July 2008 Archives

While the effects of anti-amyloid agents in Alzheimer's disease (AD) have been less than overwhelming (see here and here, for example), a phase 2 study presented at the recent International Conference on Alzheimer's Disease suggests that going after tangle-related tau protein may be more fruitful.

A formulation of methylene blue—yeah, the Wright's stain agent—produced a significant 5.5-point difference (vs placebo) on the ADAS-cog at 24 weeks in patients with moderate AD. The proprietary drug, trade name "rember" (ugh), was assessed in an initial double-blind, randomized, placebo-controlled, dose-ranging study in mild-to-moderate AD (N = 321), followed by a blinded, extension phase. Pooled data after 19 months revealed a significant 6.8-point difference on the ADAS-cog in patients with either mild or moderate AD. Statistically significant cognitive changes at both time points were observed with the dosage of 60 mg tid, versus initial placebo treatment.

Rember was evidently well tolerated in the phase 2 trial, except for a high incidence of diarrhea, which may depend on the drug's intestinal absorption. Reports indicate that the efficacy and tolerability of a 100-mg dose may have been compromised because of formulation problems.

Rember is an investigational agent of TauRx Therapeutics and inhibits in-vitro tau aggregation, the foundation of AD's neurofibrillary tangles. The clinical study was headed and presented by Claude M. Wischik, MBChB, of the University of Aberdeen, who also happens to be founder and executive chairman of TauRx.

A large phase 3 trial of rember in AD is planned but awaits FDA approval.

Primary sources: Medpage Today; AP via Yahoo.

As if you need another reason to bang your head against a wall on Wall Street.

After phase 2 data of bapineuzumab in Alzheimier's disease (AD) were released on June 17, shares of Elan and Wyeth climbed 10.6% and 4.8%, respectively. However, after the same data were presented yesterday at the International Conference on Alzheimer's Disease (ICAD) in Chicago, the share prices dropped 19.6% and 11.2%, respectively. So what were the differences between the June press release and the meeting presentation? Not a heck of a lot.

 

Both presentations provided information about the missed primary endpoint in the trial, a change in cognition or disability at 18 months (although the primary outcome was buried in the second paragraph of the June press release). Both provided information about the post-hoc assessment of subgroup data—namely, that ApoE4 noncarriers performed statistically better on the ADAS-cog at 18 months (mean score difference: 5 points, bapinueuzumab vs placebo). And both reported a risk of vasogenic brain edema with the agent, especially in ApoE4 carriers.

In June, analysts talked up the bapineuzumab phase 2 study, despite the missed primary endpoint, and the companies' prospects. Yesterday, not so much. Nevertheless, Elan and Wyeth are apparently moving forward with phase 3 investigation of the amyloid buster in AD.

Women who live into their 90s are significantly more likely to be demented than similarly aged men, according to a report in this week's issue of Neurology. The finding supports data from previous studies, in which the prevalence of dementia among centenarians was higher among surviving women.

By using in-person examination data and telephone and informant questionnaires, US investigators assessed the all-cause dementia rate among participants in the so-called 90+ Study (N = 911). Among women, the overall dementia rate was 45% (95% CI: 41.5, 49.0), versus 28% (95% CI: 21.7, 34.2) among men. Moreover, the dementia rate in women doubled every 5 years after the age of 90 (Figure). Dementia in women, but not men, correlated inversely with education. From a glass-half-full perspective, dementia was not universal in women 100 years of age or older (61%).

In an accompanying editorial, David Hogan, MD, cites limitations of the study including differing methods used for the diagnosis of dementia; the characteristics of the study population (white, relatively well educated, upper middle class); insufficient pathologic data; a high lost-to-study rate (21%); and a low absolute number of dementia cases among men 95 years of age or older (n = 23). However, Hogan supports the overall conclusion and suggests that the lack of an age-associated increase in dementia among very old men may be due to their shortened survival with the condition.

A confirmed case of the uncommon LaCrosse encephalitis was reported recently in northern Virginia—a notable story (at least for the local news source), because the disease "typically occurs" further south in the state. The Virginia report and yesterday's news of several cases of West Nile disease in Los Angeles provide an opportunity to review here the mosquito-transmitted encephalitides that occur in the not-always-good-old summertime.

Causing about 70 cases of encephalitis per year in the United States, the LaCrosse virus belongs to the Bunyaviridae family of negative-stranded RNA viruses. The main transmission cycle is between small vertebrate hosts, like squirrels or chipmunks, and the treehole mosquito. LaCrosse encephalitis in humans occurs mainly in Appalachia and the Midwest (the disease was first recognized in 1963 in La Crosse, WI). Although most cases of infection are asymptomatic, the latency from mosquito bite to symptoms (either a flu-like illness or, less commonly, frank encephalitis) ranges from 5 to 15 days. Those who are especially susceptible to disease in endemic areas are persons engaged in outdoor activities and children younger than 16 years of age. The fatality rate, however, is less than 1%.

Both the West Nile and St. Louis viruses belong to the family Flaviviridae, genus Flavivirus—positive-stranded RNA viruses. The transmission cycle for these viruses, like that for most arboviruses, is between wild birds and mosquitoes. In 2003, there were more than 9800 cases of documented West Nile encephalitis in the United States, and the average annual number of cases of St. Louis encephalitis is approximately 110. West Nile encephalitis has spread rapidly throughout the United States, since its recognition in New York in 1999. St. Louis encephalitis occurs most often in the central and eastern parts of the country. The latency from bite to symptoms for both infections ranges from 3 to 15 days; although, the overwhelming majority of infected persons remain asymptomatic. For the less-than-1% of those who do develop encephalitis, the fatality rate is 50% for West Nile (2002-2003 data) and 5%-30% for St. Louis disease. Older individuals are particularly vulnerable.

The Eastern and Western Equine Encephalitis viruses belong to the family Togaviridae, genus Alphavirus— positive single-stranded RNA viruses. The main transmission cycle for these viruses is also between wild birds and mosquitoes, and, as the name implies, horses are common "dead-end" hosts. Infection with the Eastern Equine Encephalitis virus (EEEV) is most common in the eastern part of the United States, with the largest number of encephalitis cases in Florida, Georgia, Massachusetts, and New Jersey. Infection with the Western Equine Encephalitis virus (WEEV) is most prevalent in the plains regions. The average annual number of EEEV and WEEV encephalitis cases in the United States is 5 and 15, respectively. Like persons infected other arboviruses, those with EEEV and WEEV are mostly likely to remain asymptomatic. Symptoms, if manifest, occur approximately 3-10 days after a bite from a transmitting mosquito. Persons older than 50 years of age or younger than 15 years are at greatest risk for developing severe infection with either virus; although, the fatality rate with EEEV (33%) among symptomatic persons is much higher than that with WEEV (3%).

The most common and reportedly efficient way to diagnose infection with these viruses is to assay for neutralizing IgM antibodies in either serum or CSF. Care is purely supportive for symptomatic individuals. There are no vaccines to prevent human disease; although vaccines to prevent EEEV and WEEV in horses are evidently available.

Primary source: CDC

Photo of Culex quinquefasciatus, known to transmit St. Louis encephalitis virus, from Galveston County Mosquito Control.

The longstanding answer to inactivity in the city kid is now an official, judged sport in NYC schools, writes the AP.

A video segment of the 2006 Double Dutch Holiday Classic at the Apollo Theater: The Harlem crowd reacts with lovable honesty to a Japan team's Best in Show win.

Reportedly one of Dustin Hoffman's favorites, Straight Time (1978) also features newbies Gary Busey (before he went absolutely meshuga), Kathy Bates, and Theresa Russell, along with M. Emmet Walsh. Rock on, casting director Dianne Crittenden.

Hoffman, playing lifelong con and current parolee Max Dembo, tries to make it—as the film title indicates—legitimately.

In honor of the upcoming Olympics and prompted by recent (alleged) doping incidents, here are the substances prohibited by the World Anti-Doping Agency (WADA). The list indicates that world-class athletes and trainers are highly enterprising in their search for (and cover-up of) that little extra edge.

Prohibited in and out of competition

1. Exogenous and endogenous anabolic androgenic steroids (AAS): A perennial favorite. Olympic athletes from East Germany, especially female swimmers, were systematically doped with AAS from 1965 to 1989, as were the obviously acned, female swimmers from China in the 1990s. According to sports medicine expert Ken Fitch, MD, AAS was the most frequently detected category of banned substances in athletes who participated in the last 2 Summer Olympics. Canadian sprinter Ben Johnson famously lost his gold medal from the 1988 games owing to the post-race detection of anabolic steroids. And last year, American medalist Marion Jones admitted to anabolic steroid use in preparation for the 2000 Olympics in Sydney. The use of designer AAS, which may evade current detection methods, has emerged as a particular problem during the last few years, writes Fitch.
2. Other anabolic agents: The β2 adrenergic agonist clenbuterol was allegedly detected in urine samples this month from US swimmer Jessica Hardy. Selective androgen-receptor modulators, investigational agents for the treatment of osteoporosis and muscle atrophy, are new to the WADA list as of this year. Tibolone is a postmenopausal hormone replacement therapy (HRT) with estrogenic, progestogenic, and androgenic properties. Also banned are the cattle-feed steroids zeranol and zilpaterol.
3. Other hormones and related substances: Doping with erythropoiesis-stimulating agents (ESAs) is notorious in endurance sports, like cycling and long-distance running. Also widely abused, human growth hormone (hGH) is reportedly taken frequently with AAS by doping athletes. However, a reliable test for distinguishing exogenous from endogenous hGH has been elusive, according to the literature, and physiologic levels of hGH can vary widely within and among individuals. Other banned endocrinologic agents include insulin-like growth factors, the new-to-me mechano growth factors (MGFs), gonadotrophins (luteinizing hormone, human chorionic gonadotropin* [in men only]), insulins, and corticotrophins.
4. β2 agonists: For example, clenbuterol. The use of inhaled anti-asthmatic drugs, like formoterol, salbutamol, salmeterol, and terbutaline, requires an Abbreviated Therapeutic Use Exemption.
5. Hormone antagonists and modulators: Here's disturbing enterprise. Athletes use agents indicated for hormone-receptor-positive breast cancer, like aromatase inhibitors (eg, anastrozole) or selective estrogen-receptor modulators (eg, tamoxifen), to produce an indirect androgenic effect. Also new to the WADA list this year are inhibitors of myostatin, an endogenous factor that limits the growth of muscle tissue.
6. Diuretics and masking agents: The general idea is either pee out the banned substance or dilute it. An example of a masking agent is epitestosterone, which is used to normalize the testosterone-to-epitestosterone ratio during traditional testing. According to Wikipedia, US runner Mary Decker failed a T/E ratio test in 1996. Other banned substances in this category, besides traditional diuretics, are probenecid, α-reductase inhibitors, and plasma expanders (eg, albumin).
7. Blood and blood substitutes
8. Gene doping: Circulating now is news of a German TV report that warns of gene doping (eg, stem cell therapy) offered in China.

Prohibited in competition

1. Stimulants: For example, amphetamine, ephedrine.
2. Narcotics
3. Cannabinoids: Not even in snowboarding, dude.
4. Nontopical glucocorticoids: Although intra-articular and similar local injections require an Abbreviated Therapeutic Use Exemption.

Prohibited in particular sports

1. Alcohol: With regard to the Olympics, alcohol levels greater than 0.10 g/L are prohibited in archery (ouch), karate (huh?), and shooting sports (bigger ouch).
2. β-blockers: The use of β-blockers is prohibited in archery (in and out of competition), bobsledding (but not luging?), curling (aw, somebody cares), gymnastics, shooting sports, skiing, snowboarding, and wrestling.

* Yes, the pregnancy hormone.

Photo: Qian Hong, winner of the 100-m butterfly at the 1992 Barcelona Olympics and possessor of killer triceps.

Contrary to reported statements made by WADA president John Fahey to the Australian Broadcasting Corp., Roche now clarifies to Bloomberg that the company did not plant a molecule in Mircera to aid detection of the drug in athletes. The drug was evidently identified in cyclist Riccardo Ricco because "WADA received the molecule well in advance and was able to develop ways to detect it, including through the current EPO detection method," commented the agency.

In an online statement, Roche writes that it provided samples of Mircera, which is functionally and structurally different from endogenous erythropoietin and all other erythropoiesis-stimulating agents, and assay reagents to WADA to ensure that the agency could conduct reliable testing.

Unfortunately it remains unclear whether Fahey misspoke to (or was misinterpreted by) the Australian news source or WADA is backtracking for reasons of trade secrecy.

WADA = World Anti-Doping Agency.

Update: Expect a whole lot more doping news in the near future. NBC's Olympics web site reports that US swimmer Jessica Hardy, 21, tested positive for the banned β2 adrenergic agonist clenbuterol. Tests for the substance on 2 samples from July 4 were both positive, but samples from July 1 and July 6 were negative, reveals the web site. According to Wikipedia, the half-life of clenbuterol is approximately 37 hours.

With the media fixation on the cholesterol-lowering combo Vytorin (ezetimibe/simvastatin)—namely, the negative results of the ENHANCE study and the SEAS trial—it's easy to forget that statins alone have their drawbacks. Case in point is the well-known risk of myopathy with the drug class, which is reported to occur approximately once per 10,000 patients who take lower-dose therapy.

This incidence rate may seem inconsequential, until you remember that about 13 million Americans take statins—some at high dosages and with drugs that can inhibit statin metabolism (thereby increasing the risk of drug-associated myopathy).

In this week's issue of the NEJM, UK investigators report a "single strong association" of simvastatin-related myopathy* with the presence of the rs436657 single-nucleotide polymorphism (SNP) on the gene SLCO1B1 (chromosome 12). The SLCO1B1 gene encodes for an organic anion-transporting polypeptide that has been shown to regulate the hepatic uptake of statins—suggesting that the SNP dictates a class effect for the risk of myopathy. The odds ratio for myopathy was 16.9 (95% CI: 4.7, 61.1) in individuals homozygous for the C (cytosine) allele, versus individuals homozygous for the T (thymidine) allele.

Genetic data were collected and analyzed from 85 subjects who developed myopathy while taking simvastatin 80 mg/d in the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) (N = 12,064) and compared with data from 90 subjects who did not develop myopathy while taking high-dose simvastatin. The SNP association with myopathy in SEARCH was corroborated by data from the Heart Protection Study of simvastatin 40 mg/d; although the relative risk with a C allele was less robust in this lower-dose study.

Other relative risks for baseline patient characteristics from SEARCH reveal a markedly elevated risk of simvastatin-associated myopathy with the concomitant use of amiodarone.

Characteristic	Relative Risk of Definite or Incipient Myopathy During First Year (95% CI)
Age ≥65 vs <65 y	2.3 (1.3, 4.1)
Female vs male	1.6 (0.9, 3.0)
GFR <60 vs ≥60 mL/min/1.73 m2	2.4 (1.3, 4.3)
Creatinine  ≥85 vs <85 µmol/L	2.5 (1.4, 4.6)
Amiodarone use vs no use	8.8 (4.2, 18.4)
Calcium antagonist use vs no use	2.7 (1.6, 4.5)
DM vs no DM	1.2 (0.6, 2.7)

The authors conclude that genotyping of SLCO1B1 polymorphisms may enable safer statin treatment, and Yusuke Nakamura, MD, PhD, advises in an accompanying editorial that SLCO1B1 variants must be tested for an association with a more severe myopathic event, statin-induced rhabomyolosis, as soon as possible.

* Reversible.

Find clever anagrams for names of friends, enemies, drugs...

A timely example: Epoetin → Pee, Not I

Italian cyclist and Tour de France competitor Riccardo Ricco was caught doping with Roche's new erythropoiesis-stimulating agent (ESA) Mircera, according to numerous news reports today. An official of the World Anti-Doping Agency (WADA) reported to Bloomberg that use of the drug—a long-acting, pegylated version of epoetin beta—was made detectable because of an implanted, traceable molecule within the product. A brief scan of relevant, online FDA documents suggests that the implanted molecule is a trade secret of Roche.

In June, Danish investigators indicated that the detection of older, shorter-acting ESAs, namely recombinant human erythropoietin (rHuEpo), in urine by WADA laboratories is highly unreliable. The official WADA method is to distinguish endogenous Epo from rHuEpo on the basis of molecular charge, a technique that has been criticized for generating a high number of false positives and negatives.

To assess the reliability of current rHuEpo testing by WADA labs, the Danish investigators injected 8 healthy, nonathlete, male university students with rHuEpo, by using a boosting (5000 IU qod x 14 d) and maintenance (q weekly x 2 weeks) program. Urine samples were submitted to 2 different WADA labs for testing, with the following results.

Phase	Laboratory A	Laboratory B
Boosting	All positive	None positive
Maintenance	6/16 positive; 2 suspect	5 suspect
Posttreatment	2/24 positive; 3 suspect	None positive

The investigators also found little correlation between suspect or positive results from the 2 WADA labs and suggest that the "only strategy which provides a possible chance for obtaining a positive urine Epo test" is to perform out-of-competition testing at more than 1 WADA lab during the suspect rHuEpo boosting period. Alternatively they suggest that efforts should be focused on reliable detection, such as that evidently facilitated by Roche for Mircera.

Photo: iStockPhoto

This may be merely an example of water seeking its own level, but World Wrestling Entertainment and Jenny McCarthy will be getting together next month on prime-time network TV* to support Generation Rescue, an organization which promotes the unfounded (and dangerous) idea that "toxins" in vaccines produce autism and other neuropsychiatric disorders in children.

I suspect between choreographed body slams, there will be no discussion of the hazards of anabolic steroids.

* NBC, to be exact.

The fact can never be emphasized sufficiently: The results of retrospective, observational studies do not necessarily predict the outcomes of prospective trials.

Case in point is the missed primary endpoint in the prospective, placebo-controlled SEAS trial, in which the combination of ezetimibe and simvastatin (Vytorin; Schering-Plough/Merck) failed to reduce major cardiovascular events associated with aortic valve or atherosclerotic disease. These results follow those of 2 double-blind, placebo-controlled studies of atorvastatin (Lipitor; Pfizer) in aortic stenosis (AS) (see here and here), which also showed that the cholesterol-lowering drug did not alter AS progression.

The proposal that statins may alter the course of AS isn't a bad one, given the association between hypercholesterolemia, coronary artery disease, and atheroma. And in fact, several retrospective, observational studies showed that statin therapy delayed AS progression, as measured by hemodynamics and valvular calcification. But the idea, clearly, has not been realized to date in prospective evaluations.*

Two other interesting results of the SEAS trial, according to the press release, are 1) a significant reduction of the secondary endpoint of atherosclerotic events (nonfatal MI, CABG, PCI, hospitalization for unstable angina, nonhemorrhagic stroke, and cardiovascular death); and 2) a significant and unexplained increase in the incidence of cancer (9.9% vs 7.0%; P = .02).

The former result may portend a positive outcome in IMPROVE-IT, a comparison of ezetimibe/simvastatin with simvastatin alone to reduce the primary composite endpoint of major coronary events, stroke, or cardiovascular death. As far as a potential cancer risk is concerned, an independent analysis of the data from IMPROVE-IT and another ezetimibe/simvastatin study, SHARP, revealed that the overall risk of cancer is not increased with the drug.

IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; PCI = percutaneous coronary intervention; SEAS = Simvastatin and Ezetimibe in Aortic Stensosis; SHARP = Study of Heart and Renal Protection.

* A prospective study of rosuvastatin in AS is ongoing. Results are expected at the end of the year.

Update: Over at the Disease Management Care Blog, Jaan Sidorov considers the blogger-fomented Vytorin-cancer scare and says, more or less, "Drink your juice, Shelby."

Immunization with synthetic amyloid beta (AN1792; Elan) clears amyloid plaques in brain but is not associated with improved cognition or survival in the long term, according to a small UK study of patients with Alzheimer's disease (AD). Results of the placebo-controlled trial, funded by the Alzheimer's Research Trust, were published in this month's issue of The Lancet.

A total of 80 patients with probable mild-to-moderate AD received either randomly assigned AN1792 (50 or 225 ug) with adjuvant (n = 64) or adjuvant alone (n = 16).* Postmortem examination of 8 actively treated AD patients revealed a significantly lower Aβ load than that in nonimmunized controls.^† However, the investigators noted considerable variation of the Aβ load and the extent of plaque removal among immunized cases.

There was no relationship between the dose of AN1792 and Aβ load or postmortem plaque removal, but the mean antibody response during treatment showed a nonsignificant correlation with Aβ load. Seven of the 8 patients, including those who demonstrated "virtually complete plaque removal," exhibited severe end-stage dementia, and there were no survival or cognitive differences between the immunized and placebo-treated groups.

A phase 2a study of AN1792 was halted when 6% of patients developed meningoencephalitis. The study did not show relative cognitive improvement at 1 year with immunization, despite the presence of high levels of Aβ antibodies. In June, Elan and Wyeth announced favorable results with the anti-Aβ monoclonal antibody bapineuzumab in mild-moderate AD, despite the fact that the primary endpoint in the phase 2 trial was not met.

* In a protocol extension, patients received either AN1792 (n = 51) or adjuvant alone (n = 13) in a modified formulation to increase Aβ solubility.

† Because no patients in the placebo-treated group underwent postmortem examination, histologic findings in an age-matched, nonimmunized control group of patients with AD were used for comparison.

Image of wild-type amyloid precursor protein (left) and amyloid fibril (right) by David S. Goodsell from Wikimedia Commons.

A wonderful girl's movie: I Know Where I'm Going! (1945) with Wendy Hiller. Any heroine whose lifetime mantra is the movie title is bound to be sidetracked on the way to her wedding in the Hebrides. Enjoy the lilt of the occasional, impenetrable Gaelic and look for a brief appearance by 12-year-old Petula Clark.

Poster image from Wikipedia and reproduced under fair use law.

Not exactly a US public health menace, but the rise of Balamuthia mandrillis encephalitis is something worth watching. The latest issue of the MMWR provides information on 10 cases identified between 1999 and 2007 by the California Encephalitis Project. Since the recognition of balamuthiasis in 1989 (in a pregnant mandrill baboon at the San Diego Zoo), 150 human cases have been identified worldwide.

What is Balamuthia mandrillis?
A free-living amoeba in soil.

How is disease transmitted?
Airborne cysts are inhaled, or skin lesions are directly contaminated.

Who or what is affected?
Immunocompetent or immunocompromised humans, nonhuman primates, horses, dogs, and sheep. People with occupational or recreational exposure to soil (agriculture, construction, dirt biking) may be especially vulnerable.

What are disease symptoms?
Those consistent with other forms of encephalitis—eg, fever, encephalopathy, cranial nerve palsies, seizures.

What does the CSF look like?
Markedly elevated protein (>100 mg/dL); elevated WBC with a predominance of lympocytes; normal or low glucose.

What does brain MRI look like?
Typically abnormal. In the California cases, multiple ring-enhancing lesions, white matter lesions, hypointense lesions, or hydrocephalus were noted.

How is disease definitively diagnosed?
Indirect immunofluorescence staining of formalin-fixed tissue—eg, brain. PCR testing for Balamuthia DNA in CSF or brain tissue has been used; although, the specificity and sensitivity of PCR testing for Balamuthia are unknown, as are the specificity and sensitivity of serologic testing.

Where are reference laboratories? 
At the CDC (gsv1@cdc.gov) and the California Department of Public Health (shilpa.gavile@cdph.ca.gov).

What is the treatment?
Three surviving patients in the United States received pentamidine isethionate, fluconazole, flucytosine, sulfadiazine, and a macrolide antibiotic (azithromycin or clarthromycin).

What is the survival rate?
In the California cases, approximately 10%.

Who or what is Balamuth?
Balamuthia co-discoverer Govinda S. Visvesvara, PhD, of the CDC, writes by e-mail that the organism was named after his major advisor, William Balamuth (1914-1981), Professor of Zoology at UC Berkeley. How's that for homage?

Photomicrograph of Balamuthia mandrillis trophozoites in brain tissue from the CDC.

Do college premeds really need a second semester of organic chemistry? That's the question asked and answered by Jules Dienstag, MD, in this week's issue of the NEJM. Dienstag argues that the longstanding premed requirements of 1 year of biology, 2 years of chemistry (including 1 year of organic chemistry), and 1 year of physics "fail to...prepare students for tackling the sciences fundamental to medicine at the advanced molecular level." He continues, "We should expect a higher standard from students who wish to pursue medicine in an era in which genomics and informatics will revolutionize biomedical science and health care."

Dienstag argues for premed science requirements that are more relevant to today's medicine, as opposed to teaching the principles of 19th-century chemistry (as my orgo professor mused more than 20 years ago) to budding doctors. Instead of a second round of orgo,* go right into introductory biochem, he proposes—introducing molecular reactions that are actually relevant to bodily function and the manifestation of disease.

Dienstag also urges the integration of traditionally compartmentalized disciplines, like physiology, anatomy, and genetics, to foster a holistic approach to health and disease. And he rightly emphasizes a foundation in writing and communications skills. On this subject, I would stress a full semester of basic grammar and style (even if it's a bloody review), perhaps focusing on medical and scientific communications. Having been on the receiving end of medical manuscripts, I've noted these skills to be embarrassingly poor in too many established, academically based physicians.

* Not once do I recall the benefit in medical practice of knowing the Grignard reaction, and I was one of those freaks who liked organic chemistry.

Image of formation of Grignard reagent from Wikipedia.

Daniel Carlat argued yesterday that Pfizer withdrew its direct commercial support of MECC-sponsored CME because MECCs―unlike other CME-producing organizations―receive most of their income from industry-funded CME. The argument is that, because MECCs are so dependent on industry for their existence, they are more likely to bias their CME to curry favor and foster continued business with the industry grantor. 

However, this explanation ignores the fact that pharma income of other CME-producing organizations, like medical societies, is not inconsequential, despite what Dr. Carlat alleges. For instance, by examining the ACCME's 2006 Annual Report (the same report that Dr. Carlat references), it is apparent that the collective, net commercial income (total commercial support – total expense) for nonprofit organizations (eg, a physician membership organization) was actually higher than that for publishing/education companies in 2006: $247,782,325 vs $210,811,540. And the average net income per nonprofit organization (n = 267) was not that far behind the net income per publishing/education company (n = 154): $928,024 vs $1,368,906.

Organization Type	2006 Net Income	Average Net Income per Organization
Government or military (n = 16)	-935,343	-58,459
Hospital/health care delivery system (n = 93)	-287,209	-3088
Insurance company/ managed care company (n = 14)	-4,308,420	-307,744
Nonprofit, other (n = 34)	26,122,848	768,319
Nonprofit (eg, MD organization) (n = 267)	247,782,325	928,024
Not classified (n = 29)	12,946,920	446,446
Publishing/education company (n = 154)	210,811,540	1,368,906
School of medicine (n = 122)	71,740,237	588,035

So while Dr. Carlat argues that loss of pharma CME income for a big-budget academic medical center would "cause barely a hiccup," this is not likely the case for a medical society operating on much smaller revenues. For instance, the 2006 expenses of the American Academy of Neurology, the flagship organization of practicing neurologists, totaled approximately $3.5 million.

Pfizer's move to cut off MECCs, I would argue, is primarily (if not solely) based on the perception of bias in MECC-generated CME, not actual bias.* Otherwise, according to Dr. Carlat's argument, Pfizer would have considered cutting off direct CME grants to medical societies as well―a questionable PR move.

ACCME = Accreditation Council for Continuing Medical Education; MECC = medical education communications company.

* And if bias did exist in Pfizer-funded CME, it's only because Pfizer expected (even demanded) bias. 

Esmin Green, whose June 19 death in the waiting room of Brooklyn's Kings County Hospital psych ward was caught on videotape, died of pulmonary embolism. The medical examiner's conclusion was reported by the New York Daily News last weekend. According to the paper, Green may have been sitting for 20 hours, after receiving a "mild sedative," while waiting for psychiatric admission to the facility.

Although it is not known how long Green may have experienced deep vein thrombosis, the source of her embolism, earlier medical attention may have alerted physicians to its presence, resulting in appropriate medical intervention. The paper reports that, because Green's death is being classified as due to natural causes, there will be no homicide charges.

As many a blog is reporting this morning (eg, WSJ Health Blog), the Massachusetts House will vote today on a proposed pharma-code bill for the state. The vote follows yesterday's honing of the proposed legislation, which led to the removal of 1) a ban on gifts and meals to physicians; 2) the reporting of physician payments for consulting and speaking, and 3) a $5000 fine per violation. The Massachusetts Senate had unanimously passed a previous version of the bill that had included the removed items.

According to the Boston Globe, the bill will require that pharma adopt a marketing code of conduct, like the one PhRMA unveiled last week, which eliminates drug-branded tchotchkes, other noneducational gifts, and anything more than pizza or sandwiches during working hours.

Unlike the PhRMA code, however, the Massachusetts bill bans pharma's purchase and use of drug-prescribing information. New Hampshire's attempt to limit the use of these data by drug companies was judged last year to be an unconstitutional violation of commercial free speech. The AMA currently offers an opt-out program to physicians, which contractually obligates pharma from sharing their prescribing information with reps.

July 17 update: The Massachusetts House unanimously approved the watered-down bill, according to today's Boston Globe. But the House voted to delay the effective date of the part of the bill that bars the purchase by pharma of prescription info (to November 2009), while New Hampshire wrestles with the issue of commercial free speech. The differences between the bill passed in the Senate and the bill passed in the House will probably be reconciled before the end of the month, the paper writes.

The use of rofecoxib (Vioxx; Merck) or valdecoxib (Bextra; Pfizer), but not celecoxib (Celebrex; Pfizer), increased the risk of stroke in a retrospective study of Medicaid enrollees. Results of the study, which are consistent with several, previous observational studies, were published in this month's issue of Stroke.

Investigators at Vanderbilt examined the incidence of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage among 336,906 noninstitutionalized enrollees, aged 50-84 years, in the Tennessee Medicaid program (TennCare) from 1999 through 2004 and the use of commonly prescribed NSAIDs, including the coxibs rofecoxib, valdecoxib, and celecoxib. The adjusted* hazard ratios (HRs) for stroke among all NSAID users and among new NSAID users (to reduce bias) are shown (reference = nonusers).