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.

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.

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.

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.

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 fece...il 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.