior. Another implication is that altered 5-HT levels or metabolism do not necessarily have to be present for 5-HT receptor abnormalities to occur. Based on the animal data, it is apparent that specific 5-HT receptors may be directly regulated in response to alterations of corticosteroid levels. Thus, in depressed patients normal levels of serotonin and its metabolites may not necessarily reflect normal central 5-HT activity.
An important therapeutic implication of this model is the prediction that agents that can reduce the stress response, and/or decrease LHPA activation, will be useful in the pharmacological treatment of anxiety, depression and perhaps suicidal behavior. In fact, patients with MDD who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole (Murphy et al 1991; Wolkowitz et al 1993). However, these agents have many side effects, and are often difficult for patients to tolerate. In this respect, CRH receptor antagonists, which are currently under development, may provide us with a new therapeutic weapon to treat these patients (De Souza 1995, Chalmers et al., 1996). These compounds could be used in conjunction with antidepressants, as adjuvants or augmenting agents, and may decrease treatment resistance. This agents may also be useful in monotherapy, since preventing hypercortisolemia may be translated into an improvement of monoaminergic receptor function. The use of modern biochemical and pharmacological tools, coupled with our increased understanding of the neurobiology of depression, should allow us to test these hypotheses, first in animal models and then directly in patients with affective illness.
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