potpourri part 1: books!

This post will probably be a bit scatterbrained, but, oh well. So, what's new? I've read some books, and I have some thoughts.

1. The House of God - I finally made it around to reading this. It was difficult, at first, to properly appreciate what appeared to be the book's unyielding cynicism on the subject of medicine (aka, the final law of the House of God: THE DELIVERY OF GOOD MEDICAL CARE IS TO DO AS MUCH NOTHING AS POSSIBLE), but, read in a different way, quickly becomes not an admission of futility but rather a valiant argument for factoring goals of care into the discussion when considering how to treat the patient. This must have been particularly heretical in the age in which it was published, where the physician was lionized for his or her ability to harness all the tools at hand to preserve life at all costs. Of course, towards its conclusion the book, written by a medicine intern who becomes a psychiatrist, becomes unsurprisingly sycophantic about psychiatry (promoting it over medicine for its enhanced ability to cure people seems particularly silly), but I'll let that slide. And I do like law #3 (AT A CARDIAC ARREST, THE FIRST PROCEDURE IS TO TAKE YOUR OWN PULSE.)

2. The Emperor of All Maladies - Nevertheless, it was comforting to move on from House of God and onto Siddhartha Mukherjee's tremendous 'biography of cancer' - or rather, biographies of Sidney Farber and Mary Lasker with a history of chemotherapy intricately weaved in between. There were so many interesting aspects of this book, beyond its charting the course of how investigations into the fundamental mechanisms driving oncogenesis intersected (or more often, failed to intersect) with relevant and/or efficacious clinical interventions. In particular, I think the book's dissection of how the "vision statement" of cancer research morphed as both drug efficacy and public pressures shifted was amazing.

The book begins with the origins of cancer, from the Egyptian physician Imhotep to Hippocrates, who was responsible for the dual titles of kankros (latin for 'crab') and onkos (for 'mass', or, more poetically, 'burden'). Even as the staging of cancer began to be determined by both local and distant spread, the prognosis remained grim due to the lack of any efficacious therapy:

[Scottish surgeon John] Hunter [in the 1760s] had begun to classify tumors into “stages.” Movable tumors were typically early-stage, local cancers. Immovable tumors were advanced, invasive, and even metastatic. Hunter concluded that only movable cancers were worth removing surgically. For more advanced forms of cancer, he advised an honest, if chilling, remedy reminiscent of Imhotep’s: “remote sympathy.”

All of this changed when the first drugs, aminopterin and methotrexate, were shown to induce temporary remissions in acute lymphoblastic leukemia. This effort was first described by the remarkable Saul Farber (whom Mukherjee champions for his tenacity while not sparing him from the rebuke of overzealousness). In a report published in 1948 in the New England Journal of Medicine, entitled "Temporary Remissions in Acute Leukemia in Children Produced by Folic Acid Antagonist, 4-Aminopteroyl-Glutamic Acid (Aminopterin)" Farber demonstrated the first temporary cancer remission achieved with pharmacotherapeutic intervention alone.

Farber quickly organized studies of other pediatric tumors, including the very common Wilms' Tumor (response seen above) and quickly escalated to the hypothesis that chemotherapy would provide a unifying cancer cure. What was missing, according to Farber, was sufficient funding. For this, he turned to the highly influential fund-raiser and activist Mary Lasker, who quickly concluded that the gateway to real progress was achieving a mainstream, socio-political effort to wage a 'new war on cancer':

“Doctors,” [Mary Lasker] wrote, “are not administrators of large amounts of money. They’re usually really small businessmen…small professional men” – men who clearly lacked a systematic vision for cancer."

As research funds poured in, temporary remissions were seen with high dose chemotherapy in many forms of cancer, both liquid (hematopoieitic in origin) and solid. The public pressure that emerged from these temporary remissions caused a paradigm shift in the goal of cancer research, from mechanistic understanding to result-driven pharmacologic studies, a conversion in which Farber himself took part. He wrote, in a statement to Congress,

The 325,000 patients with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure of cancer, for us to have the full solution of all the problems of basic research … the history of Medicine is replete with examples of cures obtained years, and even centuries before the mechanism of action was understood for these cures.

The combination of a sudden shift in approach from mechanistic to therapeutic studies, combined with increasing public pressure for early approval of chemotherapeutic drugs with even potential efficacy led to the widespread initiation of high dose, toxic chemotherapies under the idea that simply pushing maximal doses would push temporary remissions to complete cures (despite the lack of evidence to support this theory.)

This was pretty ironic, given that, just years earlier, Dr. Min Chiu Li had been fired from the National Cancer Institute for even attempted a prolonged (let alone toxically high) course of chemotherapy for patients with metastatic choriocarcinoma, a treatment which produced the both the first ever quantifiable serum cancer marker and the first ever sustained cancer remission, described in an awesome New England Journal of Medicine paper in 1958. It's heartwarming, in a sad sort of way, to see that many scientists retained a sense of caution and even averseness to this rapid increase in drug development, Nobel prize winner James Watson among them:

“Doing ‘relevant’ research is not necessarily doing ‘good’ research. In particular we must reject the notion that we will be lucky…instead we will be witnessing a massive expansion of well-intentioned mediocrity.”

Over the following twenty years, more and more toxic doses of chemotherapy were administered to patients, despite the lack of evidence that they were of any morbidity or mortality benefit. Mukherjee is unrelenting in his depiction of the hubris of oncologists in pushing toxic therapies with the hopes of achieving a 'cure,' without paying attention to the impact on the patient's quality of life.

The allure of deploying a full armamentarium of cytotoxic drugs – of driving the body to the edge of death to rid it of its malignant innards – was still irresistible. So cancer medicine charged on, even if it meant relinquishing sanctitiy, sanity, or safety. Pumped up with self-confidence, bristling with conceit, and hypnotized by the potency of medicine, oncologists pushed their patients – and their discipline – to the brink of disaster. “We shall so poison the atmosphere of the first act,” the bioligist James Watson warned about the future of cancer in 1977, “that no one of decency shall want to see the play through to the end.”

As the famous breast cancer survivor and patient advocate Rose Kushner noted chillingly, "the smiling oncologist does not know whether his patients vomit or not."

This all culminated, finally, in the sorely misguided initiation of autologous bone marrow transplant for rescue of irreversible bone marrow failure caused by high-dose chemotherapy for metastatic breast cancer. Not only did patients fail to respond to higher doses of chemotherapy, but the toxicity from such high doses caused not only bone marrow suppression but malignant transformation and untreatable myeloid leukemias.

It was only this highly publicized failure that led oncologists to realize that more was clearly not better. Mukerjee chronicles the subsequent return to the drawing board in which cancer biologists and oncologists focused once again on the fundamentals of disease pathogenesis. He describes the painstaking process by which the viral theory of oncogenesis is largely disrupted and the oncogene model is established, and brings us to the forefront of modern oncology by relating the thrilling origins of both monoclonal antibody therapy (the story of herceptin) and small molecule inhibitors (the discovery of Gleevec). Rarely has one book made me rejoice and despair so many times.

3. The Amazing Adventures of Kavalier and Clay: I'm not going to write as much about this book, but not due to any fault of Michael Chabon's. This is easily one of my favorite novels of all time. Chabon brilliantly depicts how two young immigrants struggle, one with a sense of obligation followed by vengeance, one by fear and shame, and channel these feelings into their superhero, the Escapist. Their superhero serves as their escape from paralyzing loneliness, helplessness, and isolation. It's equally fascinating that their story is modeled after Jerry Siegel and Joseph Shuster, two Jewish immigrants who created Superman as teenagers. Their hero, Superman, seems all-powerful and invulnerable, but in many ways reflects their struggles: an immigrant in a new and foreign world, largely isolated, who escapes to his Fortress of Solitude. (Also, similarly, Siegel and Shuster were screwed out of their earnings). Chabon also acknowledges Jack Kirby, the creator of Captain America who, much like the Escapist, punches out Hitler in an iconic DC cover. Anyways, this book was awesome.

4. The Checklist Manifesto: So, admittedly, a book about checklists is not going to be Atul Gawande's most fascinating book (particularly when his last book, Better, featured him iconically tying on a surgical mask. That is way cooler than a check mark.) But that's all the more reason to applaud him for writing a book that is basically antithetical to the surgeon's "my hands are my life" mentality. Gawande's premise: that reduction of simple, avoidable mistakes could actually improve mortality, was no doubt regarded as preposterous among his fellow attending surgeons, who no doubt thought of such checklists as a waste of their prodigiously valuable time. But time and again, Gawande shows that targeted, methodical incorporation of checklists improves outcomes. I was stunned to read of the study in Karachi, Pakistan, in which simply giving families instructions on proper use of soap in six vital situations reduced disease burden:

“The secret was that the soap was more than soap. It was a behavior-change delivery vehicle. The researchers hadn’t just handed out [soap] after all. They also gave out instructions – on leaflets and in person – explaining the six situations in which people should use it. This was essential to the difference they made. When one looks closely at the details of the Karachi study, one finds a striking statistic about the households in both the test and the control neighborhoods: at the start of the study, the average number of bars of soap households used was not zero. It was two bars per week. In other words, they already had soap.”

Gawande is not so naive to think that all problems can be solved with a set of instructions. He differentiates between 'simple' problems (such as reducing infection with introduction of proper cleaning procedures) from 'complex problems' (such as how to increase teamwork in the operating room.) In the case of complex problems, he fully admits that a checklist won't solve the problem, but suggests (and is supported by data) that pro-active communication between members of a team in combination with decentralization of decision-making capacity can similarly improve outcomes.

Gawande then describes the construction of a pre-operative surgical checklist to prevent common complications in the operating room. He is forthcoming about his struggles in generating a checklist that properly reduces commonly overlooked errors while not restricting autonomy. The ultimate results of the checklist study cannot be doubted or overlooked; a significant reduction in complications and mortality is seen across eight different institutions of varying size, patient population, and level of resources. But rather than stopping there, Gawande takes a step further and discusses the lack of widespread implementation of checklists despite the undeniable results of the study. In doing so, he does not flinch in his critique of himself and his colleagues. His assessment is that the hesitation of doctors to use a simple checklist to reduce mortality is two part: first, the idea that something so simple as a checklist could improve mortality (and its accompanying implication that doctors frequently err in such preventable ways) is insulting to a physician's ego,

That’s what happened when surgical robots came out – drool-inducing twenty-second-century $1.7 million remote-controlled machines designed to help surgeons do laparoscopic surgery with more maneuverability in side patients’ bodies and fewer complications. The robots increased surgical costs massively and have so far improved results only modestly for a few operations. Nevertheless, hospitals in the United States and abroad have spend billions of dollars on them…By the end of 2009, about 10% of American hospitals had either adopted the checklist or taken steps to implement it.

and second, that physicians wrongly assume that systematic approaches such as checklist work against the ability of doctors to think creatively:

The prospect [of checklists] pushes against the traditional culture of medicine, with its central belief that in situations of high risk and complexity what you want is a kind of expert audacity – the right stuff. Checklists and standard operating procedures feel like exactly the opposite, and that’s what rankles so many people...they imagine mindless automatons, heads down in a checklist, incapable of looking out their windshield and coping with the real world in front of them. But what you find, when a checklist is well made, is exactly the opposite. The checklist gets the dumb stuff out of the way, the routines your brain shouldn’t have to occupy itself with, and lets it rise above to focus on the hard stuff.

Gawande is unmoved by such argments, and I'm with him. And while the implementation of checklists such as this seems to be more useful in the surgical world, I can think of plenty of scenarios in which they are useful in medicine (a simple checklist at the completion of a patient history and physical, a systemic approach to cardiac arrest) and I don't think that anyone feels that are the first step to doctors becoming automatons.

Whew! That was long.

preventing GVHD

So I'm working on a big post about lupus (and the the the first approval of a drug specifically for lupus in fifty years), but in the meantime, I've assembled some other random thoughts that won't see the light of day unless I kind of word-vomit them out first. So, here goes.

Leukemia and lymphoma, the "liquid tumors," are so named because they arise from malignant transformation of cells whose precursors originate in the bone marrow. Leukemia occurs from overproliferation of precurors to mature hematopoietic cells which lack the function of fully developed WBCs. Lymphoma occurs from acquisition of malignant properties by differentiated white blood cells which have exited the bone marrow. While chemotherapy has shown success in some limited situations (diffuse large B cell lymphoma, for example), these tumors often recur. The last available option is often to replace the patient's entire hematopoietic lineage, via the so-called "bone marrow transplant." Traditionally, this involved two steps; irradition of the host bone marrow, followed by transplantation with new bone marrow from someone whose cells were least likely to be recognized as foreign by any remaining immune cells in the host (aka, maximal HLA matching).

This procedure was first successfully attempted in mice in 1956, and subsequently attempted in humans with refractory disease in 1957 (Thomas et al. N Engl J Med 257:491-6). The same group first successfully achieved temporary remission with BMT in 1959, in a study published in the Journal of Clinical Investigation.

Unfortunately, almost as soon as successful remissions with transplants were describe, so too were significant adverse effects, in which transplanted white blood cells would see the host as foreign and attack it. This destruction, first described in 1957 was largely focused in the skin (causing a sclerosing skin rash), and in the intestine (causing inflammatory diarrhea), known collectively as graft versus host disease. It was demonstrated in 1978 that T cells were critical for the graft versus host response. In order to try and minimize this devastating, and potentially lethal, side effect, early emphasis in BMT development was placed on achieving maximal HLA matching.

Interestingly, in 1979, a paper in the New England Journal of Medicine demonstrated an unexpected finding; patients receiving a mismatched SCT were actually less likely to relapse if they developed GVHD. Based on this, the theory was put forward that donor T cells could have both positive and negative effects; that is, they would seek out and reject tumor cells, but would inflict life-threatening collateral damage on host tissue at the same time. It has since been demonstrated that selective transfer of donor lymphocytes in patients with relapsed disease following non-selective BMT can achieve complete and permanent remission in some cases. Given this, the call for optimizing allogeneic (aka, non-HLA matched) stem cell transplants for graft-mediated tumor rejection while controlling graft versus host disease continues to grow.

One method of minimizing graft versus host disease while permitting anti-tumor immunity seems to be via increasing the presence of regulatory T cells. As shown on the left, in mice, co-transfer of regulatory T cells appears to suppress GVHD while still permitting tumor rejection and significantly improving survival. A role for Tregs is further evidenced by the relatively low rate of GVHD in patients receiving transplants of umbilical cord blood, which appears to be enriched in Tregs. Therefore, the search continues for treatments that might continue to shift this balance in favor of anti-tumor immunity and away from off-target anti-host tissue effects.

A new study in the Journal of Experimental Medicine shows some promise in doing just that. This study focuses on targeting BTLA, an inhibitory, immunoglobulin-family receptor that is expressed on Th1, but not Th2 cells. BTLA interacts with both B7 family members (similar to other co-stimulatory molecules such as CD28) but also with TNF family receptors. Ligation of BTLA induces activation of SHP family phosphatases that limit T cell activation and IL-2 production. It is required for the generation of antigen-specific Tregs in response to antigen without co-stimulation. Interestingly, BTLA expression appears to be downregulated by the presence of bacterial CpG nucleotides. It is further notable that studies have shown persistent BTLA4 expression on anti-tumor, but not anti-viral cytotoxic lymphocytes, suggesting that BTLA may have a critical role in supressing anti-tumor immunity.

In this paper, the authors treated donor bone marrow with an an agonist anti-BTLA antibody prior to transfer and found that it virtually eliminated development of GVHD as measured by clinical scoring, loss of body weight, and development of intestinal mucosal inflammation and ulceration. Further investigation showed that BTLA stimulation decreased effector T cell development while maintaining Treg development, which is in line with evidence of BTLA in inducing tolerance. Of note, treatment with agonist anti-BTLA did not successfully treat GVHD when given 14 days after transfer, suggesting that BTLA's tolerance inducing effects are restricted to initial development and do not diminish effector function of differentiated Teff cells.

Finally, the authors showed in a minimal residual disease model that agonist anti-BTLA treatment did not significantly inhibit graft versus tumor responses, which still required T cell function as evidenced by the poor response of animals receiving T cell depleted transplants. The search for highly efficacious, broadly applicable cell therapy remains elusive, but providing the proper mileu to support development of an optimal balance of anti-tumor immunity and host tolerance will rely on a combination of careful cell selection and subtle skewing of cell differentiation.

I know, that's kind of a weak ending, but I'm just not ready to jump into heart failure, stroke, or asthma tonight. (Yeah and definitely not lupus either)

spring cleaning

I know, I said a big post on lupus was coming, imaginary blog readers. But I haven't been able to read the reviews yet. So let me leave you with the few other interesting pieces I've read in the past few weeks before I vanish until December.

Eplerenone in CHF (the EMPHASIS-HF study)

Yeah, there's nothing that's going to rock your world in this recent NEJM study; following the RALES study which showed an indication for spironolactone treatment in patients with class III/IV CHF, this study looked at almost 3,000 patients with class II CHF (mild symptoms only) and an EF of no greater than 35% and found a significant morbidity and mortality benefit. Yeah. If you really want to see if mineralocorticoid antagonism works as preventive therapy, look in patients who already don't have frank evidence of pathological remodeling. Aren't these patients on the doorstep of class III heart failure already? Boo.

Tonic inhibition and recovery after stroke

Ischemic strokes are a leading cause of morbidity and mortality, especially in the elderly, whose risk factors for stroke (hypertension, diabetes, hyperlipidemia) tend to be more prevalent. Aggressive risk factor control clearly reduces the risk of developing a stroke, or a future stroke after one happens. But almost nothing has been shown to reduce functional impairment caused by a stroke after it happens. Really, the only effective intervention is early rehabilitation, which has been shown in multiple randomized control studies to improve functionality by inducing cortical remodeling following a stroke. Subsequent studies have shown that the cortical remodeling that drives partial recovery of function following a stroke is not the infarcted tissue but rather the peri-infarct tissue. Excitation of peri-infarct tissue following stroke drives long-term potentiation, resulting in effective remodeling. However, long-term potentiation requires sustained synaptic neurotransmission, which is limited in peri-infarct cortex. Why exactly is this?

Count on Nature to give us the answers. A letter published a few weeks ago describes a breakthrough in understanding the physiologic brakes on peri-infarct cortical remodeling. The study focuses on GABA, an inhibitor neurotransmitter with both activity that is both synaptic (released in response to stimulus) and tonic (released at a constant rate to set a post-synaptic excitability threshold). Tonic GABA release has been shown to oppose long term potentiation and memory. The authors of the above study wondered if similar GABA-mediated tonic inhibition repressed cortical remodeling following a stroke.

Indeed, tonic GABA-mediated inhibition was found to be markedly increased in peri-infarct cortex following photothrombotic stroke in mice. This increased GABA tone increased the excitability threshold and was completely reversed by the GABA inhibitor gabazine.

Having established the role for GABA in post-infarct tonic inhibition, the authors then addressed whether GABA inhibition following stroke could restore functional capacity. Indeed, GABA blockade improved foot paw symmetry during locomotion and decreased foot faults during measured tasks.

But is there actual utility to GABA blockade in pts who undergo a stroke? Well, its complicated. The main problem is that GABA mediated inhibition immediately following a stroke limits infarct size; accordingly, GABA blockade improved murine mortality when given 3 days after a stroke but not when given immediately afterwards. Furthermore, prolonged GABA inhibition eventually led to worsening of functional performance. While this calls for careful modulation of GABA inhibition, it actually provides a potentially clincially applicable regimen: initiation of therapy a few days after a stroke, when symptoms are sure to be present, and stopping therapy after a limited amount of time (although improvements in functional status are not completely sustained after treatment is withdrawn.

Uh, CX3CR1 will have to wait for a time when I'm not actively going into a coma.

regulation, part 1

Well, that's the best way I can make four things that I'm going to write about seem related, when they're not related.

1. Autoregulation of salt-water balance by the kidney. This has been a topic of interest for me recently, because I'm rotating on the Nephrology service at Bellevue. As a result of this, I've been trying my best to understand the kidney.

So, there are two major functions of the kidney. The first is to filter and excrete toxins and toxic metabolites (important, but not that interesting). The second is to sense, and carefully regulate, total body fluid and electrolyte balance. This is a difficult, and essential job: too little fluid and the body can't deliver oxygen to vital tissues; too much fluid and it starts to accumulate in the lungs, abdomen, and extremities. In healthy patients, the kidney responds quite acutely to changes in volume (changes so small that they may be beyond the limit of our measurable detection). This appears to be via a set of cells known in aggregate as the juxtaglomerular apparatus, or JGA. The JGA is composed of 2 groups of cells. First, the granular cells, which line the afferent and efferent arterioles supplying and draining each glomerulus, are thought to act as 'pressure sensors' that react to miniscule changes in arteriolar pressure and respond with appropriate vasodilation or vasoconstriction. This transmits small increases or decreases in blood volume to small changes in glomerular filtration in the kidney. Second, the 'macula densa' cells within the distal tubule sense changes in delivery of tubular fluid to the distal convoluted tuble and adjust GFR and proximal reabsorption (via renin-angiotensin-aldosterone system activation).

Of course, there are well known situations in which renal autoregulation goes wrong. The most common of these diseases is CHF, in which decreased cardiac output results in reduced renal artery perfusion; this is pathologically interpreted as a sign of low volume by the renal JGA, resulting in sodium retention, pulmonary vascular congestion, and peripheral edema.

Another common syndrome of renal dysregulation is advanced liver cirrhosis. Fluid balance is markedly altered in cirrhosis, as demonstrated by significant accumulation of fluid in the peritoneal cavity (cirrhosis) - this is thought to be due to both hypoalbuminemia that results from decreased hepatic synthetic function and pathologic sodium and water retention by the kidney. This is evidenced by chronic high renin, aldosterone, and vasopressin levels seen in cirrhotic patients, and low urinary sodium characteristic of increased proximal tubular reabsorption. However, the stimulus for sodium retention by the kidney in cirrhosis is unknown. A number of hypotheses have been put forward to explain this phenomenon:

the low plasma volume hypothesis: cirrhosis-induced portal hypertension (increased hydrostatic pressure) + hypoalbuminemia (low oncotic pressure) leads to fluid transudation, low plasma volume, and RAAS activation. Sounds good, but doesn't work, as direct measurements of plasma volume in 1967 found that patients with advance cirrhosis have high, not low plasma volume. Furthermore, an elegant temporal analysis of fluid overload in a dog with cirrhosis in the American Journal of Physiology in 1977 demonstrated that high plasma volume in the splanchnic circulation as well as sodium retention preceded portal hypertension.

the underfilling hypothesis: popularized by Robert Schrier at the University of Colorado, this suggests that systemic vasodilation leads to decreased ‘effective’ arteriolar blood volume and leads to volume expansion. This is supported by the use of various therapies to improve arteriolar filling, including vasoconstrictors and head-up water immersion (to be discussed).

The key regulator in the underfilling hypothesis is thought to be nitric oxide, which induces profound systemic vasodilation and would lead to renal underperfusion and hepatorenal syndrome; however, evidence for this is lacking, as is evidence for the utility of nitric oxide synthase inhibitors in preventing or treating HRS. However, there are physiological reasons to suspect that nitric oxide production by the liver in response to portal hypertension is possible given the fairly strong evidence that the liver, and in particular, the hepatic artery, serves as pressure sensors;

1) electrical stimulation of portal nerves has potent effects on renal blood flow and urine output
2) other acute causes of portal hypertension, such as thrombotic disease (Budd-Chiari syndrome) induce potent hepatic artery vasodilation and hepatorenal syndrome, while elimination of portal pressures with intrahepatic portocaval shunts improves HRS in patients with portal hypertension.

Treatment options for hepatorenal syndrome continue to be quite limited, but are based ultimately on the idea that systemic vasodilation secondary to portal hypertension leads to renal arteriolar underfilling and prerenal failure. The only current therapy with any basis for efficacy is a study published in the Journal of Clinical Gastroenterology in 2009, in which a combination of midodrine/octreotide (splanchnic vasoconstrictors which theoretically counteract systemic vasodilation) along with albumin (which exerts positive oncotic pressure to hold fluid within blood vessels). This combination was the first to demonstrate a mortality benefit in patients with hepatorenal syndrome, although it has been difficult to reproduce in follow-up studies.

In my quest to find weird, alternate, cost-effective therapies, however, I came across a somewhat old practice that has fallen out of favor for reasons that are not entirely clear to me. It has been proposed for centuries that water immersion leads to increased urination; this concept of so-called “immersion diuresis” is thought to be secondary to two properties: thermal heat loss and hydrostatic water pressure, both leading to systemic vasoconstriction, improved renal perfusion, suppression of ADH, and natriuresis. In case you’re wondering, this idea is what led ultimately to the clever prank in which you put a sleeping friend’s hand in water causing him or her (who are we kidding – its always him) to pee himself.

That wouldn’t much thrill Dr. HC Bazett, the physiologist from the University of Pennsylvania who first published the effect of water immersion on diuresis in humans. Dr. Bazett’s subsequent studies found that the pressure component was far more important than the temperature component; aka, total body immersion is required to achieve significant diuresis (take that, pranksters).

Subsequently, head-out water immersion (pictured above, looking like a torture machine, and so named, according to the illustrious Dr. David Golfarb, because “some idiot medical student probably drowned some poor cirrhotic, so they had to put ‘head-out’ in the title”), was shown to improve venous return, increase right atrial pressure, increase stroke volume, and improve cardiac output.

A number of nephrologists, including Dr. Schrier, applied this data to their particular field and organ of interest, demonstrating that head-out water immersion could indeed improve renal function by decreasing renin-angiotensin mediated vasoconstriction and improving renal perfusion and urine output (right, from a letter to the editor published in N Engl J Med in 1983). And while studies on the true efficacy of this practice are somewhat conflicting, one could easily say the same about the far more expensive therapy of octreotide, midodrine, and albumin. So why don’t people ever try this? Beats me.

Yikes, this post was long. Stay tuned for regulation part 2, featuring: asthma, strokes, and health care policy!

another cool new yorker piece

This one is called "Brain Gain" and its subject is stimulants such as Ritalin and Adderall, prescribed most commonly for ADHD but now commonly co-opted as neuroenhancing 'study aids'. The whole article is interesting, but 2 things of note:

1) What type of students are most likely to use neuroenhancing drugs?
According to McCabe’s research team, white male undergraduates at highly competitive schools—especially in the Northeast—are the most frequent collegiate users of neuroenhancers. Users are also more likely to belong to a fraternity or a sorority, and to have a G.P.A. of 3.0 or lower. They are ten times as likely to report that they have smoked marijuana in the past year, and twenty times as likely to say that they have used cocaine. In other words, they are decent students at schools where, to be a great student, you have to give up a lot more partying than they’re willing to give up.

It's interesting that the highest achievers/'go getters', if you will, are not the ones most likely to use neuroenhancers. Rather its the students who want to maintain a healthy lifestyle and get their work done at the same time.

2) What is the culpability of doctors in this phenomenon?
Anjan Chatterjee, a neurologist at the University of Pennsylvania, predicts, some neurologists will refashion themselves as “quality-of-life consultants,” whose role will be “to provide information while abrogating final responsibility for these decisions to patients.” The demand is certainly there: from an aging population that won’t put up with memory loss; from overwrought parents bent on giving their children every possible edge; from anxious employees in an efficiency-obsessed, BlackBerry-equipped office culture, where work never really ends.

This is what is most worrisome - doctors acting in this bogus 'consultant' role, where they can advise on 'proper use' of neurologically active substances, without bearing any responsibility for their side effects. If you want to give perfectly healthy patients elective mind-altering drugs, so be it. But doctors are the gateway to access for these drugs, and they should bear some of the responsibility for the inevitable cases in which people go batshit crazy.

4 great articles!!

1. doctors opting out of medicare - initially i assumed this would just be a populist-type piece on how, in response to the recession, doctors are prioritizing patients who will net them larger profits vs. patients who are on medicare (who offers lower reimbursement rates). and to some extent, it is. but what is much more interesting is how health care providers are using various methods to try and treat as many people as possible. Some doctors are tailoring prices to what their patients can afford. Others are providing "boutique" care, in which, in return for a yearly retainer, a doctor will both accept Medicare and provide services not covered by medicare. Another option is "concierge" medicine, in which, for a larger retainer, the doctor will coordinate a patient's health care in a more detailed fashion. And finally, there are urgent care clinics, which have a lot of potential upside (acting as triage for less complex cases) but with accompanying downsides (quality of care).

2. the recession's impact on libraries - just one of those phenomenal pieces that makes you think about all the subtle effects of the recession:

"Librarians here and elsewhere say they are seeing new challenges. They find people asleep more often at cubicles. Patrons who cannot read or write ask for help filling out job applications. Some people sit at computers trying to use the Internet, even though they have no idea what the Internet is."

3. The Atlantic meets Netanyahu - I believe this was an exclusive interview that The Atlantic had with the new Israeli PM. I won't pretend to understand 0.1% of the complexity surrounding the Middle East situation, but what this interview does is make the perspective of the incoming Israeli administration clearer. The question now is, how do Obama and the Middle East trifecta of kickassness (Mitchell, Holbrooke, and Clinton) find common ground with both Iran and a Netanyahu-led Israel?

4. Vanity Fair on Arthur Ochs Sulzberger Jr.
- Like most great pieces, this piece on the man at the helm of the (sadly sinking) New York Times does a great job of being informative, yet even-handed. It's clear by the end that the newest Sulzberger operates out of a reverence for journalism (a good thing) and the Times in its current format (probably bad, given the fact that the paper is hemorrhaging money). What is unclear is the likelihood that he, or anyone, can steer the Times out of this mess. Which sucks, because I fall squarely on the side of the Times in its battle with the Wall Street Journal. But that's just because one of my rules in life is to figure out what Karl Rove is doing, and make a beeline for the other side.

The problem of comorbidity.

The New York Times has a really nice piece on the sure-to-increase problem of comorbidity in treating patients, particularly older ones, with chronic disease. Personally, what I found most interesting was the fact that such a common problem is not just overlooked, but excluded in research looking at therapeutic efficacy:

In a medical system geared toward individual organs and diseases, there is no champion for patients with multiple illnesses — no National Institute on Multimorbidity, no charity Race for the Multimorbidity Cure, no celebrity pressuring Capitol Hill for more research.
And because studies involving uncomplicated populations are cheapest and easiest to interpret, patients with multiple diseases are routinely shut out of drug trials. A 2007 study found that 81 percent of the randomized trials published in the most prestigious medical journals excluded patients because of coexisting medical problems.

Now, this is for a good reason (its very difficult to do controlled studies using patients with multiple conditions, and would be even more difficult to interpret the result of any such studies) but it would seem that, given the increasing need, such multifactorial research could, and should, be done.

Thoughts? Particularly from current or future internists, who deal with this stuff every day?

torture doesn't work, dummy.

For any idiots still crowing about the value of harsh interrogation tactics, the patriot act, warantless wiretapping, or any of the other asinine Bush administration "security" tactics put into place without public discourse or supporting evidence, let this be the end of all that garbage:

When CIA officials subjected their first high-value captive, Abu Zubaida, to waterboarding and other harsh interrogation methods, they were convinced that they had in their custody an al-Qaeda leader who knew details of operations yet to be unleashed. The methods succeeded in breaking him, and the stories he told of al-Qaeda terrorism plots sent CIA officers around the globe chasing leads. In the end, though, not a single significant plot was foiled as a result of Abu Zubaida's tortured confessions, according to former senior government officials who closely followed the interrogations. Nearly all of the leads attained through the harsh measures quickly evaporated, while most of the useful information from Abu Zubaida -- chiefly names of al-Qaeda members and associates -- was obtained before waterboarding was introduced, they said.

So please. How many fake 'sleeper cells' need to be exposed as bullshit to continue either allowing this type of illegal behavior, or revising history to paint Dick Cheney as some type of freedom fighter? With increasing evidence that harsh interrogation methods were initiated with instructions directly from the administration, count me as someone who's happy to see warrants issued for John Yoo, Alberto Gonzalez and other deserving douchebags. Cancel that Barcelona trip, Cheney. I'm sure there will be indignance over this -- how dare Spain stand in judgment of the decisions of a former US Vice President? But let those same indignant wonder how they would respond if American citizens were tortured under the aegis of the Spanish government without being given a fair trial.

Interesting corollary: Atul Gawande's excellent piece on the psychological impact of solitary confinement.

And finally, Matt Taibbi kicks ass and takes names. Today's victim: the unregulated Federal Reserve/Treasury Department's ever-growing shadow government.

Steve's Killer Links Plus Other Fun!

My buddy steve is always sending me all sorts of cool stuff, but I haven't given it its fair blog-due yet. Well, wait no longer, world.

1. Orangutans use tools! - Intelligent designers throw a hissy fit everywhere as the link between ourselves and our evolutionary forebears grows stronger and stronger. But in any case, the story is just cool.

2. Red Meat: No Good - Sorry carnivores, but it turns out that a little sialic acid called Neu5Gc will be the bane of your future existence. What's the problem with this molecule? Humans don't make it. We make a variant of it, Neu5Ac. Who does make alot of Neu5Gc? Plenty of other mammals. Neu5Gc appears foreign to our immune system, but is perfectly normal to immune systems of other mammals, such as chimpanzees. And, to quote:

Chimpanzees do not seem to suffer from heart disease, cancers, rheumatoid arthritis or bronchial asthma - common conditions in humans. Nor do they get sick from the human malaria parasite, which uses sialic acid to latch on to our blood cells.

NeuGc is also a common component of serum sickness, a complication of treatment with, you guessed it, animal serum (which has been used because its a way to flood the body with neutralizing antibodies and prevent immune over-reactions). So: cut down on that steak.

3. Waterboarding is Definitely Torture - Because some idiot at Vanity Fair tried it. No offense, but I was already convinced. It was a pretty interesting article, though. Are you listening, everyone who thought that FIMA was OK? This is the same line of thinking.

Now, some contributions of my own!

How did Wall-E get it wrong?
1. Obesity - Daniel Engber has some interesting thoughts on this. While he enjoyed the movie (didn't we all), he took issue with the tacit association of obesity with ecological destruction. While I think his assertion that the movie attempts to pin the planet's environmental collapse on the overweight (quote: "If only society could get off its big, fat ass and go on a diet!") is an overreaction (its far, far more an indictment of consumerism), I think the article is worth reading, first because it corrects a number of inappropriate assumptions about obesity, and second because it (correctly) criticizes Pixar's choice to depict the result of such consumerism primarily as a group of obese citizens. Read the article; pay particular attention to the closing paragraph.

2. Cockroaches - Also incorrect: the the cockroach as the last remnant of life on Earth. Are cockroaches so hardy that they would outlast every other living being? Not quite, although they apparently are sturdy enough to live without their head for weeks. Sweet.

Health Related Tidbits - Two fantastic articles on the value, and danger, of 2 senses

1. The Itch - Atul Gawande delivers another impeccable anecdote, but I find the article to be most interesting because of the qualification of "itchiness" as an entirely separate sense, quite distinct from pain. This was proved with an ingenious experiment discussed in the article, in which increasing amounts of painful stimuli had no impact on the itchiness of said stimuli. What follows is some amazing insight into the transmission of 'itch' signals via distinct neuronal pathways whose sensors have a molecular makeup that will amaze you in their design.

2. Anosmia - One of the most interesting aspects of this self-portrait of losing the sense of smell by Elizabeth Zierah was how undervalued smell is ("equivalent to losing a big toe," according to the article). Not true, it turns out; the devastating impact of losing one's sense of smell is yet more evidence of the imporance of synergy between your senses.

National Election Stuff

1. Barack's "OPod" - The New Republic gives us this very interesting piece on the content of Barack Obama's IPod. Aside from the quick disemboweling of John Kerry in the initial paragraph (who couldn't even muster a preference between the Stones and the Beatles), the piece tells us what we can learn from the Senator's playlist. Most importantly:

"...The fact that he responds to Wenner's question about hip-hop with the most straight-down-the-middle liberal platitudes imaginable (praising it as "rebel music" while expressing concern about its "misogyny and materialism") clearly matters less than the fact that there's a guy running for President who knows who Jay-Z is."

2. Making fun of Obama - This is a fascinating article from the Times on the struggles of late-night and other comedians to (successfully) make fun of Obama. What's a little less clear are the reasons behind this difficulty. Two have been offered: 1) He hasn't done something identifiably stupid to serve as a rallying point, and 2) making fun of him makes you feel a little guilty. I agree with both. This is part of his whole 'teflon' image (I realize that "teflon" carries a negative connotation, but I don't mean it that way) - he seems sqeaky clean, bizarelly so when you consider that nobody really thinks that he is. Of course, the race issue doesn't help either. What's more interesting is how we react to rare circumstances in which someone chooses to poke fun at him, as in the case of:

3. The Infamous New Yorker Cover (pictured, right). So here we have a perfect scenario. A progressive magazine publishes a cover image in obvious satire of the insane stereotypes levied against Obama, all in combination - that is is a Muslim in cahoots with Osama bin Laden, that he is a flag burner whose terrorist fist-jab clearly implies Middle Eastern allegiances. (His wife's Afro is a subtle touch). But obvious satire such has this has inspired uproar, and why? Because we all know and fear the misinterpretation of this joke. Calling McCain old isn't dangerous, but calling Obama a terrorist is, because 10% of America thinks this is true. And it doesn't matter whether the tone of the cover is obviously satirical or not. To quote Jake Tapper of ABC News:

Intent factors into these matters, of course, but no Upper East Side liberal—no matter how superior they feel their intellect is—should assume that just because they're mocking such ridiculousness, the illustration won't feed into the same beast in emails and other media. It's a recruitment poster for the right-wing.

It pains me, but he's right.

4. McCain fears computers - Does this include robots? Does he refuse to watch Wall-E? We should look into this. And if he does start using the internet, maybe he can respond to this New Republic piece threatening a return to Cold War-era politics under his aegis.

This was a long-ass post. Later: myanmar and sports.