Saturday, December 29, 2007

Deck The Halls With Serology

Happy Holidays from the Annals of Medical School! Here is a little song about the serology findings in many common rheumatic diseases, including rheumatic arthritis, lupus, and more, all set to a familiar holiday tune!

Serology Christmas Song

Deck the Halls with Serology
It is quite simple, we do it in a jif
Start it off with SLE
ANA, DNA, anti-Smith!

DR 2 and 3 add to the score,
SLE is RF positive
If it's drug induced look a bit more
Anti-histone we might very well see!

When your hands hurt think RA
Look to HLA DR 4
RF positive and X-Ray,
CCP, smokes hist'ry all the more!

Sjogren's Syndrome makes my eyes dry
ANA and RF positive
When my cheeks swell then I will sigh
SS-A, SS-B or Ro and La!

Scleroderma has two subtypes
Both are ANA and RF+
PSS is antitoposiomerase
CREST think speck-led anti-centromeres!

Myositis, poly and dermato
Anti synthetase gives lung disease
SRP will cause heart problems
M i 2 is classic dermato findings!

Ankylosing Spondylitis is the end
B twenty seven, and RF minus
Now you know what to the lab you must send
Fa La La La La, La La La LA!

Tuesday, December 4, 2007

Medicine and Politics: The Surgeon General's Battlefield

Annals of Medical School interviews former U.S. Surgeon General Dr. C. Everett Koop about the events of the summer of 2007 surrounding the office of Surgeon General. It looks at how the most recent Surgeon General, Dr. Richard Carmona, brought the office into the spotlight by accusing the Bush Administration of restricting his medical message, and discusses how medicine and politics intermingle.

Monday, November 5, 2007

Kidney Development and the Recapitulation Theory

The Recapitulation Theory. A debunked postulate first popularized in the middle of the nineteenth century, the recapitulation theory famously states that "ontogeny recapitulates phylogeny." Simply put, during development, the human embryo was thought to fully repeat its evolutionary development. A human embryo would climb out of the primordial ooze, so to speak, and pass through different phases of evolution on its way to becoming a grown fetus. This recapitulation of "lower" forms is commonly demonstrated by comparing embryos at various ages between species, from fish to reptile to mammal, and seeing the similar morphology of the embryos. Granted, this theory has long since been rejected. However, I think it has provides an interesting lens through which to view the development of the kidneys.

Over the course of development, we actually have three different pairs of kidneys, which all have parallels to a different evolutionary form. The most basic of these is the pronephros, which is the most rostral (closest to the head) of the kidneys and is a functioning kidney in immature fish and amphibians. In mammals, however, it doesn't seem to do much but serve as a transitory structure before the mesonephros, the second kidneys, develop during the 4th week. The mesonephros is similar to the functioning kidney in adult amphibians, and is functional in birds and reptiles until they hatch. The mesonephros in mammals is a rudimentary, functional kidney--it has glomeruli, which are the filtering units, and which drain into the mesonephric, or Wolffian, duct, running through the center of the mesonephric tissue. This duct is the great legacy of the mesonephros, because near the distal end it sprouts a little bud, called the ureteric bud, which stimulates the metanephrogenic blastema (the precursor to the kidney) during the 5th week to form the metanephros, the third and final kidney. This metanephros will become the bean shaped organ we have all grown fond of, and then rise upward out of the pelvis and to the costovertebral angle as the fetus grows.

It is easy to see how this process apparently recapitulates lower evolutionary forms, going from amphibian to avian to a final mammalian state, and yet further inquiry has shown that this is not exactly true and that while these are important developmental stages, a human fetus does not undergo all steps of evolution during its time in the womb. What I find fascinating is how two distinct parts of this system, the ureteric bud and the metanephrogenic blastema, interact so precisely to create a connection for the kidneys. The ureteric bud induces the metanephrogenic mesenchyme to form the nephric tubules, the DCT, loop of Henle, PCT, and Bowman's capsule. This mesenchyme reciprocally acts on the ureteric bud causing it to branch and form a tree-like system of collecting ducts. Many growth factors are involved in this nephrogenesis, but of interest is the role of angiotensin II, a vasoconstrictor that interacts with the kidney to help regulate blood pressure. Angiotensin II is often blocked with ACE inhibitor or angiotensin receptor blocker (ARB) medications in people who have hypertension, effectively lowering blood pressure. Recent studies suggest that angiotensin, by interacting with receptors on the ureteric bud, stimulates branching morphogenesis as well as collecting duct elongation and papillogenesis. Therefore, patients are taken off of ACE inhibitors and ARBs when pregnant, because there can be failure of the ureteric bud to stimulate correct nephrogenesis and a wide array of kidney defects may result.

Although the recapitulation theory is defunct, there is something to be said for thinking of the kidneys evolutionarily, since they allow us to concentrate our urine, and regulate body water, so that we can live on land in the first place. An impressive feat, given the extensive multistep process it takes for a single adult kidney to develop.

Wednesday, October 3, 2007

Fetal Circulation and Baby's First Breath

I am not usually one to brag, but I am pretty good at holding my breath. You may have heard that pearl divers can hold their breaths for minutes at a time; my all-time record makes that seem like a fleeting moment. Yes, at one point I did not take a single breath for over 9 months.

Of course, I am being a little gratuitous here. As you may have guessed, I am talking about the time I spent in the womb, when there was no air to fill my immature lungs anyway. The cardiovascular system is at times remarkable in its simple elegance of function, and one place I think that exemplifies this is in the fetal circulation at the heart and lungs. Normally, all of the blood in our bodies must first be pumped by the heart into the lungs to be oxygenated, and then pumped into the rest of our body to distribute that oxygen. In the fetus, as I alluded to a little bit ago, there is no oxygen in the lungs because you are living in the fluid of the amniotic sac. Oxygenated blood must instead come from the mother by way of the umbilical vein. The fetal body has a unique way of separating oxygenated blood from deoxygenated blood to make sure the most vital organs can grow during crucial stages of development.

There are basically two streams of blood inside the heart: blood from the mother enters through the eustacian valve of the inferior vena cava, and goes across the heart and through a temporary valve between the right and left atria, the foramen ovale. This well-oxygenated blood can then be pumped like in an adult, going from the left heart up into the aorta and primarily heading to the oxygen-hungry developing brain via the carotid arteries. This blood also bypasses the lungs, which would only serve to remove oxygen from the blood. The other stream is oxygen poor, comes from the rest of the body into the superior vena cava, and heads down into the right side of the heart. Normally this would then go to the lungs to become oxygenated, but remember that the lungs are don't function yet. Instead, the blood goes through the ductus arteriosus, a structure that closes after birth, and enters the aorta after the carotids to go to the brain. This steers oxygen-poor blood away from the head and into the unbilical artery, returning it to the mother to be reoxygenated.

A major factor in this shunting has to do with the very high resistance of the arteries of the lungs. In the fetus, the lungs provide a huge barrier to blood flow, which means that most of the blood entering the pulmonary trunk with be diverted through the ductus arteriosus, a good thing for reoxygenation. However, at birth, when taking the that first breath, the pulmonary vascular resistance plummets and all the circulating blood is diverted to the normal pattern of entering the lungs before the systemic circulation. This might seem a little paradoxical, because normally oxygen is a potent vasoconstrictor; vessels that have a high oxygen tension will constrict as if saying "I'm fine here, go oxygenate someone else." In the fetus, the lung vascular expansion is in part due to the mechanical strain of inhalation, but also due to vasodilation mediated by oxygen. It is thought that this is in fact due to oxygen-sensitive potassium channels: fetal pulmonary vasoconstriction may be mediated by inhibiting calcium-sensitive potassium channels. Likewise, the ductus arteriosus is kept open by circulating prostaglandin E2, generated due to the relatively hypoxic, or low oxygen, state. When the newborn begins breathing on its own, this effect will stop (as long as it isn't premature) and the ductus will close.

That shift of blood flow will normally mean the end of the fetal circulation: a large return of blood from the lungs will close the valve to the foramen ovale, and the ductus arteriosus will constrict into a ligament, the end result being that the right side of the heart pumps oxygen poor blood to the lungs and that reoxygenated blood is then returned to and pumped out from the left side of the heart to the body. So, given that I had an impressive bypass tract to leach oxygen from my mom, perhaps I was cheating a little when I held my breath all that time in the womb; nonetheless, with such an elegant fetal circulation, I remain impressed.

Thursday, September 13, 2007

One Gene, Curious Outcomes: Lesch-Nyhan Syndrome

Voyeurism is something that one might relate more to art than to medicine. As I learned in my art history course, many artists employ voyeuristic techniques that give the viewer an intimate view of the subject, and thus makes him an observer of distressing, sordid, or scandalous events. In fact, this has many parallels to my entrance into medicine. For instance, during a medical interview, I am privy to information that many would hesitate to otherwise share. Of course, it is medically relevant and important for a proper treatment outcome, but at times of reflection I realize how unique a doctor's role can be. Another aspect of the physician as voyeur, for me, lies in the unique and at times bizzare diseases that we learn about in medical school. In fact, I have a short list of favorite bizzare diseases, which I think are fascinating examples of how the human body is an incredibly intricate machine. One such favorite disease is a congenital enzyme deficiency called Lesch-Nyhan Syndrome. Imagine my surprise, then, when this obscure disorder was the topic of a column by Richard Preston in the New Yorker, titled The Possessed.

Lesch-Nyhan Syndrome is a rare disorder, affecting only one in every 380,000 people worldwide. The disorder is recessive, linked to the X chromosome. Since males only have one X chromosome, it is more likely that they will express the deficiency since they do not have another good copy of the gene, so only rarely has it been reported in females. The gene in question codes an enzyme called hypoxanthine-guanine phosphoribosyl transferase, or HGPRT. It is a lengthy name, but the function of this enzyme is relatively simple. As you may recall, your DNA is made up of little elements called nucleotides; these are divided into two classes, pyrimidines and purines. Normally, purines are recycled in the cell to make new nucleotides for DNA and other functions; this is done by HGPRT. If you lack this enzyme, you have to make new purines from scratch constantly. This means you also need to get rid of the old purines, that you no longer recycle. That process involves breaking them down into uric acid.

Some of the initial symptoms of the disease come form this uric acid accumulation. Babies will often have orange crystals in their diapers, from the crystallization of uric acid in the urine. This is often described as "orange sand." Patients may also present with a variety of neurological disorders. Cognitive function is impaired, with an average IQ of 60 and behavioral disorders. Additionally, there is often spasticity, and these patients display extrapyrimidal dysfunction, which means that the part of the brain which normally coordinates movement (as well as some emotional and impulse control) is not working: it doesn't have enough of the neurotransmitter, dopamine. The part which I find fascinating, however, is that patients with Lesch-Nyhan Syndrome somehow all develop self-mutilating behavior. Little children often present with stubby fingers and chewed up lips, which they have done to themselves in a compulsive manner. What's more, as Preston's description from the above article so vividly describes, the patient seems to be terrified of his hands while at the same time compelled to self-cannibalize them. Those that survive to adulthood (rarely do patients live beyond one or two decades) often have themselves physically restrained, to avoid this bizzare compulsion to "self-sabotage," manifested in these physical as well as strange behavioral acts, such as eating food a patient hates or acting cruelly towards people he loves.

Standard treatment is unfortunately limited to the symptoms of the disease, such as lowering the uric acid content, and most patients succumb to renal failure. However, recently, there has been some very interesting experimental work done with deep brain stimulation, which implants a "pacemaker" for the brain into the dysfunctional basal ganglia. Patients have seen a reduction in their spastic or dystonic movements as well as loss of the self-mutilating behavior. I think this is a fascinating example of how a little enzymatic defect in one gene can manifest as a child who is actually compelled to gnaw at themselves. Perhaps there is a large voyeuristic aspect to the treatment of disease, but this may serve as a reminder of how human physiology is a vast, complicated puzzle.

Wednesday, September 5, 2007

Hypertension and Heart Failure

I was sitting around the other day, just waiting to bite down into my deep-fried, salt-laden, double bacon cheeseburger sub sandwich, when a little medical school angel appeared on my shoulder and chirped, "wait Andy, what about your blood pressure? It's going to skyrocket!!"

Of course, at this point the little devil on my other shoulder retorted, "blood pressure? So what? Everyone has high blood pressure. What's the worst that this delicious bite of instant gratification could do?"

Luckily, it was cardiology section and the little medical school angel knew just how to answer such a health dilemma. We have all heard of the dangers of high blood pressure, and yet far too many of us carry the diagnosis; in 2003 there were more than 35 million doctor's visits for hypertension. I find that in order for me to want to change a behavior, such as the food that tastes so good but that I vaguely know is bad for me, I have to know why. Why is it so important that I keep my blood pressure normal?

First, let's look at circulation. I think that the circulation is most easily envisioned as a big loop, with a pump, the heart, propelling blood through progressively smaller tubes, arteries and arterioles. These eventually narrow into capillaries to distribute oxygen and nutrients and then expand again as veins to carry away waste and return to the lungs for more air. The tubes have a certain amount of resistance, especially as they get narrower, and hypertension occurs when the relationship between the output from the heart and the total peripheral resistance is altered. High blood pressure can injure many organs when the pressurized blood damages the vessels, including those of the retina (which may result in vision damage), the kidneys, and the brain (which may cause stroke). As we are in cardiology, however, I am worried now about the damage that hypertension inflicts on the heart.

The heart is a fairly simple pump. Blood flows into the right atrium, is contracted into the right ventricle, then sent into the pulmonary, or lung, circulation where it becomes oxygenated. It returns from there and enters the left atrium, is "kicked" into the left ventricle, and this, the strongest chamber of the heart, contracts to send fresh blood to the body. The principle behind this directional flow is that pressure must always decrease from one chamber to the next. Thus, pressure in the atrium is lower than in the veins, and pressure in the ventricle, when it is relaxed, is lower or equal to pressure of the atrium. When the ventricles contract, they increase the blood pressure so that it can perfuse the body, return to the heart, and the cycle begins again. When the heart contracts, this is called systole and the pressure produced is your systolic blood pressure. When it relaxes, this is diastole, and the pressure that remains in the vessels is diastolic blood pressure. This is higher in the vessel than in the heart because there is a valve that closes after the heart contracts. This means that the heart can relax and refill, while the vessels remain pressurized and able to go forward.

For such a simple pump, many things can go wrong. If the left ventricle is trying to pump against high blood pressure, as in hypertension, the ventricle will have to work harder to expel its blood. Recall that blood must go from high pressure to low; the ventricle has to work harder to overcome the high pressure in the aorta. Just like any other muscle, the heart will "get jacked" and you see hypertrophy, or increased size, of the ventricle. This bulking up means that less blood can get into the ventricle chamber, and so you might begin to experience heart failure. The problem is that since the circulation is a big loop, blocking one step results in backing up all the others. So, less blood pumped through the ventricle means blood, and pressure, builds up in the atrium, which then backs up in the lungs. This can result in congestive heart failure, where fluid can actually build up in the small alveoli of the lungs because of the pressure forcing it out of the small, weak capillaries. Pressure can continue back, so that you may get the right side of the heart involved, and even the venous return. So it is that the failure of your left heart to pump past the high blood pressure in your aorta can result in pulmonary edema (swelling with fluid) and right heart failure.

So, when my little medical school angel on my shoulder is confronted with a deep-fried, salt-laden, double bacon cheeseburger sub sandwich, it can fight back, knowing that since the circulation is one big loop, pumping up the pressure in one part will cause the rest of it to try and compensate. Heart failure (and maybe more) just isn't so appetizing.

P.S. Here is a very fun story of hypertension presenting as a medical mystery, from the New York Times.

Big Hearts

Sunday, August 5, 2007

Campylobacter Jejuni, Guillain-Barré, and Cooking Chicken

Although I am a second year medical student, that is not the only position I currently hold. I also happen to be a second year chef. Yes, as a newcomer to the world of preparing my own meals thrice a day, I have been experiencing all of the thrills, and potential hazards, of cooking on my own. Perhaps more than most, I have also been acutely aware of the dangers of amateur cooking and my health.

Of these dangers, one that is rather unique to my station in life is a particular bacteria, Campylobacter jejuni. This is a seagull shaped gram negative bacteria with a flagella, or tail, that is one of the leading causes of diarrhea in the world, with 2 million cases a year in the United States. It is not spread person-to-person, but instead is carried in wild and domestic animals, especially birds. While most bacteria that infect the GI tract are only common to the very young and very old, C. jejuni has a large spike among people in their twenties, who you would think have excellent health; this might be because it is very common in undercooked chicken. My naive cooking skills, and the cleanliness of my prep area, are therefore constantly tested by this slender "S"-shaped bacteria.

C. jejuni is microaerophilic, which means that it likes a low oxygen environment, around 5-10%, such as that of your gut. It requires as few as 100 bacteria to be infectious, and the result is a watery or bloody diarrhea that is self-limited, ending in 4-5 days. While unpleasant, and unappetizing, this is nothing remarkable aside from its somewhat unusual target population. More unusual is that roughly 1 in every 1000 infected individuals go on to develop Guillain-Barré Syndrome, an autoimmune disease that affects the myelin coating of your peripheral, motor, and cranial nerves.

Many nerves are wrapped in a fatty cellular coating called myelin. In the periphery, this is composed of specialized cells called Schwann cells, which wrap around the nerve axon as it heads to or from its target tissue. This insulating layer helps the nerve transmission move more quickly, and also keeps it contained to that single axon. If you lose this layer, you can have slowed, abnormal, or even absent nerve signal conduction. Essentially, you may experience symptoms such as fatigue, loss of sensation or strange sensation, and possibly even paralysis, which can be dangerous if it affects your breathing.

In Guillain-Barré Syndrome, it is thought that following an infection, such as C. jejuni, you form an autoimmune response against the myelin coating your nerves. It may also occur after a viral infection, vaccination, or even medication. Any of these may cause your T cells to attack your myelin through molecular mimickry, where the myelin "looks like" the bodily insult. Recovery can take as long as 200 days, and while most people recover from even the most severe cases, there are often lingering effects, such as a degree of weakness. There is no current cure; replacing the serum of your blood or giving intravenous immune globulin (giving an outside antibody will decrease your own antibody production) have been shown to shorten recovery by up to 50%. Interestingly, steroids, which are known to lower your immune response, do not seem to be effective on their own in treating GBS.

What exactly induces Guillain-Barré Syndrome remains a mystery, confounded by the large number of suspected causes. If I were to avoid just one infectious cause, however, my money's on C. jejuni; it is found in the serology of up to 40% of people who present with GBS. Future research may help us solve this puzzle, but for now I might just stick to salad. Bon Appétit!

Thursday, August 2, 2007

Sunday, July 15, 2007

Sunburns, Sunscreens, and Skin Cancer

Summertime and the living's easy. Easy enough, for instance, to fall asleep in the sun and wake up medium rare. As our parents taught us, before hitting the water we should slap on the sunscreen, lest we become extra crispy, or worse, we get skin cancer.

We put on sunscreen to block out one particularly vicious element of sunlight: ultraviolet (UV) rays. These are waves of light that are a higher frequency than visible violet rays, and are known for their ability to damage the DNA of our cells, for instance creating a bond between two Thymidines in our DNA known as a Thymidine dimer or introducing free radicals that can then damage the cell. When too much damage is dealt to a cell's DNA, it triggers a type of abort sequence and that cell undergoes programmed cell death, or apoptosis. When UV light hits your skin, it can injure the cells that populate the epidermis, or outermost layer, of the skin: commonly, keratinocytes and melanocytes. By then undergoing cell death, the epidermis becomes inflammed and reddened in the phenomenon known as sunburn, or solar erythema. If too many cells die the epidermis may seperate from the dermis underneath it, resulting in the blistering so common to second degree burns.

Actually, in some ways the sunburn is a good sign: it means that the cells that have been damaged by the sun are dying. On the other hand, if damage is not "caught" and the skin cells don't die by apoptosis, certain DNA injuries may cause malignant changes. The most common skin cancers (95%) are basal cell and squamous cell carcinomas, which stem from keratinocytes. Melanocyte (pigment cell) cancers, or melanomas, only make up 5% of skin cancers but are responsible for 75% of the mortality associated with skin cancer. This can be a brutal illness, often metastasizing to the liver, lungs, bone, and brain. The interesting thing is that there appears to be an association between the type of UV light and the type of cancer. UVB light, which has long been associated with sunburns, creates Thymidine dimers, which are more easily seen by the cell and usually cause cell death, but may also cause cancer. This was the light normally blocked by most sunscreens. There is also UVA light, which is a longer wavelength and does not nomally cause burns. However, it may cause sub-lethal mutations in your skin cells, particularly melanocytes, which can mean cancerous change. So while your sunscreen blocks UVB, it may let UVA through with deleterious results.

The bottom line: have fun in the sun but be safe. Make sure you use a sunblock that works against both UVA and UVB light. And, as an article on sunscreen from The New York Times last week discusses, make sure that you use it correctly. A shotglass of sunscreen for the body and a teaspoon for the face, reapplying every few hours. Don't let a sunburn (or worse) get in the way of your summer fun.

Wednesday, July 11, 2007

Poison Ivy and Hypersensitivity Reactions

It is a common summer scene: you are on a camping trip, or looking for a lost ball in the woods, or finding some impromptu private thicket in order to take care of "business." Suddenly, a glance down and thoughts of concern course through your mind: was that...poison ivy?!? Did I step in it? Is that a rash? Do I feel itchy? I feel a little itchy, I must have touched it!

Poison Ivy enacts its damage by a chemical called urushiol, which is a catechol molecule that is part of the oily sap. This oil is in all parts of the plant: leaves, stems, roots, and berries. When human skin is exposed to the oil the catechols may combine with skin proteins and the response is the typical itching rash from a mechanism called a type IV hypersensitivity reaction. Understanding this is crucial to understanding what is, and what isn't, caused by a brush with poison ivy, oak, or sumac.

A type IV hypersensitivity reaction, also called a delayed type hypersensitivity reaction, is a type of allergic reaction that is mediated by the T cells of your immune system rather than antibodies, the mediator of other allergic reactions. This is important because an adverse response requires two encounters with the offending agent, be it a chronic bacteria (such as tuberculosis) or an environmental contact like poison ivy. During the first encounter, macrophages engulf the invading agent and present this to your T cells, which become sensitive to that specific antigen. When you are re-exposed, the T cells can interact directly with the antigen (the urushiol in this case) and elicit an aggressive immune response.

Basically, the first time you see the poison ivy you educate your T cells, which takes roughly three weeks. Then, the second time you are exposed, the memory T cells are ready in waiting and can immediately start responding. This isn't the fastest of allergic responses: since actual cells are responding, and not just an antibody, it takes time for them to divide and signal for others to go to the site of the lesion. The peak response will be 2 days following encounter with the antigen (the same reason a PPD test for TB takes 2 days to read); therefore if you are in the woods and suddenly get a poison ivy-like rash, you must have touched the plant 2 days prior.

Poison ivy will cause a rash, or contact dermatitis, that often starts as little red bumps and later blisters and may crust or ooze. Keep in mind that leakage of blisters does NOT spread the rash, only lingering oils on skin and clothing or tools. If you have been exposed the best treatment is to try and remove the oil within 10 minutes; rubbing alcohol can break it up and help in this process. The FDA recommends you first use rubbing alcohol, and then rinse generously with water; don't use soap yet because it may spread the oil. After this, take a shower with soap and water if possible. Of course, avoiding poison ivy in the first place is the best medicine: if you see "leaves of three, let it be."

Wednesday, June 27, 2007

Tuesday, June 26, 2007

Botox and Botulism and Celebrity Crazes

As a medical student free time can be scarce. Except, of course, when you have access to celebrity gossip. One week a tummy-tuck, the next week rhinoplasty, all topped off with a face-lift, there are ample excuses to read about the stars as part of my "medical education." Of all these "enhancements," one of the most commonplace is the Botox injection; speculation about the use of which is constantly attributed to various celebs. There are also questions about the safety of the use of this treatment, which may be clearer after learning how it works.

Botox is a medical and cosmetic form of a toxin produced by Clostridium botulinum, a spore-forming bacteria. The Clostridia family of bacteria are gram positive and are obligate anaerobes; they cannot survive in the prescence of oxygen. They have worked around this weakness, however, and can coat themselves in a thick coat to make an environmentally resistant spore. When they find an anaerobic environment, such as the GI tract, the bacteria can uncoat and proliferate.

It is not this proliferation that you need to worry about, at least not directly. The bacteria enacts its damage by releasing an A-B toxin, a two subunit toxin where the B subunit binds a cell and the A subunit is the active agent. In this case, the B subunit binds motor neurons and the A subunit cleaves a protein involved in synaptic vesicle release. Basically, the neurotransmitter acetylcholine, which signals for your muscles to contract and is inside the vesicle, is no longer released and you succumb to flacid paralysis, in a disease process called botulism. This is why Botox is known to smooth wrinkles; it paralyzes that area of the face and so the skin becomes relaxed. It also becomes immobile, and you often see Botox parodied for making patients expressionless.

One of the things to keep in mind is that botulinum toxin is one of the most potent and deadly toxins known to man. Just one picogram (1x10^-12g) of this toxin per kilogram (roughly 2.2lbs) that you weigh is the lethal dose in humans. Incidence of botulinum poisoning is fairly rare; in adults, it is most often seen when someone eats home-canned foods, which provide that anaerobic environment needed for proliferation and toxin release. Interestingly, infants tend to be affected not by ingesting the toxin, but by getting infested with the bacteria in their guts. Infants lack the normal flora that would otherwise occlude the GI surfaces, and so C. botulinum can proliferate when eaten, commonly from honey (spores are in 10% of honey). Botulinum toxin can also be an agent of bioterrorism: since it is so potent, a small amount can be released and incapacitate thousands of people.

In spite of this, botulism is no longer always fatal; affected individuals can be placed on a ventilator and make it through the paralysis. Its diluted relative, Botox, is used both medically and cosmetically and can have a positive role in many treatment plans. Clearly there can be concern with using this extremely potent toxin, but with proper regulation it has a role, as seen in the New York Times article on the business of Botox from last week. While it may be all the rage among the stars, be sure to be safe about any treatment you may seek and consult your physician.

Tuesday, June 19, 2007

Avandia, Type II Diabetes, and Heart Attacks

I happened to be watching television earlier this afternoon when I noticed a trend in the commercials: at least two of the commercials during each of the breaks were asking for people who have recently experienced a cardiac event and who were taking Avandia for their type II diabetes. Now, these advertisements were to seek plaintiffs for a suit against the maker of Avandia, but they also highlight the process by which medications are scrutinized following distribution. For Avandia, a widely prescribed medication for type II diabetes, this scrutiny most recently comes from an article published in the New England Journal of Medicine on June 14, 2007.

Avandia, or by its generic name Rosiglitazone, is a member of the thiazolidinedione class of anti-diabetic drugs. It is indicated for type II diabetes, which is, basically, an acquired state of insulin insensitivity. A better description of insulin is given by my co-contributor below, but as a brief refresher this hormone regulates your blood glucose level. When you have eaten a high sugar meal, insulin is released from the pancreas and makes tissues, especially the liver and your muscles, take up glucose. This is important because a chronic high blood glucose level can cause the morbid complications of diabetes, including neuropathy, renal failure, eye damage, and damage to your circulatory system and heart, relevant to this study.

Key to understanding how thiazolinediones (TZDs) work is this idea of type II diabetes stemming from decreased tissue sensitivity to insulin. Essentially, the tissues no longer take in as much sugar from the blood when insulin is secreted. Thiazolinediones act by activating transcription of genes that would normally be activated by an insulin signal. Basically, this means that they amplify the signal to the DNA in the nucleus to make proteins, and these proteins do the actions that insulin tells the cell to do. They act on the peroxisome proliferator-activated receptor (PPAR gamma) signal pathway, which are nuclear receptors part of the insulin response that increase lipid synthesis and carbohydrate metabolism. Giving a TZD boosts a response to insulin by activating this additional route of gene transcription.

In the study published by Nissen and Wolski in the NEJM, they found that patients had a significant increase in deaths from heart attacks, or myocardial infarction, and a borderline significant increase in risk of death from other cardiovascular consequences. Already GlaxoSmithKline, the maker of Avandia, has responded to the article and cited several other studies, including the ADOPT, DREAM, and RECORD trials which followed Avandia users and all failed to find any increase in cardiac events. Moreover, the FDA issued a statement acknowledging both the previous studies and this new finding, and does not recommend drastic treatment changes or new warnings for Avandia use yet. Ironically, changing your diabetes medications can also increase your risk for cardiac events, and so discontinuing Avandia may be worse than a possible side effect.

Whether or not the drug carries an increased risk for cardiac events, the mechanism by which rosiglitazone affects the heart remains uncertain. The NEJM article highlights some of the possible ways this might occur. One is that the drug appears to be detrimental to the lipids in your serum, or blood. There is an increase in LDL cholesterol, the so-called "bad" cholesterol, by 18.6% over 26 weeks, which may contribute to a poor cardiovascular outcome, such as the increased death from heart attacks seen here. Another proposal is that Avandia, and other TZDs, have been shown to precipitate congestive heart failure, which would place greater stress on the heart wall and thereby increase oxygen demand. There is also data showing that TZDs reduce hemoglobin, the protein in your blood that holds oxygen, which could provoke the ischemia, or lack of blood supply, that causes the heart attack.

Whatever the mechanism, I think it is safe to say the jury is still out on Avandia's role in adverse cardiac events, and further investigation is certainly needed. Nonetheless, as the FDA recommends, concerns with medication should be directed to your physician, to ensure individualized treatment.

Wednesday, June 13, 2007

Lyme Disease

Summertime is upon us here in New England, and you know what that means. Trips to the beaches of Cape Cod or the islands, backyard barbeques with friends and neighbors, and, as some of us know far too well, a sharp increase in bug bites. Mosquitoes might be the more frequent agitators, but around these parts they pose a much smaller medical risk than the other major arthropod: the tick population.

Of import, Lyme disease is carried by ticks, as well as other illnesses, and is especially prevalent along the east coast between Maryland and Boston. It is an interesting disease, as its discovery was one of the great victories of epidemiology. In 1975, in the small town of Lyme, Connecticut, there was an outbreak of juvenile rheumatoid arthritis, a fairly rare disease. This prompted the CDC to do further investigation, and they discovered that the arthritis was a result of a tick-borne agent, Borrelia burgdorferi. Here in Rhode Island there are about 80 cases per 100,000 people, Connecticut is at 133, New York about 30, and the highest incidence was Columbia County, NY, with 1,583 cases per 100,000. And it is becoming more prevalent; Connecticut recently noted that cases are underreported, and even across the Atlantic in England concerns of Lyme disease are mounting.

Borrelia burgdorferi is an interesting type of bacteria. Instead of having the typical oval-rod shape that we think of with bacteria, borrelia is a spirochete, and it looks almost exactly like it sounds it might. It likens a corkscrew, and is so thin that it is very hard to see with most standard microscope techniques. The spirochete has two membranes, and between these inner and outer membrane is a series of 7 to 11 endoflagella, which are basically like little tails that make the spirochete undulate and move around, somewhat akin to a snake.

With Lyme disease, the spriochete is carried in Ixodes scapularis, the common deer tick. The deer tick has an interesting life cycle. It feeds three times in its life: first as a larvae, on a white footed mouse where it gains the spirochete; then as a nymph it bites and infects a human or dog; and finally as an adult it bites its namesake, the deer.

Disease commonly presents with three stages. First, you present with erythema migrans, a bulls eye rash around the initial bite that is caused by the spirochetes moving within the skin centrifugally around the wound. You may also have generic flu symptoms, which don't tell much about the disease, or neurologic symptoms from the migration of the spirochetes. This stage lasts a few weeks and 50% don't recall a tick bite. The infection then goes underground, only to resurface weeks to months later. Here you commonly get meningitis, and an interesting neurological symptom called Bell's Palsy, where the infection irritates the facial nerve and half of your face becomes paralyzed and "droops." Patients can have heart complications that vary in severity; rarely they may also see eye involvement. This stage will also subside, and in another 6 months to a year the end-stage complications of the infection will manifest. These include frank arthritis, which is thought to be an autoimmune disease initiated because the spirochete may mimic a cellular antigen. The majority of patients will also have neurologic involvement, with difficulty concentrating, symptoms that may appear like multiple sclerosis or a progressive encephalitis, and an incapacitating fatigue.

The good news is that we can treat the illness rather effectively if we catch it early. Some of the late effects cannot be reversed, and the arthritis often remains because it is an autoimmune reaction that persists after the spirochete is gone. Moreover, the tick needs to bite for more than 24 hours to transmit a high enough dose of spirochetes to infect. If you find a tick on you, pull it out slowly but firmly with some tweezers perpendicular to your skin. Of course, if you are going to be out in the woods, prevention is the best cure, and using DEET or tucking your pants into your socks can help avoid the deer ticks in the first place. Above all, have some fun this summer, and don't let a bug bite make you miss a barbeque!

Wednesday, May 30, 2007

Diabetes and Stem Cells

Tuberculosis Scare

Today in the New York Times I came across an article on an intercontinental medical crisis. The way the story unfolded was nearly cinematic, chasing down passengers on international flights and quarantining parties that have suspected contact with this one carrier of a grave illness. It would seem that an American man has recently been found with an extensively drug resistant (XDR) form of tuberculosis, and had possibly been infectious earlier in the month when he was travelling internationally.

This is the latest outbreak scare in only a handful of years; this type of event appears to be getting more and more common. SARS was traced from a single source through several countries and across an ocean, the West Nile virus came to the United States from what was thought to be a single mosquito on a ship traversing the Atlantic, and fears of the Bird Flu remain in the public eye. Clearly with our new global community, disease control has to be handled in a different way.

With this current tuberculosis outbreak, the concern lies in spreading an extremely resistant form of the bacteria through several countries, since the ill man recently visited Paris, Prague, and Montreal. It could very well become an international health crisis if the people on the flight and in contact with the infected American also become ill or carriers of the disease.

On this same day that news spread of the XDR TB scare, we learned about tuberculosis infection in class. It is caused by Mycobacterium tuberculosis, a type of bacteria that has a waxy coat instead of the normal bacterial cell walls. If you look at my previous entry, I discuss what makes up a cell wall; in mycobacteria, unlike gram negative and gram positive bacteria, they have Mycolic acids linked to arabinogalactin. This basically makes the bacterial surface somewhat protected from your body's immune response. It also means that instead of staining with gram stain or safranin, these bacteria are acid fast, and a sample will stain in the presence of acid.

What I mean when I say that these bacteria are protected from your immune response is that they actually go on to live inside the very cells trying to kill them, the macrophages. When your body notices it is infected, the macrophage cells try to respond by surrounding and swallowing the bacteria. Normally, they would then kill the bacteria; however, because of the waxy coat, the fact that mycobacteria love oxygen, and for other reasons, many of the pathogens survive inside their macrophage assassins.

When the macrophage realizes it has found a pathogen, it releases a large burst of signals, cytokines and chemokines, that attract other immune responders. These form a large cluster around the original pathogen, called a granuloma. The granuloma walls off the infection inside, and with such cellular response the center of the granuloma will begin to die, leaving a lesion that in normal, healthy people becomes fibrous or calcified. The granuloma is the infection being contained by your immune system, and this group of 91% of the infected population fail to show disease.

However, of the other 9%, two-thirds have clinical TB and one-third with go on to have progressive systemic disease and death. It is this 9% that is of greatest concern, not only because they suffer from the disease, but also because these active cases of TB are what can spread the pathogen. Which is why the CDC is so concerned with the current outbreak. With active cases of TB, there are several treatment options, but the pathogen over time has become more resistant to the few drugs available for treatment. There are first line and second line drugs, based on how effective they are for treatment. There are guidelines for treatment of course, but as you would expect it is worse when the bacteria is resistant to the first line of medications.

XDR Tuberculosis, or extensively drug resistant TB, doesn't respond to any of the first-line drugs nor 3 of the 6 second line drugs, making it very evasive of our current medical arsenal. We aren't facing a disease as dangerous as the subject of the film Outbreak, but there is concern. TB is spread through droplets in the air, which only reach those in close proximity, and only active TB infections are spread by coughing. Moreover, you need a high dose of the bacteria in order to get a productive infection; just a few mycobacteria will be non-infectious to nearly any normal host. This TB scare is not frightening because of its ability to spread rapidly or its high host fatality, but rather because modern medicine isn't equipped to deal with large numbers of cases of this disease.

Tuesday, May 29, 2007

How Penicillin Works

Penicillin is more than just a drug, it is a symbol of the introduction of pharmacy into our national conciousness. The very name is common to almost any vernacular. And yet, until my infectious diseases class the other day, I had no idea of the actual mechanism by which this archetypal drug overpowers a bacterial foe.

To understand the bacteriocidal action, one must first know a little bit about what bacteria look like. I envision the basic bacteria as a single cell, with little arms, or pili, coming off of it. This cell is surrounded by a membrane, just like human cells, and it also has a cell wall, a more rigid coating. There is a very high pressure inside the cell on the order of 10 to 20 atmospheres of pressure, which means that the bacteria can easily burst if they lack a strong cell wall.

Bacteria multiply very rapidly: roughly every 20 minutes the number of bacteria in a culture will double. This can have bad consequences for a host, since you need to mount a rapid and extensive immune response lest the infection get out of control. But it also illustrates one of bacteria's achilles heels: because they are constantly dividing, they need to keep making new cell materials, including those to build the new cell walls.

This is where penicillin comes in. One of the key components to the bacterial cell wall is a component called peptidoglycan. Think of this as a net surrounding the cell, made up of two sugars: N-acetylglucosamine and N-acetylmuramic acid. These two components make up a bunch of "ropes" which are then attached by short peptide strings to make the grid of the net.

This grid is what makes the cell wall strong; if it were just a bunch of parallel ropes, you can see how the pressurized bacterial cell could push apart two side-by-side chains and burst. In order to make the rigid grid, an enzyme called transpeptidase connects the little peptide strings perpendicular to the N-acetylglucosamine and N-acetylmuramic acid chains.

Penicillin acts by competitively inhibiting the transpeptidase enzyme, leaving the new bacteria without a strong net for a cell wall. Without this grid, the rapidly dividing bacteria cannot maintain a strong cell wall in themselves and their progeny, and so begin to pop, as seen in this video of e. coli treated with penicillin. For the chemically-curious, penicillin is a Beta-lactam, which means that it is a molecule with a square Beta-lactam ring as shown in the picture. This molecule looks like a dipeptide of 2 alanines, which is the peptide string that transpeptidase wants to tie to make a grid.

Interestingly, you may have heard of gram negative and gram positive bacteria. One of the major things that distinguish these two types of bacteria is the amount of peptidoglycan, or netting, that they have in their cell wall. Gram positive bacteria have a lot of peptidoglycan, and this thick net is what holds in the gram stain, hence their positivity. Gram negatives have a very thin layer of peptidoglycan, and so do not hold the stain. Since penicillin inhibits peptidoglycan synthesis, it is much better at attacking gram positive bacteria such as Staphylococcus or Streptococcus than gram negatives, such as E. coli.

Of course, the rapid rate of bacterial division also means that a mutant that is resistant to a drug will flourish. Nonetheless, penicillin remains one of the best drugs to use against a non-resistant bug: next time you are on an antibiotic, think of each little bacteria bursting out of its now-flimsy cell wall.

Monday, May 21, 2007

Purchasing Medical Guarantees

I recently purchased a thermos online. Nothing fancy, but something in which to carry tea to class in the mornings. When it arrived, I found that this thermos came with a 5 year guarantee; should any bad fate befall my thermos, I won't be out of a hot beverage container for long. This type of warranty is fairly common to the items we buy; from the 30,000 mile guarantee that comes with a new car to the 1 year warranty on a new computer, consumer goods are almost always insured.

Last week, the New York Times discussed an interesting article on the idea of medicine with a warranty. In a novel healthcare system overhaul, Geisinger Health System of Danville, PA, in the northeastern corner of the state has created a surgical care system in which a flat fee covers the operation and any follow-up treatment that might be needed over the following 90 days. This 'guarantee' is a "distinct departure from the typical medical reimbursement system in this country, under which doctors and hospitals are paid mainly for delivering more care — not necessarily better care."

In the most pragmatic sense, this Geisinger system means that physicians have the greatest economic incentive if they treat patients once and completely, and can move on to other sick individuals, rather than treating the same person repeatedly with (supposedly) suboptimal care. Currently, this program is being used primarily on elective heart bypass surgery, and the improvement in care has been significant, even given the few months the plan has been enacted. There are fewer patients going to the ICU, more patients heading straight home, and a 4% decrease in patients with any complication.

The main way in which this has been accomplished has been through creating a 40 point standard of care checklist, where the various surgeons came together to come up with what they thought were the "40 best practices" in bypass surgery. In my experience, this idea of a simple list or algorithm proscribing treatment is often met with resistance. Whether our egos demand that we physicians could not be replaced by an advanced computer, or perhaps because appropriate health care requires flexibility in tailoring treatment to a patient, the 40 steps for bypass surgery remain open to the discretion of the surgeon.

Reading this reminds me of an article by Atul Gawande, published in the New Yorker, titled The Score. In it, Gawande discusses the Apgar score, a value that describes the condition of an infant at birth. Granted, the Apgar is a retrospective assessment, but it has changed the way care is provided during birthing as doctors aim to maintain higher scores. It gives a comparative framework similar to that of the 40 step bypass which may provide better comparison of techniques and outcomes.

As a medical student, I am only tangentially aware of the hospital's balance of quantity and quality. I constantly hear about the dwindling reimbursement rates for physicians, the enormity of the debt we incur in the educational process, and the long hours and other demands of the hospital that will threaten that balance. I see the figures that Geisinger is presented, and wonder, are these improvements in care transient? Is this a product of the novelty and scrutiny given to this new experiment? Or, like the Apgar score and other such stratifications of care, can it take hold and stimulate further improvement in the field?

It is probably too early to tell. The only insurance that is covering the operation, as of now, is the insurance offered by the Geisinger Health System. Moreover, this has only been used in basically one type of operation, and in one hospital; I can only hope that its results are generalizable. Nonetheless, it is a great step towards improving both the care we receive and how we pay for it, and I can't argue about my favorite statistic from their trial, a decrease in in-hospital mortality from 1.5% to none.

Monday, May 14, 2007

Politics of the new HPV Vaccine

There is a new article in the NEJM this week about the implications of mandated HPV vaccination in the US. Texas and Virginia have mandated that girls at roughly 5th grade age be vaccinated. The Texas executive mandate has been widely talked about in the news, and this article in the New York Times illustrates some of the political battle that has occurred. Meanwhile, several states have rejected this kind of legislation, while a dozen others are currently exploring some sort of response to the new vaccine, Gardasil, recently released by Merck.

First, a little information on HPV. a great review article is "Vaccines for the Prevention of Human Papillomavirus and Associated Gynecologic Diseases: A Review" by Dr. Kevin Ault. How important is HPV in developing cervical cancer? There are several aspects to this group of viruses that can cause warts. There are over 100 of these viruses, not all of which can cause cancer. The wart that people get is a local manifestation of HPV; the skin that sheds off of that contains the virus.

HPV is a double stranded DNA virus with an icosahedral capsule around the DNA and a membrane, or envelope, around this. Some of its gene products affect the machinery of the cell, such as by inhibiting p53, a protein that regulates the cell to make sure it isn't defected when it replicates.

HPV 16 and 18 are the two most implicated in cervical cancer -- they appear to be involved in about 70% of these cancers. Interestingly, some strain of HPV is found in more than 99% of cervical cancers. It makes sense that vaccinating against something that is so closely linked epidemiologically could slow down or eliminate much of the disease.

Part of the controversy is that HPV is considered a sexually transmitted disease. Two of the other strains covered by the vaccine are HPV 6 and 11, which together cause roughly 90% of genital warts. These are unsightly, but tend to not be much of a health problem. Nonetheless, the political debate rages over whether treating this so-called std is in effect advocating for promiscuity and lax morals.

The vaccine works incredibly well, being practically 100% effective in creating antibodies against these 4 types of HPV. It brings us to the interesting ethical impasse that so many state legislatures also find themselves at: in one hand a quasi-miracle vaccine and in the other the weight of their constituency's moral demands.

One point is that HPV aims to protect the single vaccinated person, instead of the herd. This is different from other vaccines, which get spread from person to person and thereby can cause herd immunity with less effort. Also, HPV is an expensive vaccine, and the mandate is for girls between ages 11 and 12, rather young.

Some argue that introducing this at an early age suggests a mandate for sexual promiscuity. However, that has not happened with education about AIDS or pregnancy, which are more imminent dangers than cervical cancer. As the NEJM points out, it is almost as if recognizing that teenage sexual activity occurs is the same as endorsing such activity.

Compounding the concern is the fact that girls who begin sexual activity early may be those at highest risk for obtaining HPV, and of a lower socioeconomic status. As it is available today, the vaccine costs $119.75 per dose, in a series of three doses. Clearly, without a change in policy, these most at-risk populations would be among the last to benefit from the commercially available vaccine.

The issue remains controversial politically, but scientifically, it is clear that this vaccine can provide an almost instant public health benefit. The Centers for Disease Control (CDC) has voted unanimously that girls of 11-12 years receive the vaccine, and added Gardasil to the Vaccines for Children Program, which gives free vaccines to needy children.

Friday, May 4, 2007

In the Beginning...

While it is not the beginning of medical school for me (we had our start last August, which seems like it was several years ago at this point), it is the start of the Annals, a blog which I hope will better distribute a bit of what I am learning to whoever might be interested. The hope is that this will become a bit of a vlog (video blog), with some more dynamic presentations and a display of the attempted acting skills of my classmates and myself.
When I applied to medical school, I was determined to change the way medicine reaches the community. That determination hasn't changed, but the sheer volume of information we digest could be a bit of a distraction at the beginning of the year. Now, however, I am a bit more accustomed to the routine, and can try to focus more on that original goal. I remember a poem given to us in my immunology class in college. My professor, a very dynamic and brilliant man named Hidde Ploegh, gave us a few lines by C.F. Cavafy's "Che gran rifiuto"

For some people the day comes
when they have to declare the great Yes
or the great No. It's clear at once who has the Yes
ready within him; and saying it,
he goes from honor to honor, strong in his conviction.
He who refuses does not repent. Asked again,
he'd still say no. Yet that no-the right no-
drags him down all his life.

The great yes can come at any point for any of us, and we simply have to be ready to accept its responsibilities. For me, medical school is a way of preparing myself for some as-of-yet undetermined great yes. This post probably won't be like the others on the blog, but I hope that anyone who reads this will learn as much as they might from a later, more information-packed post. Nonetheless, I think it is important that we who are lucky enough to go into a career of medicine should never forget that we rely upon our patients as much as they may someday rely upon us (this is ambitious talk for a pre-clinical student, but still), and so I hope this blog inspires some real open conversation about how health and medicine affect us every day.