A cool disease with a cool name

Devil facial tumor disease (DFTD)is, unfortunately, devastating the Tasmanian devil population.

Devil facial tumor disease is grotesque; the mother of Rosie and her brothers died when grotesque tumors ballooned out of her face and neck, choking off her ability to eat. It is also an extraordinary puzzle. Scientists do not understand its cause, mode of transmission, time from infection until the tumors appear, or potential to infect others.

Here is the cool part (from a scientific perspective, not cool if you are a Tasmanian devil): DFTD is apparently a tumor which is passed from devil to devil.

While I wouldnt go as far as the article and say:

Their current best guess breaks all the rules of modern biology.

the idea of a transmissable cancer is pretty odd.

To consider why, let's step back and think about why cancer isn't generally transmissable in humans. The reason is that immune markers on cells vary from person to person, particularly one specialized kind of marker that is used to present antigens to T cells. These are called Major Histiocompatability Complex (MHC) molecules. They come in 2 basic flavors, I and II, and are expressed on every cell in the body. When cells with foreign MHC enter the body, they are recognized as intruders by the immune system and killed off. This is one of the reason organ transplantation is so problematic. Depending on the organ, MHC matching is often helpful and patients require profound immune suppression to prevent rejection of the organs (or bone marrow). So any cancer cells that got transmitted from one person to another would almost certainly be killed off by the recipient's immune system

There are rare exceptions to this such as twins who both develop the same leukemia while in utero and this case in which a surgeon operating on a patient with an unusual tumor injured his hand and then developed a cancer at the site of injury, which was excised with apparent cure. Investigation showed the tumors from the patient and surgeon were genetically identical. The MHC alleles varied between surgeon and patient so it isn't clear why the surgeon's immune system didn't kill off the tumor.

It seems that something similar is happening in Tasmanian devils. The devil life style is, shall we say, conducive to spread of tumors, particularly those on the face:

Devil sex turns up the volume. In March and April, males engage in vicious, blood-soaked combat, said Dr. Menna Jones, a wildlife biologist who also works in the environment department. Females select "big butch dudes," Dr. Jones said, and allow themselves to be dragged by the scruff of the neck into a burrow. There they scream and fight for several days, mating many times for hours at a time. At the end of such bouts, the male thrusts his sperm into the female every two minutes.

So we can see how the tumor might be spread, particularly since it affects the face.

It is a bit hard to tell from the article, but it sounds like they have done fairly sophisticated analysis of tumor cells from various affected devils and they are all genetically identical (tumor cells often have rearrangements of the DNA that lead to increased growth) which is pretty good evidence for the transmission of the tumor itself.

The article goes on to speculate that Tasmanian devils have only small differences in genes, perhaps due to a recent population "bottleneck" when there were only a few living devils that then expanded into a larger population. Since all devils descended from those few devils, they lack genetic diversity, meaning they may not recognize the tumor cell as foreign. In addition, tumor cells often develop strategies to avoid detection by the immune system (more formally, mutations that prevent immune recognition are favored by increased survival in the mini-evolution of the tumor) and this tumor may have been particularly succesful at such invasion.

Grand Rounds XXXVI

is here.

I'm an idiot

Or, more specifically, Craig Edward Amshal is an idiot. After he failed his board exams in surgery, he availed himself of the option of reviewing his answers, and then wrote down questons and sold them on E-bay. The astute Dr. Amshal

sold two or three sets of questions for $180 to $300, said his lawyer, David R. Dearden.

By my calculations grossing some $360 to $900. Of course, word of this sale got out and Dr. Amshal has lost his board certifications and

agreed to pay $36,000, the estimated cost of assembling teams of surgeons to go through the process of creating and testing new questions.

Quite a deal, wouldn't you say?

What a run

My long run today started off okay, but about halfway into the 4 hours, I found myself running downhill on a rocky, muddy trail that was increasingly covered with puddles from the ongoing downpour. Since it hadn't been raining when I started my run I didn't have a hat. My glasses were covered with rain making it pretty hard to see. Finally, I didn't quite know where I was. For my long runs, I like to go to Frick Park, a few miles from home, and just explore the many trails.

As I continued down the trail I realized that right now, running down this muddy/rocky puddle covered trail in a downpour, lost, barely able to see the trail, I was having one of the peak experiences of my life.

I doubted briefly when I realized I could be running uphill. But then it struck me that once I got to the bottom I'd turn around and head back up, prolonging the experience.

I enjoyed myself and this experience for some time, before I was (figuratively) struck by lightning. It was light out! A truly peak experience would be going down this rocky/muddy trail, lost in a downpour in the dark!

Nonetheless, I enjoyed tremendously the rest of my run, although I couldn't help feeling a bit sorry for everyone else who was still sleeping or else sitting inside, drinking hot coffee and relaxing. Poor saps!

Everyone enjoy their weekend.

This sounds good

Education is not my area of expertise, but I've long felt that the biggest obstacle for disadvantaged groups was low expectations. This (via Eduwonk) sounds like I might be right:

Spurred by President Bush's No Child Left Behind law, educators across the nation are putting extraordinary effort into improving the achievement of minority students, who lag so sharply that by 12th grade, the average black or Hispanic student can read and do arithmetic only as well as the average eighth-grade white student.

Here in Boston, low-achieving students, most of them blacks and Hispanics, are seeing tutors during lunch hours for help with math. In a Sacramento junior high, low-achieving students are barred from orchestra and chorus to free up time for remedial English and math. And in Minnesota, where American Indian students, on average, score lower than whites on standardized tests, educators rearranged schedules so that Chippewa teenagers who once sewed beads onto native costumes during school now work on grammar and algebra.

One can only wonder why these things didn't happen before, but I suspect there is a lot of underlying racism in the U.S. educational system that doesn't think minorities are capable as achieving as much as whites. I think Bush called it "the soft bigotry of low expecations."

Remeber this movie.

I was surprised to see this article in the NY Times which seems resolutely opposed to education reform, but even more surprised to see it referred to as "President Bush's law" as it was actually a bipartisan effort. I wish politicians would spend more time on things like this and fighting poverty and less on bickering.

Marburg

An interesting view of the scene on the ground from a WHO epidemiologist in this weeks NEJM. Not a ton of new information if you've been following closely, but a cool diagram of the virus. Plus, I think we should support free full text when available

Allergic Disease on the rise

Two good studies in the May 21 British Medical Journal (catching up on our reading, are we? ed Sort of, I've been trying to flag particularly pertinent articles when downloading and read them first) about the increasing prevalence of allergic disease.

It is well established that allergic diseases (eczema, food allergy, allergic rhinitis, and asthma) have increased in prevalance over the last 40 years or so. Some of this may be due to better recognition and diagnosis, but some is almost certainly due to a true increase in prevalance. There has been some data in Europe, that at least for asthma, the rise in cases has stopped and numbers may even be coming down.

The reason for the overall increase is still unclear. The leading theory is the so-called "hygeine hypothesis" which postulates that less exposure to dirt and bacteria predisposes to allergy. While this hypothesis has some good evidence for it (decreased allergic disease in farmers, for example) it also has some weaknesses (e.g. why is asthma epidemic in the American inner city).

The first article, by Latvala et al, measures asthma in young Finnish men, almost all of whom get physicals at age 18-19 as part of compulsory military service. This study showed that the number of men with asthma (and allergic rhinitis) continued to increase throught 2003, the last year studied.

The number of men with "disabling asthma" decreased significantly, however, almost certainly due to the availability of better treatments, like inhaled corticosteroids.

An even cooler study in the same issue, by Law et al., used stored blood samples from a British hospital to see if the incidence of atopy (basically allergy to specific things) had increased. They looked at the blood samples of men presenting for physical exams from three periods, 1975-6, 1981-2, and 1996-8. The prevalence of positive tests for allergy The percentage showing any allergy rose by >1/3 and for specific allergens like cat and tree the prevalence more than doubled.

One potential objection they didn’t address was that the prevalence of specific antigens may vary over time. Perhaps more people have cats now, or different trees are more common. I doubt that would explain much of the difference, however.

In summary, more and more evidence shows that allergies and allergic disease are getting worse. What a great time to be an allergist.

Can I at least use it until I need glasses?

Federal health officials are examining rare reports of blindness among some men using the impotence drugs Viagra and Cialis, a disclosure that comes at a time when the drug industry can ill afford negative publicity about another class of blockbuster medicine

To be fair it sounds like this blindness typically occurs in those with diabetes and cardiovascular disease, the same conditions that predispose to impotence.

More Moonda

The wife says she is innocent, but her situation is pretty curious: she is addicted to drugs, involved with another addict she met in rehab, and listed on the car loan of a 3rd, who owns a car similar to that used by the robber/murderer.

I don't see anyway she was't involved

Revenge of the thin

The anti-obesity establishment strikes back:

The new federal study suggesting that people tend to live longer if they are slightly overweight was challenged yesterday by scientists from the Harvard School of Public Health and the American Cancer Society as well as a heart disease researcher.

In a seminar and news conference yesterday at the public health school, in Boston, the critics said other studies, including their own, had found that the death risk from excess pounds increased continuously from normal weight to overweight to obesity.

It is a bit unusual for the response to come in a press conference, as opposed to, say, a letter to the journal where the original study was published. As I've blogged about at length, his study is very different from the received wisdom on weight and longevity, but it was a very good study.

The leaders of the insurgency are not backing down:

Another reason for the differing conclusions, Dr. Flegal and Dr. Williamson said, may be that the Harvard and cancer society researchers excluded large numbers of subjects from their analysis for one reason or another; one analysis of the nurses' study excluded nearly 90 percent of the deaths, Dr. Flegal said.

Or, she added, the federal researchers, who used actual measured weights and heights, not self-reported ones, may have had more accurate numbers to work with.

In these kinds of arguments, people too often forget that we should be searching for the correct answer, not defending what we think should be true.

My sense is that dramatic improvements in caring for diabetes and heart disease have made obesity much less of a predictor of mortality than it was in the past, and therefore, the new study is closest to the actual truth. This won't be the last we hear of this.

World's worst doctors

A doctor turned off a woman’s life support ventilator in an Australian hospital because the director of surgery, dubbed "Dr. Death," wanted her bed to operate on another patient, an investigation finds.

The surgeon, Jayant "Jay" Patel, 56, is the subject of an official inquiry in the Australian state of Queensland examining why the doctor was permitted to practice medicine in 2003 despite a nearly 20-year history of criticism and sanctions imposed by medical authorities in Oregon and New York as a result of his work practices

Despite that, he got glowing references from a number of colleagues when he applied for credentials in Australia.

To me this case highlights how poorly the medical profession weeds out incompetence. It seems clear this guy was a butcher, but he moved from New York to Oregon to Australia, somehow getting credentialled along the way despite a disciplinary history.

Part of the problem is he is apparently very incompetent, and as a surgeon, could really do a lot of damage. A bad pediatrician or allergist, say, would kill a lot less people. At my intern orientation in my peds residency a distinguished neonatologist got up and told us the following

“The first law of pediatrics is as follows: if you identify a child with something wrong, you must intervene immediately before the child gets better on their own.”

There is a lot of truth in that; most of pediatrics is correcting single problems or keeping kids comfortable while “tincture of time” works its magic. (I don’t mean to diss pediatricians here, just point out you’ll notice an incompetent surgeon a whole lot sooner).

The major problem is just how big a factor being able to practice medicine is in an individual’s life. I’ve seen this in several medical students who probably shouldn’t have been awarded an M.D. or D.O. But the first two years are class work, so if you are smart you can muddle through. Third year, problems become apparent, but the first impulse, appropriately, is to try to work with the student to overcome their difficulties. By then they are 3 years and $140,000 into medical school and it becomes pretty hard to kick them out.

Those who are geniuses with horrible people skills can be guided into research or a specialty with minimal exposure to patients, but for the generally incompetent who somehow made it into medical school, most end up in a primary care residency at a not-so-good program.

It is a similar situation for an incompetent surgeon. This guy is probably a nice person, and he’s put in a lot of time training to be a surgeon. Plus, every surgeon has the occasional bad outcome, so how do you know if someone has bad skills or bad luck? As a licensed surgeon the guy has a guaranteed high-paying job. Take away his license and his life is completely changed for the worse. Perhaps there should be a program to retrain surgeons with poor surgical skills in other specialties, although, in fairness, this guy seemed to have horrible judgment as well.

The principle of double effect

A child has metastatic cancer with no hope of cure. The metastases to the bone cause severe pain. Morphine is given with some relief but she continues to complain of pain.
More morphine can be given, but will likely result in cessation of breathing and death. Is it ethical to increase the morphine dose? Would it be ethical not to?

The offical, bioethicist-approved answer is to increase the morphine even if it hastens death. The reason this is okay is something called the principle of double effect. You can order more morphine only for the purpose of relieving pain. The adverse, or double, effect of bringing on death is tolerable only because the medicine is given for another, purer purpose.

I basically agree with this formulation, but it has some problems. First, what about patients in severe pain with better outlooks. If the child instead had a compound leg fracture, no one would ever think about giving enough morphine to kill her, because her long term prognosis is better. Second, theory and practice can be quite different. In the few cases like the original I've been involved in, things went more or less according to plan, although titration of the opiate dose was more to parent's assesment of difficulty breathing than any objective measure of pain. I have heard other's tell of experiences in adults where the opiate was regularly increased with the understanding on the team that the point was to stop the patients breathing, not to relieve pain. Residents were admonished for not turning up the infusion fast enough, even though there was no evidence the patient was in pain. Of course, the result is indistnguishable (terminal cancer patient gets lots of morphine and goes out in comfort) whatever the intent of the ordering doc.

I don't have a better way of looking at things, and generally feel that pain in under- not overtreated (though pain treatment in patients with terminal cancer is pretty good in my experience), so I'm not complaining, just commenting

Good Samaritan

Walking home last night I found a cell phone laying on the ground. What should I do?

I initially walked by, but then decided I couldn't do nothing and walked back to pick it up. The route is frequented by high schools students (we live just down the street from a large high school) so I figured it was one of theirs. I figured out how to use the phone book feature and called the "home" number, where I reached the owner's babysitter.

The owner eventually called me back and was quite grateful. She was coming by our home to pick it up today.

Overall, minimal hassle for me, but one very greatful stranger

Subgroup analysis

The answer to a randomized controlled trial that does not confirm one’s beliefs is not the conduct of several subanalyses until one can see what one believes. Rather, the answer is to re-examine one’s beliefs carefully.

Oei et al (BMJ 1999) quoted by Schulz and Grimes in a review of the problems inherent in subgroup analysis (in May 7 Lancet, subscribers only)

They also provide the following illuminating example:

The Lancet published an illustrative example. Aspirin displayed a strongly beneficial effect in preventing death after myocardial infarction (p< 0·00001, with a narrow confidence interval). The editors urged the researchers to include nearly 40 subgroup analyses. The investigators reluctantly agreed under the condition that they could provide a subgroup analysis of their own to illustrate their unreliability. They showed that participants born under the astrological signs Gemini or Libra had a slightly adverse effect on death from aspirin (9% increase, SD 13; not significant) whereas participants born under all other astrological signs reaped a strikingly beneficial effect (28% reduction, SD 5; p 0·00001).

Anecdotal reports of support from astrologers to the contrary, this chance zodiac finding has generated little interest from the medical community.

For non-medico’s subgroup analysis is when you breakdown the data from a trial by patient characteristics like age, sex, underlying risk factors, or severity of disease. The problem is that as you increase the number of comparisons, the risk of finding a spuriously significant result increases.

In their defense, subgroup analysis can reasonably, IMHO, be used as the basis for further research.

Grand Rounds XXXV

is up here, sorry I am a day late.

I particularly appreciated this post from Orac Knows about how annoying people and their cell phones have become:

Holy crap! (An appropriate exclamation, given the situation.) Dr. X was having a long and involved conversation on a cell phone about a patient with another physician while sitting on the throne! As I sat there, I could not help but become engrossed (another seemingly appropriate word) in the conversation. He was going into great details about this patient's course of treatment, the likelihood of success, the potential side effects, and how those side effects could be managed.

UPDATE: fixed formatting of quote. %*$(^ Blogger.

John Kerry and SF 180

I don't generally blog about politics, but it annoys me when politicians say they'll do something and don't:

On Friday, May 20, Kerry obtained a copy of Form 180 and signed it. ''The next step is to send it to the Navy, which will happen in the next few days. The Navy will then send out the records," e-mailed Wade. Kerry first said he would sign Form 180 when pressed by Tim Russert during a Jan. 30 appearance on ''Meet the Press."

How hard can this be? I searched "military form SF 180" on Google, hit the first link and voila, there is the form in PDF. There is even a number to fax your signed version to : 314-801-9195.

Why do I suspect it is better Kerry didn't win?

Moonda murder

Looked like I called this one:

Authorities investigating the killing of a Mercer County doctor along the Ohio Turnpike are focusing on the relationship between the victim's wife and a Beaver County man with a history of gun and drug arrests.

I think this just shows how brilliant I am how obvious the whole thing was.

More natural selection at work

These kinds of things seem to come in runs

Two Star Wars fans are in a critical condition in hospital after apparently trying to make light sabres by filling fluorescent light tubes with petrol.

A man, aged 20, and a girl of 17 are believed to have been filming a mock duel when they poured fuel into two glass tubes and lit it.

The pair were rushed to hospital after one of the devices exploded

My 7 year old son is constantly bugging me to "have a duel" with his toy light sabres. He's bummed out I won't let him see Revenge of the Sith, but it sounds a bit too violent.

UPDATE: sorry for the duplication. Blogger was down and I tried this both as a new post and an addendum before figuring it out. Blogger subsequently published both. Blogger is also why I'm fat and slow.

Natural selection at work

A man was injured when he jumped from a car traveling 55-60 mph in an effort to retrieve a cigarette blown out of a passenger-side window

From the WP, via Best of the Web

UPDATE: These kinds of things seem to come in runs

Two Star Wars fans are in a critical condition in hospital after apparently trying to make light sabres by filling fluorescent light tubes with petrol.

A man, aged 20, and a girl of 17 are believed to have been filming a mock duel when they poured fuel into two glass tubes and lit it.

The pair were rushed to hospital after one of the devices exploded

My 7 year old son is constantly bugging me to "have a duel" with his toy light sabers. He's bummed out I won't let him see Revenge of the Sith, but it sounds a bit too violent.

Fidgeting for weight loss

This article suggests that small increases in activity during the day can add up to big changes in calories burned and weight

Their study, published in Science, did not involve deliberate exercise, but it measured - with the help of the sensors - how much people moved about naturally and spontaneously.

The heavier ones tended to sit, while the lean ones were more restless and spent two more hours a day on their feet - standing, pacing around and fidgeting. The difference translated into 350 calories a day, enough for the heavy people to take off 30 to 40 pounds a year, if they would get moving.

This makes intuitive sense to me, the question is how effectively can you increase your energy use. The leader of the studies actually put a treadmill in his office and walks at a slow pace (o.7 mph) while working at his desk. Seems crazy at first, not so much so after you think about it.

So maybe I could lose weight just by fidgeting more.

Marburg smolders on

New cases of Marburg virus are continuing to appear, including some among people without contact with others known to be infected:

in some areas where the virus had been detected before, new cases were seemingly inexplicable, striking people who had not been identified as contacts of previously infected patients. The cases probably did not mean there were new sources of infection, Ms. Bhatiasevi said; more likely, the health workers trying to identify people who had been exposed to the disease did not have complete information

The fact the outbreak hasn't been brought under control is bad, I'm just not sure how bad. Perhaps it smolders along and then dies out, perhaps it smolders along and then we get a big breakout or it jumps to another city.

The new diet

So I've gone and started a crazy new diet. My wife will tell you, for a basically rational guy, I am very susceptible to crazy nutritional ideas (Atkins? -ed. Not that crazy!).

One of my friends from running lost 20lbs by the simple fact of not taking in calories one day per week. He drank non-caloric liquids like black coffee, tea and water, but that was it. On the other days he ate his normal diet. According to him, the weight just came off.

Since, I haven't had much success recently throught cutting back in general I figured I'd give it a try.

My approach is as follows
1. One day per week no calories.
2. Eat sensibly on the other days.
3. Try to work my exercise around the fasting day to avoid long or important workouts on the day of fasting or the day after.

I start this process with a height 0f 6'2", weight about 212, BMI 27, so I'm not obese to start. I don't really think I need to lose weight for health reasons, but I think my running would go much better if I weighed less. My friend who used the diet found his times dropped at all distances (he isn't an ultrarunner, though)

Yesterday was my second fasting day, so here are my thoughts
1. Fasting for a day is surprisingly easy. I was quite hungry in the morning, but if anything it got better throughout the day

2. Social cues to eat are strong. The hunger itself didn't bother me that much, but it was weird not to eat dinner or get a snack after I got home from work

3. You don't feel quite the same the next morning. I did medium distance runs (7-8 miles) both mornings after fasting and I definitely noticed not having the same energy, particularly at the end. I ate a big bowl of cereal before the runs, which I don't usually do. I think it helped, but not competely

4. You lose a lot of weight in the 32 hours or so you don't eat. I lost 5-6 lbs each time. I think most of this is water. Since you don't eat, you don't take in sodium, but you lose sodium in your urine since you drink a lot of fluids. The sodium loss leads to water loss, which is temporary

5. I can see how this would work, as I haven't noticed a dramatic jump in my appetite the days after fasting

I'll keep you updated on how it is going and if it is working

PS: I know this diet is crazy. Don't think just because I use Dr. before my name that this is some sensible thing you should try. It is a crazy thing and don't blame me if you try it and get low blood sugar or sick or whatever.

What have I gotten myself into?

I am a pediatric allergist. While I am board certified in pediatric and adult allergy, I don't have much experience with adults, except for allergies, asthma, and immune deficiencies..

Nonetheless, at the end of June, I will be the doctor at a major aid station at the Western States 100 mile endurance run.

I had hoped to run the race, but wasn't selected in the lottery. A colleague, who is a pediatric pulmonologist at my hospital usually works at the Foresthill aid staion, 62 miles into the run and at the end of the hellish (and I don't use the word lightly) canyons, but he is running this year.

Since I was to be in northern California on holiday the week before, I volunteered. It sounds like all I'll have to do is give some people IV hydration and send them on to the ED if they look horrible, but I'm still a bit nervous. Hopefully, I'll have some experienced nurses to help me out (that is key at every level of medicine) and no one will be too ill.

Stem Cell Funding

I'm beginning to wonder if they refusal of the NIH/Bush administration has actually increased the total amount of funding:

a private foundation says it will give $50 million for such work to three Upper East Side medical institutions, a gift they say will position New York City as a player in an increasingly competitive field.

While this is a drop in the bucket compared to the $3 billion California is planning to spend, it is a lot more than the $200,ooo per year the South Korean government is said to give to the Hwang lab.

Sunlight is good for you

at least in moderation

The story of Vitamin D protecting against cancer has been building for some time.

As I grow older I become increasingly impressed by how much moderation in most areas is good. You don't need to eliminate all fat, alcohol or sunlight, but moderation is the key. The same with exercise (advice I don't follow) where a little goes a long way.

Smoking remains a no-no, but maybe soon we'll learn that an occasional cigarette is okay.

Why doctors are cranky

The widow of the eminent evolutionary biologist Stephen Jay Gould filed a wrongful-death lawsuit on Friday against doctors at two of Boston's most prominent hospitals, accusing them of negligence because, she said, they inexplicably failed to notice a tumor that ultimately tripled in size and caused Dr. Gould to die of cancer

I can't comment on the validity of this case, although my impression is it is unlikely the cancer was curable at the time of the first x-ray.

What I find amazing is that included is a defendant is Dr. Robert Mayer, who treated Gould for his first cancer, which was eventually cured, was among those named.

That is being a doctor in America today. You save someone's life from cancer, they unluckily develop a second cancer and die and the widow sues your ass. The cure rate from Gould's first tumor, GIST or gastrointestinal stromal tumor was under 10%. So if he had died of that, his widow would have had no recourse. But since Mayer saved him, she can now sue for millions.

Next time you complain about the cost of your insurance or copayments, or wonder why we order so many tests, think about the lessons of this case.

UPDATE: A somewhat different take here. The creationists are a bit like weeds, they'll take any opening you give them.

What class am I?

This NYTimes graphic allows you to see where you fit in America today.

As a physician, I am in the most prestigious profession. #1 out of more than 400. Go doctors!

One problem with the graphic is that many people, like me fall in multiple categories. I am also a "post-secondary" teacher (medical school faculty) and I have a doctoral (Ph.D.) as well as a professional degree (M.D.)

But what really caught my eye is that to achieve the same percentile in wealth as I do in occupaton and education, I'd need 50 million dollars! If there are any billionares out there who'd like to trade $50 million for my Ph.D., I'm not really using it much.

Also, the math seems odd. The graphic notes that only 19% of people don't finish high schoo, but then sets high school graduate at the 50th percentile.

Inside the S. Korean stem cell lab

A good article about Dr. Woo Suk Hwang and his team who made the stem cell nuclear transfer breakthrough in Time.

Opponents of therapeutic cloning may oppose this research, but it seems clear the South Koreans are doing it for the right reasons.

UPDATE: fixed title

Reading between the lines

A Pennsylvania urologist was killed last weekend, in an apparently random robbery on the Ohio Turnpike. 69 year old Gulam Moonda was shot in the head after surrendering money to a robber who had pulled up behind his Jaguar as he and his wife switched drivers.

From the start, this case seemed a bit unusual. Why Moonda? Armed robberies are not common along the turnpike, particularly in broad daylight. How did a van happen to pull up behind them when they stopped along the road, not at a rest stop? Why did the robber shoot when Moonda had already given him money? Why did he leave Moonda's wife and mother-in-law alone?

On the news this week, I saw Moonda's wife who is much younger (45) and attractive. From this article we learn that Moonda's wife was driving and that she had recently gotten out of drug rehab (she is a nurse anesthetist who is/was addicted to fentanyl).

My guess is something like this
1. The wife has a lover and they want to get on with their life, but with the money she'll get when Moonda dies
2. They set up a trip and bring the mother-in-law along as a witness
3. The lover (or hired killer) follows in the van
4. At a prearranged spot the wife pulls over, saying she wants him to drive
5. Van pulls up, goes through "robbing" Moonda, then shoots him.

Pretty neat set-up. The initial crime looks like a robbery gone bad and the mother-in-law is a credible witness that it really was a robbery (if it had just been the wife, people might have doubted her story).

Regulate, don't ban, stem cell research

Those who oppose cloning for research do so because they want you to treat embryos as people. But since this position is impossible to defend they fall back again and again on the scare tactic that if cloning for research is allowed then human clones will be living in your neighborhood soon thereafter. And who knows what these human clones might do once they get a load of the neighborhood! If you think “Desperate Housewives” is a den of inequity, just wait until the clones set up shop on Wisteria Lane.

Making people by cloning them interests only the opponents of stem cell research, nuts, fruit balls and Hollywood film producers. If the prospect of a clone moving to your neighborhood really frightens you then urge the president and his political pals to pass a law forbidding human reproductive cloning. But don’t hold the science hostage. Having no rules at all except "don’t do any cloning for any reason" is neither ethically sensible nor, as the work in South Korea shows, practical. The best way to keep an eye on cloning is to regulate it rather than to hide behind the fig leaf that it has to be banned, lest it be used to make people.

From an excellent commentary by bioethicist Arthur Kaplan. I'd only add that embryos are created everyday in in vitro fertilization clinics which will never be used. Is that mass murder?

The wrong side of progress

Compare the optimism from the South Koreans who are working to help cure disease

A leading stem cell researcher said Friday it will be years - and maybe decades - before recent breakthroughs by his team of scientists will benefit humans, but he expressed high hopes that they'll eventually help people with incurable diseases.

with this:

"I've made very clear to Congress that the use of federal taxpayer money to promote science that destroys life in order to save life, I am against this," said Mr. Bush, speaking in the Oval Office during a brief joint appearance with the Danish prime minister, Anders Rasmussen. "Therefore, if the bill does that, I will veto it."

Bad moon rising

2 articles on avian flu here and here. Not much new info. Deaths continue in Vietnam and the WHO is worried about a pandemic if/once efficient human to human spread emerges.

The Ebola outbreak in the Republic of Congo continues:

Authorities in the Republic of Congo have quarantined two northwestern districts hit by the deadly Ebola virus to ensure the highly contagious disease does not spread, officials said Friday.

This sounds drastic, but should ensure limited spread outside the effected areas.

Good and bad news on Marburg

The outbreak of Marburg virus, which causes a hemorrhagic fever, is still not controlled, but neither is it getting worse, according to a WHO official:

“The situation is improving. We are trying to strengthen our surveillance but the outbreak is not yet over,” Bhatiasevi said by telephone from Uige, the northern Angolan province that is the epicenter of the disease.

“In Uige there are patients being reported every day. We are getting information at an earlier phase instead of getting information when people have (already) died,” she said.

It sounds like the fatality rate is declining as well:

“Yesterday two more people were released from hospital. People are getting better because they are being brought into hospital earlier and being put under hospital care so we are seeing more survivors,” she added.

Given that treatment is only syptomatic, it is also possible, that milder cases are being increasingly recognized.

Overall, I remain hopeful that this outbreak will be brought under control soon.

Video games and stroke

When stroke victims played virtual reality games in which they imagined they were diving with sharks or snowboarding down a narrow slope, their ability to walk eventually improved, researchers reported in a small study.

Doctors called the findings promising, especially since the patients had all had strokes more than a year earlier, a time frame within which further recovery is unlikely.

I'm just guessing the patients were primarily male

Older Runners

An interesting article about how much runners slow down as they age.

With the 3 hour marathon barrier now falling to 74 year olds it is a bit unclear exactly what the limits of performance by senior athletes is.

The article notes research showing a precipatous drop in performance after age 75:

The worst is yet to come, according to a University of Pittsburgh research team that examined performances at the 2001 national Senior Olympics in Baton Rouge, La., and among other record-holding senior athletes.

The study, yet to be published, found moderate decline in performance among athletes in their 50s and 60s, and then a steep decline starting at 75.

I think this is probably right, but there are a few issues with the study, at least as reported. First it compares drops in age group times, and shows a steep drop off between the 70-74 and 75-79 group. That might suggest the precipatous decline occurs earlier, as most of the best times will be among the youngest members of an age group. Second, it doesn't control for athletes dropping out. There are very few runners after age 70, probably because of injuries. If many of the best runners stop competing, the drop in the best times in a group may be much more than the decline in each individual runner. In other words, the 30th best runner in the 70-74 age group may be the 5th best runner in the 75+ group, just because so many better runners have stopped competing (died, injured, too sick, etc).

In any case these guys are quite an inspiration.

I also wonder if the recent move toward wide spread strength training will incresae performance in older athletes in the years to come.

More sperm donaton

The Pennsylvania Supreme Court is weighing a case with the potential to strike fear in the hearts of sperm donors who thought they were getting $50 for their genetic material and nothing more -- certainly no responsibility for babies created with it.

The justices heard arguments this week in a case that forces them to weigh the right of children to financial aid from two parents against the right of men to provide sperm for in-vitro fertilization without the donors being held responsible for any offspring.

The case goes beyond the usual anonymous donor, as the donor was an ex-lover of the mother. But they had an agreement that she would absolve him of responsibility for the children, in this case twins. The initial judge ruled that the contract was invalid because the mother couldn't bargain away the rights of the children to support. While that seem a plausible argument from a legal perspective, from a utilitarian one, such a ruling would certainly keep a lot of potential donors away.

The article does note California has a law protecting donors, which Pennsylvania does not, but probably should

Progress on human cloning

This is huge.

A South Korean team is reporting in Science that it has overcome considerable technical hurdles and can now reliably produce human embryos by "Somatic Cell Nuclear Transfer" where DNA is removed from an egg and replaced by DNA from a donor, which can then be grown into a blastocyst, which can potentially serve as a source of stem cells for the donor, to which it will be gentically identical, obviating any problems with compatablity of the tissue.

This is so called therapeutic cloning, although SCNT sounds so much less ominous.

This advance is technical, not scientific, but is still very important. Previously there has been some concern over whether this sort of cloning was feasible in humans; that doubt is gone.

The anti-stem cell forces are predictably unhappy about this:

Dr. Leon Kass, chairman of the President's Council on Bioethics, said in an e-mail message that "whatever its technical merit, this research is morally troubling: it creates human embryos solely for research, makes it much easier to produce cloned babies, and exploits women as egg donors not for their benefit. "

The United States Conference of Catholic Bishops shares those concerns, said Richard Doerflinger, director of pro-life activities there. He added that he also worried that a cloned baby might be next.

They are also sounding increasingly like Luddites. This kind of research is going forward; Kass et al. would be alot more effective trying to channel the tide, not turn it back.

If you desire more background my 3 part primer on stem cells is here, here and here

Race and Medicine

Does race matter in medicine? Only a few people would answer an absolute no. Most would accept that even if only a marker for social class, race does have an effect, and many would go much farther in assigning poor health in minorities to societal factors directly related to race

A more intriguing questions is if genetic differences between races should play a role in medicine. As a recent BMJ editorial (Rahemtulla and Bhopal) notes

In 2001 NitroMed began the African-American heart failure trial (A-HeFT), the first heart failure trial conducted exclusively in African-American patients, claiming that “observed racial disparities in mortality and therapeutic response rates in Black heart failure patients may be due in part to ethnic differences in the underlying pathophysiology of heart failure.” The study found that BiDil (a fixed dose of isosorbide dinitrate and hydralazine, . . . ) combined with standard therapy for heart failure reduced mortality by 43% among black patients.

I believe that the therapy had failed to show efficacy in a trial of the general population (all races). Presumably, this effect in a single racial group is due to genetic differences between races, although it is possible that environmental factors (smoking, diet, exposure to pollution) could explain some of the difference.

Given the trial results, is “race-based” medicine justifiable? Not everyone thinks so.

Many researchers and policy makers argue against the use of racial or ethnic categories in medicine, saying that classifying people according to race and ethnicity reinforces existing social divisions in society or leads to discriminatory practices.

I would find it hard to withhold beneficial medicine (in this case BiDil) from patients it would help on the basis of political correctness. “Sorry Mr. Jones, this medicine would reduce you risk of death by nearly half, but I won’t prescribe it for you because I don’t agree with using racial categories in medicine.”

But race must just be a proxy for underlying biological differences. Whether the variations are genetic or environmental, race is just a marker for differences in the disease itself (heart failure in this case). What we really need is a better understanding of these variations.

In 20 years, we should be prescribing BiDil for patient A not because he is black, but because he has genetic polymorphisms B and C, low levels of D and E in his blood and environmental risk factors F and G.

I hope this kind of tailored medicine is what we are moving to, and race based therapies will be but a rest stop on that path.

The "polypill" for heart disease

From the May 7 BMJ

They propose a combined strategy for primary and secondary prevention— targeting all people with pre-existing cardiovascular disease (secondary prevention) but more controversially, targeting all adults aged over 55 (primary prevention) as well. The underlying assumption concerning the efficacy of this strategy is that the six individual ingredients of the polypill (thiazide diuretic, angiotensin converting enzyme inhibitor, blocker, statin, aspirin, and folic acid) when combined together have synergistic treatment effects—calculated by multiplying the relative risk reductions on each class of treatment.

In plain English, this means advocating that every adult >55 take this multi-ingredient pill for the rest of their life (primary prevention), along with everyone with a history of cardiovascular disease (secondary prevention).

I think the primary prevention idea is nuts. It is hard to show efficacy in primary prevention even in relatively high risk groups, to treat everyone, even those at low risk is crazy. You not only send everyone the message that there is something wrong with them, but you spend a ton of money and guarantee a lot of adverse effects for people who were at low risk anyway. Not to mention how good treatment for CVD, has gotten.

Given how low rates of use of the various components of the polypill are for those with known disesae, however, the idea of combination therapy makes sense. But in secondary prevention you are treating people you already know are sick, which is a whole different story.

The war on terrorism

hit home for fellow medical blogger Blogborygmi when his flight from Europe was diverted to pull off someone on the "no-fly" list

Kiss-ass book review of the week

Ramsey Fuleihan in the May 5th NEJM reviewing this book

The 98 authors, including the three editors, who have contributed to this updated textbook use excellent figures to illustrate immunologic processes and many tables to summarize data in an organized manner.

The previous edition is a fine book, but no book with 98 authors has data summarized in an organized matter, it is a logical impossibility.

Note Amazon has the first editor wrong, listing him as E. Rich, not E. Richard Stiehm.

Carnival of the Vanities

number 139 is here, with varied posts from all over blogosphere. I wonder at what point most carnivals stop using Roman numerals? I suspect around 50, since many people (me, for example) aren't comfortable with them once we get past the X.

Drug Recycling

This seems like a good idea which will never be practical. Maybe nursing home and hospitals could recycle drugs, but I doubt we'll ever see recycling once meds are dispensed to consumers.

The paperless physician

I want to expand on a comment I made in response to this post on Ad libitum.
As the original post puts it:

I did a strange thing yesterday. I went to the library. Yes, I meant the actual physical library – you know, the one where books are kept. When I entered it, it was quiet and cool. It brought back a lot of memories – of hours and hours spent in such libraries, reading text books, searching for bound volumes of journals, lugging stacks of bound journals to the photocopier and making photocopies, browsing through the racks of new issues of journals.

I remember as a first year graduate student photocopying article after article. I got very good at knowing which machines were best and starting with the last page so the copies were already in order

I have been in this job 10 1/2 months and I don’t even know where the library is! I have gone completely paperless, at least as far as journals and articles. No stacks of unread journals or piles photocopied articles waiting to be filed for me.

I download articles directly onto my laptop in PDF form. It helps being associated with an academic medical center because almost any journal I’d ever want if available online with no incremental cost to me (Pitt probably spends a fortune in aggregate).

Every weekday I receive an email from MDLinx with papers published in Allergy/Immunology. This is a free service (unobtrusive advertising) and is available in myriad specialties and sub-areas within each specialty. I recommend it highly.

Then each Thursday, I scan the table of contents (TOC) of major general journals (NEJM, Lancet, BMJ, JAMA) and download articles I want to read. I also have a spreadsheet that keeps track of major pediatric journals (Pediatrics and Journal of Pediatrics) and journals is my field (many, high noise to signal ratio in many) and in basic immunology (few, mostly reviews) which I go through. I download articles and put them in a “to read” folder, the electronic equivalent of the pile of paper journals. An occasionally very important article I’ll read right away, but most get lumped in with the rest.

As regular Dr. Andy readers know, I’m generally between 10-14 days behind in my reading (that is I get to an article about that many days after it is published). Most articles I read (often just the abstract) and then throw away, but ones I want to keep I give a name (usually author, journal, basic idea) and file. Periodically I burn a CD with all the articles on it, but I’m in no danger of running out of hard drive space.

This system takes time, but a lot of it is time I’d spend with paper journals too. I believe people read slower off a monitor than paper, but I’d be interested in seeing how big the difference is in those who regularly read off a monitor, like me. Organizing/renaming takes a bit of time, but not that much.

But the payoff is huge. No more thinking I’ve read something and having to search my office for it. I just find the appropriate folder an voila. Of course things can get misfiled electronically, too, but the “find” function on my Powerbook really helps.

And information is right at my fingertips. No more not being able to remember what an article says (don’t you hate that? people arguing about what they think they remember). I bring my laptop to meetings and conferences and we get the answer right away. Once we get WiFi (why are universities so behind on this?) I’ll even be able to prospectively search for answers to question (Dr. Google as I call him in addition to pubmed). Finally, when I want to pass on an article I don’t have to waste paper and time photocopying. I simply forward it by email.

I don't think many physicians have made the step, but my impression is that in the harder sciences, particularly physics, it is more common.

One other point is that most journals will forward you their TOC by email each month. I don't use this because most don't allow you to download the articles, even if you have free access (they do if you are actually an individual subscriber), limiting it's usefulness.

Tangled Bank

is a blog carnival devoted to science and medicine, with a strong dose of evolution. This week it takes on "questionable" medical practices. My contribution is here.

Is Type I diabetes an evolutionary adoptation?

At least one evolutionary biologist thinks so. According to this NYTimes report, Dr. Sharon Moalem proposes that Type I diabetes “evolved” in Northern Europe during a period of sudden increase in cold weather 14,000 years ago. The paper is here (full text only with subscription, as usual. Note the ridiculous $30 to read the article).

The basic idea is that increases in glucose and various alcohols associated with type I diabetes in the blood may be protective against freezing of tissue during extreme cold. Type I diabetes is most common in northern European populations, Therefore, type I diabetes was selected for by cold exposure. They throw in a bunch of mumbo jumbo about ice ages and adaptations of other animals, but this doesn't advance their argument much

Let me first say I applaud the authors for trying to find an evolutionary explanation for this disease. This approach may be misguided, but I like this kind of thinking.

That said, the theory is wildly speculative.

First, it is not clear to me that type I diabetes evolved. More likely, it is an unfortunate side effect of an effective immune system. Evolutionarily, there is a trade off between an immune system that can effectively fight off infections and autoimmunity (the “horror autotoxicus” as Paul Ehrlich termed it). Type I diabetes indubitably results from immune system mediated destruction of insulin producing beta cells in the pancreas. Thus, type I DM, and other autoimmune diseases, may simply be a result of a vigorous immune system. Given how rare type 1 DM is, it doesn’t seem an unreasonable price for the ability to fight off infections, particularly given how common those were as a cause of death until 60 years or so ago.

Second, Type 1 DM is a rare disease today, and it was probably much rarer 10,000 years ago, as incidence has dramatically increased in the last few decades In a figure in the article, the highest prevalence is <40/100,000/year. Assuming about people are at risk for ~10 years you get a lifetime incidence of about 1/2000. I’m not an evolutionary theorist, but that seems a low frequency for something that provides a significant evolutionary advantage.

Third, having actually taken care of kids with type I diabetes, I find it hard to believe they could ever have a selective advantage. They are very sick and die if they don’t get insulin, which obviously wasn’t available 10,000+ years ago. In the article they hand wave about limited life spans at that time, but the life span of an untreated diabetic is generally very short. In addition, poorly controlled blood sugars during pregnancy are linked to high rates of fetal defects and trouble with blood sugars at birth (they have very high insulin levels in reaction to all the glucose they get from mom in utero), so I doubt the offspring of untreated female diabetics would have very good survival.

Finally, if anything I’d think type 2 diabetes would be selected for. After all, type 2 diabetics have high blood sugars and less severe forms of many of the metabolic derangements seen in type 1. But the disease progresses much less slowly and they are much less sick.

To summarize while I approve of generating interesting hypothesis, I find this one implausible.

Grand Rounds XXXIV

is up at Galen's Log

More influenza

I’ve argued previously that the risk of an avian flu pandemic is overstated.

A Perspective piece (free full text!) in the May 5 NEJM says I’m wrong. Michael Osterholm argues that another influenza pandemic is a question of when, not if.
He raises some interesting points, including the increased risk of recombination between bird and human flu viruses with increasing affluence in China:

It is sobering to realize that in 1968, when the most recent influenza pandemic occurred, the virus emerged in a China that had a human population of 790 million, a pig population of 5.2 million, and a poultry population of 12.3 million; today, these populations number 1.3 billion, 508 million, and 13 billion, respectively. Similar changes have occurred in the human and animal populations of other Asian countries, creating an incredible mixing vessel for viruses. Given this reality, as well as the exponential growth in foreign travel during the past 50 years, we must accept that a pandemic is coming — although whether it will be caused by H5N1 or by another novel strain remains to be seen

I agree another pandemic will come eventually, but have said that advances in supportive care, along with anti-viral drugs should mitigate the scope of the problem, at least in rich countries

Osterholm says I’m wrong, that there just isn’t excess capacity in the system. For example, how many mechanical ventilators are there in the US?

About 105,000, of which 75-80K are in use at any given time. During a typical influenza season the number approaches 100K. So there isn’t much slack for an influenza pandemic. He thinks we will need temporary hospitals in high school gyms and community centers for up to 2 years to care for all the sick. Who will provide the care remains to be seen.

As far as deaths, he thinks it could be as bad as 1918

If we translate the rate of death associated with the 1918 influenza virus to that in the current population, there could be 1.7 million deaths in the United States and 180 million to 360 million deaths globally.

That would certainly be bad.

I’m still not convinced. SARS showed that isolation of the ill can control spread and I still think that supportive care and anti-virals would dramatically lower mortality rates. Previous influenza vaccines may provide some protection and a vaccine with at least partial efficacy could probably be produced quickly. It wouldn’t be perfect, but even an imperfect virus might slow the spread and give the immune system enough of a head start to dramatically decrease mortality.

I do agree we need to increase our commitment to research now, especially research towards developing an effective vaccine response.

Blogrolling is up

My slow and painful HTML education continues. If medicine was this hard for me to pick up, I'd had dropped out and gone to law school.

I'll add more links as time goes on, but if you've linked me, I'd be happy to reciprocate, just drop me a line.

Wine ruling

I fully support the Supreme Court's ruling freeing up interstate wine shipments. I can't comment intelligently on the underlying legal issues (that doesn't stop you on medical topics!- ed.) but my libertarian streak supports anything anti-regulation

I also find the idea that these regulations are based on preventing minors obtaining alcohol absurd. Any teenager with the foresight to order wine from out-of-state, pay for it and arrange delivery in a way that no parents would know, can easily get alcohol some other way (friends, fake IDs, etc).

Patients like e-mail

but they don’t want to pay for it. No surprise, but no one has really studied this. Anand et al. have an article in this month’s Pediatrics (subscribers only) looking at parent reaction to communicating with their children’s pediatrician by email.

Ninety-eight percent were very satisfied with their e-mail experience with their pediatrician. Although 80% felt that all pediatricians should use e-mail to communicate with parents and 65% stated they would be more likely to choose a pediatrician based on access by e-mail, 63% were unwilling to pay for
access

It was encouraging that email seemed to be an efficient means of communication. The pediatricans estimated they spend 1/2 hour a day answering emails and 86% of parent e-mails were dealt with a single e-mail from the pediatrican.

It should be noted that this practice is pretty upscale, or at least the parents who used e-mail are: 86% werer college graduates

I think this is going to become increasingly popular and as I’ve noted before, for young technology savvy docs like me (you, techno savvy? –ed. Compared to my colleagues, I am. You have no idea how techno phobic many MDs are) it saves a ton of time wasted playing phone tag.

P.S. 2nd and 3rd authors Mitchell Feldman and David Geller are apparently the pediatricians whose email use was studied, although the article doesn't bother to come out and say that.

UPDATE: fixed title

More cool immune system evolution

Or how did an inhibitory receptor turn into a activating one.

NK (natural killer) cells are a special kind of white blood cell that specialize in killing tumor and virally infected cells. Unlike T and B cells they can’t shuffle segments of DNA to generated diverse antigen receptors (antibodies from B cells and T cell receptors) to recognize “foreign" material. Instead they integrate signals through a number of cell surface receptors to make a decision about whether or not to lyse another cell

Some of these receptors, such as one’s that recognize the body’s own MHC molecules, are inhibitory and prevent NK cell activation and subsequent killing of the targeted cell. Others, expressed preferentially by cancerous or infected cells, are stimulatory. The balance of inhibitory and activating signals allows NK cells to ignore normal cells, but, hopefully, kill "abnormal" cells such as those that are infected or cancerous. What all the NK cell receptors recognize, how they signal and how the NK cells sums their signals is just beign worked out

2B4 is an one NK receptor. In mice it is clearly inhibitory; that is, signaling through it prevents NK cell mediated killing. But in humans it appears to be stimulatory, when it binds CD48, its ligand, it activates the NK cell. This activation requires binding of it’s intracellular tail to another protein called SAP. Mouse 2B4 can't bind SAP.

Why the difference? No one knows for sure, but one possibility (as detailed by Kumar and McNerney in the May Nature Reviews Immunology is the evolutionary pressure brought to bear on humans by a particularly successful virus, Epstein-Barr, has driven evolution of 2B4's function.

EBV, as Epstein Barr Virus is abbreviated, infects 90+% of US residents by the time they reach adulthood. Most people have either no symptoms or a mild illness similar to a cold, but for some it can cause significant enlargement of lymphoid organs (tonsils, spleen and lymph node) and relatively severe illness called mononucleosis, because of the proliferation of characteristic white blood cells, called atypical lymphocytes.

The infection is never really cleared but lays dormant in most people not causing much problem. But rarely EBV infected cells can turn cancerous, causing lymphoma, and emerging data links EBV infection to multiple sclerosis, although infection is so prevalent and MS so rare, it is clearly not sufficient to cause the illness.

EBV infection leads to upregulation of CD48 which is the ligand for 2B4 (that is it binds it). In mice (and probably humans many years ago) this binding leads to inhibition of NK cell lysis of infected cells. Presumably, evolutionary pressure from severe EBV infection lead to 2B4 gaining the ability to bind SAP and activate, rather than inhibit NK cells.

Speculative? Yes, but consider that there is a rare genetic defect of SAP, called the X-linked lymphoproliferative syndrome (XLP). In XLP patients, 2B4 can’t bind SAP and acts as an inhibitor of NK cells, as in mice. XLP patients are uniquely sensitive to EBV, developing a fulminant infection that is almost uniformly fatal.

So many years ago, EBV was a severe, often fatal illness that decimated early human populations. When, by chance, a mutation in 2B4 lead to the ability to bind SAP, an enormous selective advantage was obtained, allowing individualswith the new variant to fight off EBV infection (as most of us have). Not surprisingly, this mutation became established and spread throughout the population.

Cool, huh?

Of course, this is probably an oversimplification. It probably wasn't just one mutations, but several, over time, that allowed efficient binding of SAP by 2B4.

Who are all these doctors?

One thing that can bewilder patients in an academic medical center is the sheer number of doctors involved in their care.

Let’s walk through an admission I might consult on, and go over each doctory

Say your child has a straightforward asthma exacerbation, status asthmaticus in medical argot, so you bring her to the ED. After seeing the triage nurse, maybe getting a neb (short for nebulization treatment, in this case with albuterol, which helps open up the lungs), she is shown into a room where she meets another nurse.

After waiting a while (hopefully not too long) doctor #1 comes in, talks to you and examines her. He agrees it is asthma, which you already knew, maybe mentions she’ll get more nebs and some steroids (to quell the inflammation in her lungs).

Doctor #1 is probably a resident. In a pediatric teaching hospital he could be either a pediatric resident or a resident in emergency medicine getting experience in pediatrics. He could be in anywhere from his first to fourth year of training.

45 minutes or so later, another doctor #2 walks in , listens quickly and tells you again that it is asthma.

Doctor #2 is probably the attending. She has done both 3 years of pediatric residency and 3 more years of specialized training in pediatric emergency medicine.

A few hours and several nebs later, your daughter is not doing so well. Doctor # 1 is back in and says she’ll have to be admitted. He says as soon as there is a bed for her upstairs she’ll move to the main part of the hospital and meet a new team of doctors. Since it is now 2am you wonder exactly who will be leaving the bed she’s taking

Before you make it upstairs, another doctor comes in to see your daughter. Doctor #3 says something about being another resident doing something called night float. She seems to know most of what is going on “from the chart” and is in and out quickly.

Doctor #3 is the resident assigned to admit patients overnight, so called “night float”. With new work hour restrictions (no more than 80 hours per week or 24 hours in a row) hospitals have set up all kinds of systems to comply. One of the most common is to have residents come into work night shifts, so the on-call team can sleep or take care of patients who have already been admitted. Doctor #3 is likely a 3rd year resident.

You finally make it upstairs, where a nurse asks you makes you fill out lots more forms with pointless questions about how much pain your daughter is in and whether you prefer to be told things or shown them, and you can finally get some sleep. Being a children’s hospital your chair folds out to a cot so you can sleep right next to her. You get some sleep but she needs neb treatments every 2 hours, so you keep getting woken up.

At about 8 the next morning doctors # 4 and 5 come in. #4 introduces herself as a “student doctor” and says her first name. Dr #4 refers to herself only as doctor. They says they’ll be the doctors taking care of you on the floor, which you thought Dr. #3 would be doing. Dr. #3 is home sleeping. They stay for a while, listen and then they are off.

Dr. #4 isn’t a doctor at all, yet. She is a 3rd year medical student doing her pediatrics rotations. Doctor #5 is the infamous intern, in her first year after finishing medical school. Forgive her if she seems a bit weary, in medicine we believe in learning by doing and intern year can be like drinking from a fire hose.

Before lunch, here comes #6. She is a bit older than the rest and seems a bit calmer. She says the magic word “attending” and explains she is in charge of your daughter’s care. She listens, sits and talks for a few minutes, and says maybe you can go home later, since your daughter is doing better, only needing the treatments every 3-4 hours.

Doctor #6 is the attending. She has done pediatric residency and maybe subspecialty training as well. She could be young or old, but is the ultimate one in charge of your daughters care. In many cases she would be your daughters pediatrician or one of her partners. She could be a “hospitalist” who specializes in the care of inpatients, or a subspecialist like me, roped into doing some time on the inpatient service as part of a faculty job.

Just after lunch, and by the way your daughter is up and playing now, comes doctor#7. He say hi, listens, says she sounds great, asks how long ago her last neb was (shouldn’t he know that?) and says she can go later. He tells you they want the allergists, who specialize in asthma, to come by and give some recommendations about what medicines she should go home on.

Doctor #7 is the senior resident. He is in his 3rd year of pediatrics residency and oversees the interns. He is below the attending, but makes sure everything goes well and nothing gets screwed up. He may be looking forward to private practice pediatrics next year or to further training in a pediatric subspecialty (GI, cardiology, heme/onc, etc.)

After he leaves, Doctor #8 waltzes in. She introduces herself as the allergy fellow. She asks a lot of questions about pets, carpeting, and whether your basement has mold. She also quizzes you about which medicines your daughter is on at home, how she uses them and whether she forgets to take them. She leaves, saying she’ll be back in a bit with her attending, who you thought you had already met.

Dr #8 is the allergy/immunology fellow. She has already completed her pediatric residency and is now taking or 2 or 3 more years to become an allergist. When the general

Finally, about 4PM, Dr. #8 comes in with me, Dr. Andy aka Dr. #9. I say something like “I’ve been hearing all about your daughter from Dr. #8. Sounds like she’s had asthma for a while, but it really flared with this viral infection. We’ll make some suggestions to the floor team about adding a medicine for her to use everyday to keep the inflammation in her lung under control. We’d like to see your daughter back in our clinic in a couple weeks. You can make the appointment with Dr. #8” We are in or out.

Dr. # 9, besides being me, is the attending allergist. Dr.#8 and I come to given advice to the primary team when asked. Our consults range from straightforward ones like this to more difficult ones (e.g. whether or not a patient has an immune deficiency).

An hour later comes the final Dr., #10. She notes she is just covering for the other intern, who has already gone home. She just gives you some prescriptions and paperwork, goes over some instructions and under what conditions you should bring your daughter back to the hospital and you are on your way.

A straightforward asthma admission, 24 hours and you saw 10 doctors! Imagine if your child had a complex illness or a medical mystery, requiring multiple consults. Or if you were in over the weekend and got to meet all the covering docs.

Are all these doctors necessary? Absolutely not. If instead of an august academic children’s hospital you had gone to a community hospital you might have seen as few as 2 doctors: an ED attending and your pediatrician or a covering colleague. In the community, the allergist, if called at all, would have just made some recommendations and seen the patient in his clinic. More likely, the pediatrician would have just set up an outpatient appointment.

Ready for a beer

I am tired! I am going to shower and then sit out back, drink a Newcastle Brown Ale and enjoy the view.

After a 2o mile run this morning, I spent about 4 hours working on our yard/garden. We bought our house 10 months ago, and it seems that almost nothing had been done in the garden for several years. Given the previous owners were quite old, I'm not surprised, but there is a lot to do. I cleared ivy off the wall between our house and the streets, trimmed our front hedges, cut back the ivy from the back walk and stairs and bagged a lot of the climbing vine that was choking all the trees/bushes until I hacked it out over the last week.

I find the gardening/yard work goes better in small doses. I've taken to trying to do an hour or so several weeknights so there isn't so much for weekends. Plus, when there is so much to be done, trying to do to much at once can get discouraging.

Hemorrhagic Fevers

There are new cases of Marburg virus in Anglola. This is bad news, given it seemed to be coming under control:

The new cases were identified in the last few days in Uige, the epicentre of the outbreak. "As some chains of transmission are still ongoing, mobile teams are investigating suspect cases and following contacts," the statement said.

Reading between the lines it still seems things are going better, or at least not getting worse. Of course, one infected person (the incubation period is 21 days could spread it to a new area.

And there is a probable new outbreak of Ebola in the Congo. Luckily it sounds like the Congolese are much more prepared than were the Angolans:

Health officials in two Congolese cities already have mobilized to battle the suspected outbreak of Ebola, which has repeatedly surfaced in central Africa in the past five years. Epidemiologists are tracking 52 people who had contact with those who died, the officials said.

No one knows for sure, but these viruses are thought to infect other primates. They probably infect hunters who butcher monkeys for sale (primate meat is apparently quite popular in parts of Africa) and they then pass it on to others.

Why the Pirates stink

The Pirates are terrible. Pittsburgh is a small market, so the payroll is small. As I've blogged before it is suspiciously small, less than the revenue the Pirates get from revenue sharing and national TV, but they will never compete with the Dodgers or Yankees monetarily.

But it is more than that. In effect, the Pirates have given up. 25 years ago, in high school, I started reading Bill James, the founder of sabremetrics (which is, roughly, the study of baseball statistics). From the very beginning he emphasized how important, and underrated, the walk was. As I went off to college and on with life, I paid increasingly less attention to baseball, but I assumed professional baseball, as it became more and more a busines, would incorporate these and other insights.

In fact that was not that case. As detailed in Moneyball, published in 2003, Oakland A general manager Billy Beane brillantly exploited the reluctance of more traditional baseball men to take advantage of sabremetrics. He built the A's into a consistent winner despite a modest payroll.

I loved the book and highly recommend it, even if you aren't a baseball fan. One thing I always wondered was why Beane agreed to cooperate with the book. He had an incredible competitive advantage, using statistical insights that are largely in the public domain, but ignored by other teams. Now I know the answer. He knew teams like the Pirates were too stupid and/or stubborn to learn.

10 million people have read Moneyball. Even the ones who knew nothing about baseball now know that walks are a key offensive statistic and batting average is overrated. The Pirates remain clueless. From the Post Gazette:

Most troublesome to many who follow the team closely, the Pirates have shown precious little patience at the plate in Perry's tenure. Last year, they ranked last in the majors with 415 walks. This year, they rank 23rd out of the 30 teams with 95.

Although there is greater value being placed on walks and on-base percentage in the baseball community, Perry is adamant that coaching players to seek a free pass is unwise.

"I don't want my hitters to be defensive," he said. "I think you have to go out there to swing the bat. You have to have a zone and try to stay within that zone, but I don't want anybody getting into that box and thinking, 'Oh, man, I need to get a walk.'"

There you have it. Bill James has been preaching walks for 25 years; Moneyball has been out two years, detailing how a small money team can compete with the big boys, and the Pirates have a hitting coach who wants them up there swinging. No wonder they've had so many losing seasons in a row.

Good advice

“Injecting olive oil or any liquid into penises is extremely risky,” Chatri Banchuin, chief of the Department of Medical Services, said after his office issued the public warning.

Not to be elitist again, but I doubt many readers of this blog are stupid enough to do this, but apparently it is common in Thailand

Prostate Cancer

Or a chance to cut really is a chance to cure.

Radical prostatectomy for prostate cancer is life saving, at least in men under 65, according to a new study in this weeks NEJM (subscribers, but NYT article here). In general prostate cancer is slow growing and men are more likely to die with it, than of it. So who should get potentially curative surgery and who should be treated less aggressively is still not clear. Other options are watchful waiting and use of radiotherapy implants which help control local disease but aren’t curative.

This study, from Sweden, randomized men with prostate cancer that hadn’t yet spread beyone the prostate (that could be detected) to watchful waiting or surgery. Radical prostatectomy (RP) is pretty brutal surgery where they remove the prostate and surrounding lymph nodes. Important structures are packed pretty tight down there, so the risk of collateral damage is high. Most (perhaps all) surgeries currently are “modified” or “nerve sparing” to try to preserve bladder control and erectile function, but more than 1/2 of men are impotent and ~10% incontinent. My impression is that this is a surgery you want done by an expert, because surgeons who do a lot have much better results. Patrick Walsh, a urologist at Johns, developed the nerve-sparing surgery, and all over the US his trainees are chiefs of urology and experts in the surgery.

The study showed that there were significantly fewer deaths in the surgery group, as well as fewer metastases 10 years after surgery. The benefit, on retrospective analysis, was confined to men under 65, who are likely to live longer. The study also didn’t differentiate between aggressive and less-aggressive tumors.

Raw numbers were as follows: watchful waiting 348 patients, 106 total deaths and 50 deaths from prostate cancer; RP 347 patients, 83 deaths, 30 deaths from prostate cancer.

So for patients <65, and perhaps older patients who would otherwise live a while, RP is probably the way to go. They’ll continue following their patients so we’ll see if the effect increases with more follow up.

An incredible story

from a patient’s perspective at Acid Test (via Galen via Arnold Kling). Well worth the time.

The writer concludes that the organization of our medical system is to blame for what she perceives as the problems with her care (overworked nurses and doctors, incomprehensible bills, etc.) I agree to some extent, but I’m not sure how a single payer system would make things better. Medicare, which allegedly has low administration costs, is constantly threatening to slash payments to doctors and hospitals.

I agree with Galen:

Instead of raging against the system, I think she should pause for a second and think very deeply about how incredibly lucky she was. She could have very easily lost her vision or worse, and much of the rest of the world would kill for all the resources at her disposal

To the authors credit she is honest about when advice she rebelled against turned out to be spot on.

I also thought it was interesting how her view of the health care system improved as her heatlth did.

I'll have more thoughts about the activist care issue later.

Too much information

I am becoming increasingly convinced that the biggest problem facing biomedical research going forward is how to deal with all the information. One aspect of this is the multiple variations in a single gene and how to sort out which, if any, are important in predisposing to disease. As a review (Holloway et al. in linked article, subscribers only, alas) of the association between variations in the beta-adrenergic receptor (BAR) gene and asthma puts it:

The ever increasing availability of data on single nucleotide polymorphisms in the human genome and the vast range of clinical phenotypes against which they can be tested for association has led to an explosion of publications in the literature reporting associations between polymorphisms in candidate genes and disease-related phenotypes, with allergy and asthma being no exception. It has become readily apparent that few reported genetic associations can be replicated unequivocally, that the first published report is usually a poor guide to the final conclusions regarding a particular association, and that if it is correct, it usually greatly overestimates the contribution of the polymorphism to disease risk.

Basically, when you do small studies you often find correlations which may not represent underlying reality.

The BAR polymorphism field is know in the situation where effects are seen, at least in severity and response to medications, but the effects are in the opposite direction one would expect from functional data.

Another review from the same issue of JACI (Journal of Allergy and Clinical Immunology, article is Bochner and Busse) notes the following study

Raby et al performed a family-based study with 652 nuclear families. Seventeen ADAM33 single nucleotide polymorphisms (SNPs) were genotyped. Because no single SNP had an association with asthma, the possibility exists that the association between ADAM33 and asthma might be found in only selected populations with very specific characteristics

17 polymorphisms (a polymorphism is a change in a single DNA base) to study in one gene. It doesn’t take a statistician to realize that if you study each variant and several outcomes you’ll end up with a lot of spurious correlations.

And things are only made more complex by the fact that the polymorphisms aren't independent but tend to be linked to one another in what are called haplotypes.

How a clinician like me can make sense of all the data published is another aspect of the overall issue.

Super elite frequent fliers

I am just a peon frequent flier, but my dad is near the top of the heap.
I think it would be cool to be always in first class but there are several odd things in this article.

First, the definition of super-elite varies widely. Continental has 21 super-elite members, while United has 18,000. I’d think you’d be able to provide a lot better service if you focused on 28 people instead of 1000 times as many. Also, spening $20K on United in one year doesn’t seem much of a bar. If you fly a $500 roundtrip 40x/year you are in. I’m not surprised 10,000 people are in it. United’s highest public frequent flier level is 100K miles. I suspect most people who fly that many miles hit the $20K barrier.

Becoming a member of this beyond-platinum club is "the most coveted award" for the frequent traveler, according to Hal Brierley, a loyalty-program consultant with Brierley & Partners in Dallas. He estimates that fewer than one-tenth of 1 percent of elite-level fliers hold super-elite status.

Using this math, United would have 18 million elite-level fliers, which sounds, uh, a bit high.

I also thought it was bizarre that the frequent flier they found to comment was a law student who complained about not being upgraded when he bought cheap tickets:

Vincent Petty, a law student at Stetson University in St. Petersburg, Fla., and a Platinum Medallion-level member of Delta's SkyMiles frequent-flier program, recently received a letter from the airline promising new benefits that exceeded his elite level. "But things haven't gotten any better," he said. "If anything, they are worse. I wait for an upgrade, and even though I'm the only Platinum-level passenger, the first-class seats go to the Silver Medallions who maybe paid more for their tickets than I did. I don't see how a new program is going to change that.”

I doubt bargain ticket buying students are the the target market for these progrmas

UPDATE: more at View from the Wing my favorite travel blog. Luckily in my work I make only one or two trips a year.

Grandstanding

Mitt Romney, govenor of Massachusetts, wants to be president, so he is trying to impress religious conservatives by opposing stem cell research:

Mr. Romney, a Republican, wants the largely Democratic legislature to adopt a definition that says that life begins at fertilization.

"To change the definition of when life begins is a very significant moral and ethical change," Mr. Romney said. "They can accomplish all the stem cell research they wish to without making that change."

I don't seem to remeber Romney running for election as a social conservative (and I was living in Boston when he was elected). For more of my thougths on stem cell research see here.

Individualized therapy

is getting closer and closer. A recent study in PNAS (Proceedings of the National Academy of Science, free for all) demonstrates that polymorphisms in the gene targeted by common anti-epileptic meds carbamezapime and phenytoin and the enzyme that metabolizes the latter predict the effective dose.

The obvious implication is that one could test patients for the polymorphisms and use that to guide dosing. In the case of CYP2C9, the enzyme that metabolizes phenytoin, the difference was in activity, in the anti-epileptic target, SCN1A, the polymorphisms lead to different levels of protein in the brain.

Lead poisoning

is much better than it used to be, but still a problem. Our Grand Rounds (the old fashioned kind, not the new-fangled one) this morning was a case of lead poisoning, and an article out in this weeks JAMA (subscribers only, I believe)is getting publicity.

Encouragingly, the percentage of kids with lead levels >10 mcg/dl, the current cut off for it being too high has fallen from 88% of the population to <5%. Mostly from outlawing leaded gasoline and paint.

While the cut off for what is acceptable has steadily come down from 60 in the 1960s to 10 today, it may still be too high. A recent study suggested each 1mcg/dl increase in blood lead was associated with a 1.37 point drop in IQ. They tried to control for other factors like socioeconomic status and maternal IQ, so it is not just that stupid parents have stupid kids and live in old, dilapidated houses. Based on that, the difference between a lead level of 0 and 1 of 10 would be about 14 IQ points or 1 full standard deviation. That is a lot. Interestingly, the incremental difference in IQ declines as lead levels rise

One caution is that in the IQ study, the population was none-too-bright to start with an average IQ of around 90 and an average maternal IQ of just over 80. Studies with premature infants have shown that being premature and poor stimulation (like you might expect if your mom had an IQ of 80) act synergistically to lower IQ and delay development. The system is resilient to insults, but once the insults add up, you get into trouble. I wonder if a similar situation could be at play here. That the combination of lead and poor social environement is negatively synergisitc.

Anyway, if you believe the IQ data, kids should be much smarter than they were in the past: 15 or more points on average. That seems a bit unlikely, but maybe they'll be a lot more physicists soon. On the other hand, the kids in this study were almost 10 IQ points smarter than their mom's, which could be lead.

The new study in JAMA this week shows that follow up of kids with high lead levels is poor. Almost 1/2 of kids with blood lead levels >10 are never retested. Part of the problem is they don't follow up, but almost 60% get some medical care in the next 6 months, so that isn't the only reason.

Treatment is not great. Education about avoiding lead exposure is obvious. Remediation to remove lead from the home is effective, but expensive and landlords have a lot more political pull than poor families, so, as a society, we haven't been willing to pay for it. For very high levels you can give agents that chelate (basically bind up) the lead.