The Doctor Weighs In

By Dov Michaeli MD, Ph.D

We recently had to make a large (really large) purchase – a condominium. What went through my mind in making the bid? This question, in a more general sense, is the subject of a new field – psychoeconomics and neuroeconomics. In 2002, Daniel Kahneman, of Princeton and the Hebrew University, received the Nobel Prize in Economics “for having integrated insights from psychological research into economic science, especially concerning human judgment and decision-making under uncertainty”.

So I put myself on the couch, and pretended to be Prof. Kahneman. What was I thinking when I made the bid?

Here are my thoughts when I saw the asking price: no @#$% way! After all, the real estate market is crumbling. On the other hand, not in this town…On the other hand, I am going to feel like an idiot paying the asking price, although it was actually quite reasonable…On the other hand, the sellers are loaded, they don’t even live in the condo, a low bid will probably not faze them…On the other hand, if I come with a really low-ball offer I may push them to respond emotionally (i.e. become insulted and angry) and cut off the negotiation. You get the point: negotiation is a complex psychological process, and neuroscience wants to understand it.

The neural basis of decision- making

Exactly five years ago, a paper in Science, bearing the above title, explored the neurological brain circuits that are involved in economic decision-making. They used two well-known techniques: functional magnetic resonance imaging (fMRI) to investigate neural substrates of cognitive and emotional processes involved in economic decision-making, and the Ultimatum Game. In the Ultimatum Game, two players are offered a chance to win a certain sum of money. All they must do is divide it. The proposer suggests how to split the sum. The responder can accept or reject the deal. If the deal is rejected, neither player gets anything. The rational solution, suggested by game theory, is for the proposer to offer the smallest possible share and for the responder to accept it. If humans play the game, however, the most frequent outcome is a fair share. Unfair offers elicits activity in brain areas related to both emotion (anterior insula, INS) and cognition (dorsolateral prefrontal cortex, DLPFC).

The investigators scanned players as they responded to fair and unfair proposals. Indeed, unfair offers elicited increased activity in the anterior insula, as expected. This suggests an important role for emotions in decision-making, a nice confirmation of what we knew all along: there is an emotional component in any negotiation, and the perception of unfairness tends to increase the role of emotions, at the expense of rational analysis.

Better life through chemistry

This study provided the anatomical locations where decision-making takes place. But what about function? What makes these neurological circuits come to life and contribute to decision-making? Knowing how things happen is in a way even more important than knowing where they happen. We know, for instance, that neurons communicate with each other through chemicals called neurotransmitters. So it would be nice to identify the neurotransmitters involved in decision-making. Once we understand how things work, or which chemicals are involved, it allows us to intervene, to modulate and modify the process. This remained unknown until a publication in Science magazine this month shed light on the mystery. In a paper titled “Serotonin Modulates Behavioral Reactions to Unfairness” scientists from Cambridge University in the U.K. found that serotonin (5 hydroxytryptamine, or 5HT) is it!

Serotonin has long been implicated in social behavior and impulsivity, but the mechanisms through which it modulates self-control remain unclear. The Cambridge scientists observed the effects of manipulating serotonin function on behavior in the Ultimatum Game. Normally, if the first player proposes to keep the lion’s share for himself, the second player will accept the deal about 50% of the time. He may resent the inequity, but he realizes that a small share is better than nothing. In this experiment, half the participants had low serotonin levels, and half had normal levels. Participants with depleted serotonin levels rejected 80% of unfair, but not fair offers. You would guess they were depressed, or cranky; but no, they were not; they showed no changes in mood or fairness judgments. “Lower levels of serotonin selectively alter reactions to unfairness…[it] increased retaliation to perceived unfairness ”, concluded the authors. Or more generally, these results suggest that serotonin plays a critical role in regulating emotion during social decision-making.

Can brain serotonin levels be increased?

Serotonin (5 HT) is secreted by a neuron (called presynaptic neuron) into the space (synapse) between it and the adjacent neuron (the postsynaptic neuron). The serotonin in the synapse is taken up by the postsynaptic neuron and metabolized. This is how the nervous system maintains a constant level of serotonin. Various agents can raise the level of serotonin in the brain through inhibition of serotonin reuptake by postsynaptic neurons. These include MDMA (ecstasy), amphetamine, cocaine, dextromorphan(an antitussive or anti cough agent), tricyclic antidepressant (TCAs), like valium, and selective serotonin reuptake inhibitors (SSRIs), like Prozac and Paxil.

The three-martini lunch, and more

So now we can begin to understand the concept of a “business lunch”. Food and alcohol stimulate the reward circuits in the brain, and serotonin is one of the neurotransmitters involved. Everybody is in an agreeable frame of mind, anger is muted and negotiations flow smoothly. Even weighty life-and-death decisions could be affected. Could have Osama bin Laden been a nicer person had his religion permit something stronger than yogurt? Could the course of history have changed had Bush-Cheney-Rumsfeld had a pleasant three martini lunch before deciding to go to war? Should we pass a constitutional amendment barring teetotalers from the presidency? All important questions that, as scientists are fond of saying, require further study.

Oh yes, that condo negotiation? Our offer was accepted as is, no counter-offer. My initial reaction  was surprise and elation. On the other hand, did we offer too much?... On the other hand, had we offered a lower price would we have made them angry?... On the other hand…

A glass of wine resolved all my doubts: we are simply great negotiators.

By Dov Michaeli MD, Ph.D

Phew…that was something. We ate and we ate, and drank and drank—I thought we are going to burst. Literally. I hope everybody in our Thanksgiving party (over 30 people) survived intact. Being a doctor, and a worrier, the thoughts of what could go wrong were never quite banished by the pleasures of gluttony. What dangers were going through my mind?

The burst stomach

Have you ever seen a snake swallowing a whole turkey? You can actually see the poor creature traveling through the long intestines of the tubular glutton. Well, a burst stomach is extremely rare, and happens only in rare conditions where the brain center controlling hunger and satiety is malfunctioning. Normal stomach capacity is about 8 cups, although it can range form 4 to 12, according to Dr. Edward Saltzman of Tufts Medical School, quoted in a New York Times article on the hazards of Thanksgiving. But for us regular gluttons, there are more common dangers lurking in stuffing our faces.

Heart attacks

This is probably the most serious problem of serious overeating. Here is what happens:

A normal meal of about 1500 calories sits in the stomach 1-3 hours, depending on the amount of fat in the diet; fat slows down stomach emptying. How is this night different from all other nights? The average American consumed yesterday 4500 calories and 229 grams of fat, according to the Calorie Control Council (full disclosure: they represent the makers of low-calorie foods). The average time to empty this humongous amount of fatty food is 8 hours. This in itself can cause only a sensation of fullness (loosen your belts) and flatulence (leave the room, please). But what goes on in your physiology is more serious: in order for the stomach and intestines to perform their job, they get an increased supply of blood coursing through the arteries and veins that supply them. This blood is diverted from vital organs such as the heart (vital for all of us) and the brain (less vital for some people I know). Now if instead of 1-3 hours the blood has to take an 8 hour detour, and a lot more blood diverted, to boot, and you can see the stress the heart and the brain are undergoing. In fact, if the blood supply to the heart is marginal to begin with, this massive diversion of blood volume will tip the balance and result in a heart attack.

To add insult to injury, the high fat content in a typical Thanksgiving meal results in a massive influx of lipids and triglycerides into the blood. This situation, called hyperlipidemia and hypertriglyceridemia, causes an increase in platelet aggregation. Those tiny cells, when sticking together to form a platelet clot, can cause blockage of the coronary precipitating, yes you guessed it, a heart attack. The combination of reduced volume of blood flow to the heart, and the increase in blood coagulability is more than additive; the risk is not 1+1=2, it is more like 1+1=10.

The gall of it all

In order to absorb dietary fat our digestive system needs to break it up into microscopically small particles. This is accomplished by the bile, a juice flowing from the gallbladder. Sometimes, the solids in the bile precipitate out and form gallstones. They can then occlude the bile duct, the narrow outlet from the gallbladder to the small intestine. When there is a lot fat in the diet, the hormone chlecystokinin signals that a large amount of bile is required. But if the bile duct is occluded the bile backs up, and the result is excrutiating abdominal pain that may mimic the pain of a heart attack.

What about the brain?

Here the consequences can be just as serious. The reason we feel drowsy after a heavy meal is that blood supply to the brain is reduced. This in itself never killed anybody. But add to this the amount of alcohol we consume with the meal—and put us behind the wheel, and you can see why the accident rate is sky high and Highway Patrol is out in force on Thanksgiving Day.

Before you rush to your computers to berate me for omitting your favorite culprit or theory, here is one subject you shouldn’t bother about: the urban legend that the amino acid tryptophan is the culprit of the meal-induced drowsiness. Tryptophan is indeed the precursor of melatonin, the sleep-inducing hormone. But the amounts required to increase significantly the level of melatonin are much higher than even the most outrageously gluttonous feast can provide.

Now that I told you how badly we behaved yesterday, did I restrain myself? As they say in New York, fuggeddaboudit; I stuffed my face and enjoyed every calorie of it. Today, though, starts the hard task of atoning for my sins. But I enjoyed it while it lasted. I hope you did too.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

Several months ago I received an alarming phone call from my nephew: he had terrific pain in his abdomen which caused him to double over. His stool was pitch black. It was obvious that he had an acute stomach ulcer, probably bleeding. What could cause this painful disease?

Since the late 19^th century doctors described the existence of bacteria in the stomach, but for a variety of reasons these reports did not gain traction, or were simply not believed. The bacterium, later named Helicobacter pylori was rediscovered in 1979 by Australian pathologist Robin Warren, who did further research on it with Barry Marshall beginning in 1981; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by infection by this bacterium and not by stress or spicy foods as had been assumed before. Their report was met with universal disbelief. I remember my own dismissive reaction when I read the first papers. An organism living in such an acidic environment (pH 2-3)? And not as a transient tenant, but a permanent resident? “everybody” knew that stomach ulcer is caused by stress…there must be some mistake here.

The experiment that changed everybody’s mind was when Barry Marshall, in a dramatic effort to convince the medical world, swallowed a petri dish of H. pylori, showed with gastric biopsy that the bacteria indeed colonized his stomach, developed gastritis within weeks after swallowing it, eradicated it with a combination of bismuth subsalicylate (Pepto Bismol) and metronidazole (Flagyl), and a second endoscopy 10 days later confirmed that the gastritis resolved. It was only then, in 1994, that NIH ( the National Institutues of Health) published an opinion stating that most recurrent gastric ulcers were caused by H. pylori, and recommended that antibiotics be included in the treatment regimen. In 2005 Warren and Marshall were awarded the Nobel Prize for their work.

What is H.pylori?

This bacterium is wonderful example of biological adaptation. It burrows into the mucous layer (a gel-like mucus layer) of the stomach, and that’s where it stays. But to survive in this hostile environment it had to somehow protect itself from the acid. Urea is normally secreted by the epithelial cells (these are the cells lining the stomach). The bacteria secrete an enzyme, urease, which breaks down urea to ammonia and CO 2 . Ammonia does a wonderful thing for these bacteria: it neutralizes the acid in the vicinity, thus allowing them to thrive in this forbidding environment. But it does something else: it kills the epithelial cells that come in contact with it. Thus it, and some other proteins secreted by the bacterium, cause gastritis (inflammation of the stomach lining) and eventually, an ulcer.

What about the acid?

We are not completely blameless--H. pylori gets some help from us in causing gastritis and ulcers. Once the mucous layer is damaged by  bacterial colonization, the epithelial cells lie bare and defenseless against the destructive effects of the acid. This can explain the relationship between emotional upset and ulcer disease: stress hormones cause an increased secretion of acid. Coffee has also been shown to increase acid secretion.  Unfortunately, decaffeinated coffee is not going to help;  chemicals that cause increase in acid secretion are present also in decaf. The same is true for excessive alcohol consumption; it damages the mucous layer, and exposes the cells to acid. add to that H. pylori--and you are in trouble.

Eradicate! eradicate?

H. pylori is an ancient organism that has lived in human stomachs probably since the beginning of our species, about 4 million years ago. It is disseminated with the drinking water, and probably infected 100% of the human population before sanitary conditions became widespread in the 19^th and 20^th century. As we saw, the ulcer formation is really incidental, collateral damage, to the ingenious secretion of urease and neutralization of stomach acid. Even more alarming, it is now generally accepted that H. pylori is responsible for most cases of stomach cancer. So obviously, if we just treated this pesky bacterium to a dose of antibiotics-we’d solve the problem once and for all. Indeed, while the incidence of H. pylori infection in humans is decreasing in developing countries, presumably because of improving sanitation and increasing use of antibiotics, in the United States the incidence of gastric cancer has decreased by 80 percent from 1900 to 2000.

However, there are always coseqences; some of them unintended. Parallel to the decrease in H. pylori infection there is an increase in the incidence of acid reflux from the stomach into the esophagus. And even more alarming: esophageal cancer is now the most rapidly rising cancer in the U.S. and Europe.

Fortunately, in most cases we can deal with this problem quite easily: we have now powerful drugs that are called proton-pump inhibitors, such as prilosec, that inhibit acid formation in the stomach and its reflux to the esophagus.

So here is another example of the delicate balance between us and our environment, in this case our internal environment. Recent studies showed that gut bacteria may contribute to obesity or even to our mood. So before we indiscriminately eradicate the flora that inhabited us for millions of years and upset the delicate biological balance we live in, we should carefully consider the consequences.

Dov michaeli MD, Ph.D is in the biotech industry

"Most heart attacks in women are preventable," is the headline of an article posted on NBC.com.  The article describes a study, published in the Archives of Internal Medicine, that was done by the researchers at the Karoinska Institute in Sweden.  Dr. Agneta Akesson and colleagues looked at the diet and lifestyle patterns of almost 25,000 postmenopausal women.  At the time of enrollment none of the women had heart disease, diabetes or cancer.

The researchers asked the women to fill out "food frequency" questionnaires to identify how often they ate 96 different foods.  The researchers analyzed the data and found four major dietary patterns:

• Healthy - vegetables, fruits, and legumes
• Western/Swedish - red meat, processed meat, poultry, rice, pasta, eggs, fried potatoes, and fish
• Alcohol - wine, beer and some snacks
• Sweets - sweet baked goods, candy, chocolate, jam, and ice cream

Other information collected included family history of heart disease, education level, physical activity, and body measurements.

The women were followed for an average of 6 years.  During that time, 308 women had heart attacks.  The investigators found that two of the dietary patterns (healthy and alcohol) were associated with a decreased risk of heart attack.  Women who drank less than a quarter ounce of alcohol daily (that is just a splash in the bottom of your glass) and ate lots of veggies, fruit, whole grains, legumes, and fish had a 57% lower risk of having a first heart attack.  That is a whopping big difference.

If women added three other healthy lifestyle habits into the mix (not smoking, being physically active, and avoiding too much weight gain), they had a 92% lower risk of heart attack.  In other words, most heart attacks in women are preventable by making healthy lifestyle choices.

Now, it is one thing to say, eat healthy, drink in moderation, exercise and maintain a healthy weight.  It is quite another thing to actually do all of those things over the course of an entire lifetime.  On the other hand, if you look at the amount of money the US (and, indeed, the entire world) spends to treat cardiovascular disease, I believe you would find there is enough there to buy each and every person a personal cook and a personal trainer (I believe this is the secret to Oprah's weight loss and maintenance).

I say this tongue in cheek, but it does make the point that we aren't spending our "health" care dollars on the right things.  We spend generously to fix disease, but we are very stingy when it comes to funding health.   It is time to get this right.  There aren't enough dollars in any treasury to treat all of the heart disease we are going to see as a result of the global epidemic of obesity and physical inactivity.  This must be  a top priority of policy makers and health reformers.  Studies, like the Karolinska study, should be used to promote changes in public policy - such as healthy school foods, ensuring that all neighborhoods have access to fresh fruits and vegetables and that they have safe places where kids and adults can move their bodies (without worrying about getting shot in the process).

Every politician, health reformer, and policy wonk ought to know about this study and others that prove that healthy lifestyles mean fewer heart (expensive) attacks - not just in women, but in men as well.  The bottom line is most heart attacks are preventable!

By Dov Michaeli MD, Ph.D

Here are three headlines from today’s paper:

1. Front page: “GOP Losing Grip On Core Business Vote”. For obvious reasons.
2. Opinion page: “Immigration Losers” by Richard Nadler, President of Americas Majority Foundation, a Midwest public policy think tank (and I might add, a Republican organization in the mold of the Taft dynasty): “ …Republicans need to repudiate… the immoral, uneconomical goal of mass deportation”.
3. Opinion page: “The Future of Bioenergy”, by Juan Enriquez, managing director of Excel Medical Ventures, cofounder of Synthetic Genomics, and founding director of Harvard Business School Life science Project.

The first article Chronicles the takeover of the Republican party by the social conservatives, and the virtual disappearance of the fiscal conservatives/social moderates from the party. The second decries the xenophobic and punitive stance of the Republican party with regard to immigration issues. The last one calls for innovative approaches, using biology to solve the energy and global warming dilemmas we are confronted with.

Quiz: which newspaper was I reading?

1. The New York Times.
2. The Washington Post.
3. The Los Angeles Times.

Answer: none of the above. It was the Wall Street Journal, the bastion and mouthpiece of conservative (read: regressive) ideology, and a fierce opponent of anything liberal, such as fiscal responsibility and global warming. The editorial page had labeled the global warming issue as a liberal hoax, a figment of liberal scientists’ imagination, invented out of whole cloth and computer models.

But the purpose of this posting is not to harangue one particular political view. I want to highlight the salient points made in Enriquez’s article as to what Biology can bring to the table in solving our energy and climate problems. I had intended to write about this issue for a long time and this article was the catalyst.

A paradigm shift

One of the deepest thinkers of the history of science was Thomas Kuhn who, in 1962, published his seminal book “The Structure of Scientific Revolutions”. In it he argued that we all share a certain view of the world (paradigm) at a given time, on which the science of the time is based. But then and insight occurs, which shakes the foundation of our old world view and on which a new paradigm is founded. For example, until the 17^th century Anatomy and Medicine were based on the writings of Galen, a Greek physician from the 2^nd century. For 15 centuries scientists and physicians did not bother to dissect an animal in order to observe and verify the Galenic dogmas handed down to them since antiquity. But then William Harvey, a British physician, had an insight: why not observe how blood flows-- which led to the discovery of the circulation. But more happened: the demonstration that Galen’s writings about blood flow were wrong led other scientists to question his other assertions, test them through direct observations- which led to the modern sciences of Anatomy and Physiology. In fact, the revolution did not stop there; people learned to view with suspicion “received wisdom” handed down by higher authorities. These momentous changes in world view were a “paradigm shift”.

We are changing our world view,again

When our agricultural practices, inherited from the time we began to cultivate crop plants about 10,000 years ago, no longer sufficed to feed an exploding population we invented better ploughs, bigger machines, synthetic fertilizers, powerful insecticides. But this solution finally reached its inherent limitations. In the 20^th century the world could not feed the hungry multitudes of China, India and Africa. Malthus was triumphant. But then another revolution took place.

‘We began to apply more Gregor Mendel and less Henry Ford. Plant geneticists like Nobel Prize winner Norman Borlaug found that altering plants biologically was even more powerful and efficient than brute-force mechanical solutions. By altering seeds, harvest cycles and climate range, Mr. Borlaug and his colleagues launched the green revolution. Poor farmers in China and India, who could never afford a mechanical solution, became net exporters using a biological solution.’

The new world view is that the cleanest and most efficient solutions to our environmental and energy problems will be provided by Biology.

Consider coal, the most abundant and most polluting source of energy we have. Hydrocarbons are, in essence, sunlight concentrated in plant, animal or bacterial matter. Be it coal, gas or oil, what we are extracting and burning is bioenergy concentrated in carbon. Molecular Biology, the science that launched a thousand medical advances, is now enabling us to convert coal into ethanol in the ground; no more mining, no more environmental degradation, no more millions of tons of carbon emission, no more global warming.

And how is this miracle going to be accomplished? By genetically engineering bacteria that will break down the hydrocarbons of coal (or oil, for that matter) and convert it into ethanol. This is eminently doable, the technology is already here—all we need to do is change our thinking from big engineering solutions to clean and elegant biological ones.

You ain’t seen nothing yet

In the August 3 2007 issue of Science, an article titled “ Genome Transplantation in Bacteria: Changing One Species to Another” was published by scientists from the Craig Ventner Institute in Bethesda Maryland . (In its previous incarnation as the Celera Corporation, it was one of the two teams that deciphered the human genome). The article begins thus: “ As a step toward propagation of synthetic genomes, we completely replaced the genome of a bacterial cell with one from another species by transplanting a whole genome as naked DNA” (italics mine).

The significance of this simple statement is hard for the layman to fathom. In fact, it is almost impossible to grasp the enormity of the consequences of such a statement. What it means is that it will be possible in the not too distant future to synthesize new organisms. Not preexisting ones—completely synthetic new species! Now think of it:

· Synthetic bacteria whose whole mission in life is to convert coal and oil into ethanol at a rate faster than we could extract the hydrocarbons from the ground. And much cleaner and enormously cheaper, to boot.

· Synthetic bacteria that will consume any pollutant or toxic material we manage to create.

· Synthetic bacteria that will consume prodigious amount of carbon dioxide from the atmosphere, and convert it into ethanol—a two’fer.

· Synthetic bacteria that will course our blood vessels and convert LDL into HDL particles, and consume triglycerides while they are at it.

· Synthetic bacteria that will be able to sense glucose levels in the blood and release the appropriate amount of synthetic insulin in response.

Need I go on? The possibilities of this scientific revolution are mind boggling. Our world view will become totally biological. Sounds like science fiction or at least a distant dream: not at all. In an interview Craig Ventner stated that his team will have the first synthetic bacterial “species” in 5-10 years!

There is an ancient Chinese curse “may you live in interesting times”. Science will convert the curse into a blessing.

Dov Michaeli MD, Ph.D is in the Biotech industry.

Poor Mattel; three huge recalls of lead-tainted toys, despite conscientious testing efforts. Those babe-in-the-woods quality control experts were no match to the wily new capitalists from China, determined to maximize profit. Isn’t that the name of the game?

What’s next? A toxic Barbie? That may actually be a blessing in disguise.

But, it’s not only toys. Here is an item from today’s San Jose Mercury:

SACRAMENTO - "The state's public health department asked parents Thursday to toss certain Chinese-made lunchboxes potentially containing dangerous levels of lead - the same ones it distributed in a campaign to promote healthy eating.                                                                                 

The department distributed more than 350,000 of the canvas lunchboxes, only to find out that at least three that were tested in a batch of 56,000 contained "significant" levels of lead."

The toxic legacy of lead

Lead was mined in Asia Minor as early as 8000 years ago. Because of its easy malleability it was used in making ornaments, like the 7^th millennium BC old necklace found in Anatolia. Even today, Richard Serra, one of our foremost sculptors, used lead in his early work, before switching to the less malleable, but also much less toxic iron. Lead as a poison was recognized in 250 BC by a Greek physician and poet (Nicander of Colophon) living in Anatolia. To the history buffs among you, here is a fascinating story. Wealthy Romans suffered more than their fair share from gout. Their riches enabled them to drink their wine, an expensive luxury in those days, from ceramic amphoras (wine vessels) and cups. To avoid leaching of the lead, the ceramic material needs to be fired at high temperatures. Alas, they did not possess the technology for that. To add insult to injury, the rich preferred decorated vessels over the plebeian looking plain vessels. But those decorations contained lead paint, and the glazing process to lock in the paint was done with inadequately hot fire. But wait, wait, there is more. The Romans imported their Port wine from Oporto, Portugal, and they liked it sweet. So those wily early Portuguese farmer capitalists added a sweet additive to the wine: lead acetate. Now we know where the belief that red wine can cause gout came from.

What makes it toxic?

Lead causes its harm by mimicking iron, calcium and zinc, biologically important metals. It interferes with the synthesis of hemoglobin, hence the anemia that it causes looks just like iron deficiency anemia. It also wreaks havoc with the GI system, causing nausea, vomiting, diarrhea, constipation.

But the most insidious action of this metal is in the nervous system. The symptoms range from irritability, lethargy and loss of appetite to cognitive abilities like loss of memory, irrational behavior, and in children-deficient development of the nervous system.

The reason for the devastating effect on nervous system is that interferes with the neurotransmitter glutamate (an amino acid). In fact, more than half the neurons in the brain are glutaminergic. One of the receptors for glutamate is called N-methyl-D-aspartate or NMDA, and lead binds avidly to this receptor, inhibiting its action. What do neurons with this receptor do? You guessed it: they are important in brain development of children, and they are crucial to the acquisition of knowledge and memory. Most of the neurons in the hippocampus, a sea horse-like structure in the brain, contain NMDA receptors; the hippocampus also happens to be the site of long term memory formation.

And the implication of lead exposure?

The obvious ones are its GI, hematological and neurological toxicities. But did anybody look at the role of lead exposure in the huge rise in ADHD diagnoses? Hyperactivity, short attention span, learning disorders are all consequences of lead toxicity. A study measuring blood lead levels in these kids is sorely needed.

And for you history buffs. Is it possible that one of the many reasons leading to the decline and fall of the Roman Empire was chronic lead exposure? Consider this: A few skeletons of Roman nobles were tested for lead content; it was extremely high, in the toxic range.

Is the American Empire next?

Dov Michaeli MD, Ph.D is in the biotech industry and was probably exposed to lead in his childhood.

By Dov Michaeli MD, Ph.D

Some of the health advice we come across in the media and the internet is so outrageous it borders on quackery; no, it is quackery. If it wasn’t so dangerous it would be hilarious. So I thought we should all share in the hilarity. But before we proceed, a disclaimer: the following is based on actual Q and A, but the author took  literary license to highlight their innaneness (there, I finally got to use this word). So here goes:

HEALTH QUESTION & ANSWER SESSION
Q: I've heard that cardiovascular exercise can prolong life; is this true?
A: Your heart is only good for so many beats, and that's it... don't waste them on exercise. Everything wears out eventually. Speeding up your heart will not make you live longer; that's like saying you can extend the life of your car by driving it faster. Want to live longer? Take a nap.

Q: Should I cut down on meat and eat more fruits and vegetables?
A: You must grasp logistical efficiencies. What does a cow eat? Hay and corn. And what are these? Vegetables. So a steak is nothing more than an efficient mechanism of delivering vegetables to your system. Need grain? Eat chicken. Beef is also a good source of field grass (green leafy vegetable). And a pork chop can give you 100% of your recommended daily allowance of vegetable products.

Q: Should I reduce my alcohol intake?
A: No, not at all. Wine is made from fruit. Brandy is distilled wine, that means they take the water out of the fruity bit so you get even more of the goodness that way. Beer is also made out of grain. Bottoms up!

Q: How can I calculate my body/fat ratio?
A: Well, if you have a body and you have fat, your ratio is one to one. If you have two bodies, your ratio is two to one, etc.

Q: What are some of the advantages of participating in a regular exercise program?
A: Can't think of a single one, sorry. My philosophy is: No Pain...Good!

Q: Aren't fried foods bad for you?
A: YOU'RE NOT LISTENING!!! ... Foods are fried these days in vegetable oil. In fact, they're permeated in it. How could getting more vegetables be bad for you?

Q: Will sit-ups help prevent me from getting a little soft around the middle?
A: Definitely not! When you exercise a muscle, it gets bigger. You should only be doing sit-ups if you want a bigger stomach.

Q: Is chocolate bad for me?
A: Are you crazy? HELLO . Cocoa beans! Another vegetable!!! It's the best feel-good food around!

Q: Is swimming good for your figure?
A: If swimming is good for your figure, explain whales to me.


Q: Is getting in-shape important for my lifestyle?
A: Hey! 'Round' is a shape!


Well, I hope this has cleared up any misconceptions you may have had about food and diets.

Finally, an exercise regimen I found in a Man's Health magazine. I have been following it religiously:

You have to give this a try, it really works.

This exercise is suggested for mature adults, to build muscle strength in the arms and shoulders. It seems so easy, so I thought I'd pass it on. I suggest doing it three days a week.
Begin by standing on a comfortable surface, where you have plenty of room at each side. With a 5-lb potato sack in each hand, extend your arms straight out from your sides and hold them there as long as you can.

Try to reach a full minute, and then relax.

Each day, you'll find that you can hold this position for just a bit longer. After a couple of weeks, move up to 10-lb potato sacks. Then try 50-lb potato sacks and then eventually try to get to where you can lift a 100-lb potato sack in each hand and hold your arms straight for more than a full minute. (I'm at this level)

After you feel confident at that level, put a potato in each of the sacks.

And remember:

"Life should NOT be a journey to the grave with the intention of arriving safely in an attractive and well preserved body, but rather to skid in sideways - beer in one hand - chocolate in the other - body thoroughly used up, totally worn out and screaming "WOO HOO, What a Ride"

Dov Michaeli MD, Ph.D is in the biotech industry and is a nut when it comes to diet and exercise.

By Dov Michaeli, MD, Ph.D

Did you ever stop to think: how old is this wine? No, I don’t mean this bottle, or even this medieval winery in Bordeaux ? I mean, how long have people been imbibing? How did they stumble upon this wonderful drink?

The biochemical evidence

The “active ingredient” in wine (and beer, and hard liquor) is ethanol—yes, the same stuff that is supposed to power our cars in a few years. But think about it, ethanol is a foreign substance to our body. So how come we have an enzyme (alcohol dehydrogenase) that is specifically designed to metabolize it? In fact, we are not unique in this respect—most organisms (even bacteria) contain a version of this enzyme. The answer is that since very very ancient times, probably since complex aerobic organisms evolved and glucose became a source of energy (about a billion years ago), the sugar in dead organisms, both plants and animals, underwent fermentation to make ethanol. And since organisms feed upon each other ( as uncle Walt said: it’s a cruel world after all ), after the first exhilaration of getting drunk on the rotting food, cooler heads prevailed and realized that it was evolutionarily advantageous for them to be able to metabolize this elixir before it did them in. So humans were equipped to handle alcohol since they became a unique species (1 million years ago if you start counting from Homo erectus). But how much of a buzz could Uncle Erectus get from a rotting fruit? Probably not much; he would have had to ingest enormous quantities of the stuff. But Auntie Erecta, the fruit gatherer of the family, probably did ingest large amounts of the stuff, especially when times were hard and hubbie failed to bring the bacon home.

The archeological evidence

Seriously, this is the most likely scenario. Women and children were tasked with gathering plants and fruits, while our macho forefathers were chasing animals, with very mixed results I might add.

About 10,000 years ago some very observant and patient gatherers, most likely women, decided that instead of running around for miles every day looking for edible wild plants it would make a lot more sense to collect the seeds of those plants, plant them in small plots of land, and simply harvest the next generation. This was a momentous insight; that was the dawn of agriculture, and farmers, and villages, and domestication of animals and plants, and yes, alcoholic drinks.

The earliest archeological evidence of wine production comes from Georgia , not in the U.S. but in the Caucasus . Ceramic jars containing residues of red wine and dating to about 8000 years ago (6000 BC), were found in several archeological sites there. From there the art of wine making spread south to Bulgaria, Anatolia (in today’s Turkey ), Phoenicia or Canaan (today’s Syria , Lebanon and Israel ). It also spread west to Greece, Rome, and the Iberian Peninsula. In all of those places there is solid physical evidence that red wine was produced and stored in large quantities. In fact, the ancients were quite sophisticated connoisseurs: hieroglyphs in Egypt from the third dynasty period (about 3000 BC) document six varieties of wine, and rate them according to quality.

There was a lively commerce in wine across the world of antiquity. The Phoenicians, a sea-going lot, brought wine to the archaic Greeks (the Minoans and Myceneans) about 1500 BC. In fact, the word “wine” probably originates from the ancient Semitic (Canaanite, Aramaic, Hebrew) word Yain (pronounced YA-in), which the Greeks called Oinos, and the Romans later called Vinos.

Everything in moderation

The ancients recognized that wine was ‘good for you’ in small quantities, but harmful in excess. In Greek mythology, only the Gods were allowed to drink to excess and get drunk. The variety of wine they drank was called Nektar (which etymologically is made up of two words: ‘away from’ or ‘escape from’ and ‘death’). It was supposed to confer long and happy life (and they didn’t even know about Resveratrol). Mortal Greeks had to drink their wine diluted with water. In the classical period (5^th and 4^th century BC), Greeks used to gather for philosophical and political discussions (those gatherings were called ‘symposia’), which ended with a meal and wine, the latter diluted one to four with water. Drinking undiluted wine was considered definitely decalassé.

The ancient Egyptian religion was obsessed with death, and invested red wine with a religious meaning. They considered it the blood of their ancestors, which would be OK to drink in small quantities in order to commune with their spirits, but larger quantities could incur their wrath and cause delirium and death. Stripped of the religious mumbo jumbo—quite accurate!

The Bible (6^th century BC) has many allusions to wine. The idiom for peace and prosperity was “each under his vine and under his fig tree.” And King Solomon in his infinite wisdom pronounced that “wine gladdens a person’s heart.” But there are also many warnings of excess. My favorite actually comes from the Talmud, a commentary on the Bible. There is a Talmudic parable which says that Satan came one day to drink with Noah, and slew a lamb, a lion, a pig, and an ape (oy vey), to teach Noah that, before wine is in him, man is a lamb, when he drinks moderately he is a lion, when like a sot (hence ‘besotten’) he is a swine, but after that any further excess makes him an ape that senselessly chatters and jabbers.

Drinking to excess can have consequences that transcend the individual; it can have consequenses of historical proportions. Take the Romans, for example. As they became powerful and imperialistic they exacted heavy dues on their vassal states. One of those was poor little Portugal. In a valley east of Lisbon, the locals were raising grapes and making a sweet variety of wine. The wine was then exported to Rome, through the port city of Oporto. Guess what kind of wine they made. But this imported port wine was expensive, and only the aristocracy could afford to drink it. And drink they did! But there is some poetic justice in this iniquity. The amphoras (storage vessels) in which the wine was shipped were painted with lead-based paints, and the stuff leached into the wine. Bone biopsies taken from skeletons of these pillars of the community revealed toxic amounts of lead. Chronic lead toxicity can lead, among other bad things, to chronic fatigue, cognitive deficits and neurological disorders. Is it possible that those humble Portugese vintners brought about the decline and fall of Rome? Unlikely, but for sure they drove the Romans out of their mind.

Well, enough with the chatter; off to dinner and a glass or two of red wine. That’s still a lion on the Talmudic scale.

Dov Michaeli MD, Ph.D. is in the Biotech industry, engaged in the development of non-alcoholic drugs.

I recently came across an article in the April 23 issue of the Archives of Internal Medicine (vol. 167, pp. 802-807; 2007) describing a newly-discovered connection between depression and diabetes type 2 in older adults. The study enrolled 4,681 non-diabetic men and women over age 65, and followed them for 10 years. The participants filled out every year a questionnaire to measure their depressive symptoms, and every 2-4 years had their blood pressure measured. After removing confounding factors that are well known to increase the incidence of diabetes, like increased body mass index, alcohol consumption, and smoking, they discovered that even a single report of high depressive symptoms is highly associated with increased risk of diabetes type 2. In fact, there was a 60% increased chance of developing diabetes after reporting one incidence of high depression; this is significant by any measure.

Is it a good study?

I think it is an excellent study. The study group was ‘clean’, namely all diabetics and pre-diabetics were excluded from participation in the study. It was longitudinal, following the 4,581 participants for 10 years. The numbers were large enough and the observation period long. Furthermore, the authors accounted for all the obvious confounding factors, like obesity, smoking status, alcohol consumption, and anti depressant use. What is most convincing is that there was a relationship between the score of depression and the likelihood of developing diabetes, what we call in experimental medicine a ‘dose/ response’ relationship. The highest score had the highest increase in risk (60%).

How could depression cause diabetes?

There could be several explanations for this observation, and the answer is not really known. But if we look at the hormonal changes that accompany depression, we may find a possible link to diabetes. Cortisol is a stress hormone that is elevated in depressive states. Cortisol also happens to inhibit the secretion of insulin from the beta cells in the pancreas. Lower blood insulin would in turn lead to higher blood sugar, a hallmark of diabetes.

Caveat emptor

As always, when I speculate I feel obliged to caution that what ‘makes sense’, in biology it ain’t necessarily so. Biology is so complex, and largely still unknown, that any attempt to ‘dry lab’ it is an exercise in futility. Still, using speculation to form a testable hypothesis is how science works. For instance, we could test the cortisol hypothesis by measuring its blood levels in patients reporting an episode of depression and see if there is a correlation between it and the onset of diabetes. Or an experiment could be devised in which any participant reporting a depressive episode would be immediately treated with anti depressive drugs. Would that reduce the risk of developing diabetes?

I am sure many of you have other suggestions to study the depression/diabetes relationship. Send in your suggestions; we promise to publish and critique them.

Dov Michaeli, MD, Ph.D.

The recent posting by Dr. Salber describing the ostensible superiority of wine drinking over beer or spirits reminded me that I actually saw with my own eyes one of the confounding factors of the study, namely, lifestyle differences.

In the mid-80's, I was a visiting scholar at the University of Turku (also called Oulu ) where the study was done.
OuluOn weekend nights the streets were littered with drunks asleep (comatose is a more apt description of their state) on the sidewalks, the gutters, and the roads. It was a sobering sight to behold: well-dressed, seemingly upright citizens, mostly men, wallowing in the mud. I asked my colleague, a surgeon at the University hospital, what was the drink of choice. It was vodka, he said. What about beer? That’s for kids. And wine? Only women and intellectuals drink wine; and they rarely get drunk.

I remember thinking at the time: these people are not going to live very long. In fact, the three most common causes of their demise were heart disease, liver disease, and accidents (like being run over by a car while sleeping on the road). So, anybody who has been to Oulu would tell you—this is not a good study, and scientists who live in Oulu should have known better.

Wine is good for you

True, but up to a point. Studies have shown that men who drink up to 2 glasses of wine a day, and women 1 glass a day (sorry, life is not fair) are less prone to coronary disease and cardiac events.

The mechanism of such a blessed effect of wine is not really understood. Several studies have shown that wine (especially red, some claim) causes elevation of HDL, the “good” cholesterol.

But don’t forget a big caveat: Our eagerness to believe in something can color our judgment. The facts however, cannot be changed by beliefs, however ardent.

Is all “good” cholesterol the same?

In March of last year Pfizer withdrew the experimental drug torcetrapib from clinical trials because it caused excess mortality due to cardiovascular events over the placebo. That was quite a shock, because the drug was designed to elevate HDL (good cholesterol) levels. Why the drug caused higher mortality we do not know yet, but one theory is gaining prominence: not all HDL is born equal.

There are most likely variants of HDL that are actually “bad” cholesterol. Ansell and his coworkers (Circulation, vol.108, pp. 2751-2756, 2003) studied people who had very high HDL levels, but still developed heart disease. In lab assays they found that these people’s form of HDL promoted deposition rather than removal of cholesterol from the artery walls. Could it be that Pfizer’s ill-fated drug promoted the wrong kind of HDL? Quite likely.

HDL is actually a family of particles, varying in their protein components, size, and other parameters. In the heart of Tuscany (the wine country of Italy ) there is a village where people were found to have very low levels of HDL, but were not prone to heart disease. Aha! The protective effect of wine, you might eagerly conclude. But what about other villages in the area? They too drink, but have “normal” levels of cardiovascular disease (and normal levels of HDL). So what gives?

A toast to Milano

It turns out that the people in this village have a variant of a protein that is part of the HDL particle, called Apo A-1. The variant, Apo A-1 Milano is apparently responsible for the protective effect, despite the low levels of HDL in the blood. In fact, Nissen and his colleagues from the Cleveland Clinic showed that five infusions of this protein shrank plaques in the arteries (Nissen et al. J. Am. Med. Assoc. vol. 290, pp. 2292-2300, 2003).

What this study shows us is that our classification of HDL as “good cholesterol” should be reconsidered. There is probably “good” and “bad” HDL cholesterol. As scientists almost invariably say at the end of a paper: more work needs to be done.

Nothing is simple…

Dov Michaeli MD, Ph.D

Today, I am going to write about gout. Why write about gout on a website dedicated to weight loss and fitness? This is because there is a link between obesity and the development of this painful condition. People who manifest insulin resistance when they accumulate fat, particularly fat in the abdominal area, have a higher chance of developing gout. Insulin resistance About half of overweight/obese people are insulin resistant. They typically have or will develop high blood pressure, high triglycerides, low HDL (good cholesterol), glucose intolerance, and evidence of inflammation, such as elevated C reactive protein. If allowed to progress, many people who are insulin resistant will develop type 2 diabetes. They also have an increased risk of having heart attacks and strokes. Gout is an additional problem that folks with insulin resistance may develop. What is gout? Gout is a type of arthritis that is triggered when uric acid crystallizes inside of a joint. This usually happens when blood levels of uric acid are elevated. Uric acid is formed in our bodies when purine, a substance found in foodstuffs -- particularly animal proteins, are metabolized. The most common joint to be affected by gout is the metatarsophalangeal joint of the big toe – that is the joint where the big toe is attached to the rest of the foot.

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