August 2008 Archives

The food-borne outbreak of infections due to Salmonella, serotype Saintpaul, which affected nearly 1500 Americans or Canadians during the last 4 months, appears to be over. The latest analysis of the outbreak indicates that raw, Mexican-grown jalapeno peppers were a "major vehicle" for the spread of the pathogen, but the report also implicates raw, Mexican-grown serrano peppers and, to a lesser extent, certain types of tomatoes (particularly early in the outbreak).

Traceback investigations conducted by the FDA identified at least 2 suspect farms in the border state of Tamaulipas, Mexico, as the source of the bacteria. At one of these farms, the serotype was grown from a sample of serrano peppers and irrigation water, which was also used by the other Mexican farm. Additional, unnamed Mexican farms have also been implicated. The FDA did not identify a single packer, distributor, or growing area as the source of the infected tomatoes.

On August 28, the CDC and the FDA lifted the ban on the consumption of raw, Mexican-grown jalapeno and serrano peppers. An advisory ban on eating certain types of tomatoes was lifted July 17.

Photo of jalapeno pepper from FDA.

You're a has-been loser on the small-town boxing circuit.

How much of a has-been loser? 

So much of a has-been loser that your manager doesn't even let you in on the fix that you'll go down in the third round. He's relying on your clued-in opponent to clean up when the time's ripe.

That's the end-of-the-road life for aging boxer Stoker Thompson (Robert Ryan) in The Set-Up (1949), a tight-as-a-drum noir story from director Robert Wise (The Andromeda Strain, The Sound of Music). Wise, a former editor,* constructs the night of Stoker's rigged fight in real time—cutting between Stoker, his dispirited wife (Audrey Totter), and great shots of nutty boxing fans.

Among the many quotable lines from the film is this Sisyphean warning: "You'll always be just one punch away." Story of my life.

P.S. Boomers will recognize Stoker's manager, played by George Tobias, as Abner Kravitz on "Bewitched."

* Of Citizen Kane, for example.

Thanks to the Drug and Device Law Blog for providing a link to the opinion of New Jersey federal judge William Martini in the case of Gunvalson v. PTC Therapeutics. Comment on the reported opinion, which concerns access to an experimental drug for Duchenne muscular dystrophy (DMD), was made in a previous post, and follow-up information from a primary source is always welcome—particularly when plenty of questions about the case remain unanswered.

One notable issue raised in the opinion (page 7), which is pretty much dismissed by the judge, is whether the plaintiff, Jacob Gunvalson, even has DMD or, instead, a related and less severe condition, Becker muscular dystrophy (BMD). The distinction is important because the 2 conditions depend on the nature and consequence of the mutation in the gene that encodes the dystrophin protein. Deletion mutations in the gene that cause an out-of-frame mRNA transcript are likely to produce nonfunctional dystrophin, which manifests clinically (in general) as the more severe DMD. Patients with BMD are believed to produce partially functional dystrophin, which accounts for the milder illness.

The nature of Jacob Gunvalson's dystrophin mutation (if detectable), his dystrophin production, and the clinical severity of his illness are important (if not crucial) for 1) anticipating whether PTC's experimental suppressor of nonsense mutations, PTC124, is even likely to work; and 2) ensuring the clinical uniformity of enrollees in clinical trials (if patients with BMD are not eligible).

I can only assume that these issues were laid aside by the judge because either 1) he is incapable of understanding them or their importance; 2) they weren't argued sufficiently by the defendants; or 3) they're resolved issues in the minds of the defendants (meaning that Jacob Gunvalson is known to harbor a nonsense mutation and, indeed, had DMD). [See information in the Addendum below, which suggests that Jacob's diagnosis is not resolved.]

Alright, those fundamental medical concerns raised, back to the opinion:

The undisputed background on the case is that, in early 2006, PTC began a 28-day, open-label phase 2a trial of PTC124 in patients with DMD. At the time, Jacob was taking the well-known aminoglycoside antibiotic gentamicin, which is known to suppress nonsense mutations. (It is unclear how Jacob was receiving gentamicin: from his personal physician or through a clinical trial.) According to the opinion, Jacob's mother consulted PTC vice president Claudia Hirawat about whether Jacob should discontinue gentamicin, so that he could enroll in the PTC124 clinical trial. (Why Hirawat, who is evidently not a medical professional, would be consulted over Jacob's personal physician on this issue is not known, nor addressed, in the opinion.)

According to the affidavit of Jacob's mother, Hirawat told her that Jacob should continue the gentamicin, "which appeared to have some beneficial effect, and wait for later PTC124 clinical trials." This is the alleged exchange (along with similar exchanges) on which the entire case apparently rests: Whether PTC (as represented primarily by Hirawat) led Jacob and his mother to believe that Jacob would have access to the unapproved PTC124, even though he was advised not to and/or didn't enroll in the phase 2a trial of PTC124.

As it turns out, the phase 2a trial was a "success," as Judge Martini describes it. (Frankly it's hard to call such a small, early-phase trial a success—unless by success, one means "not a failure.") According to the PTC web site, enrollees with DMD and a nonsense mutation in the dystrophin gene received 1 of 3 dosages of PTC124 for 28 days. Data from 26 patients who received low or medium dosages were presented at the Third Annual Congress of Myology in May. 

Muscle biopsies showed evidence of dose-dependent increases in dystrophin expression and significant reductions in creatine kinase levels. Also parents and teachers reported clinical improvement in this non-blinded, non-placebo-controlled study, and the drug appeared to be reasonably well tolerated. Given the positive phase 2a trial results, a 2-year extension phase was initiated. 

At this point in time, Jacob's clinical status had deteriorated, according to the opinion, but it does not describe how. (News reports suggest that Jacob had become nonambulatory.) Consequently Jacob sought access to PTC124; however, he was not eligible to participate in the 2a extension trial, because he had not been enrolled in the 28-day study (which PTC had discouraged, claimed the Gunvalsons).* Therefore the Gunvalsons sought access to PTC124 through the FDA's compassionate-use program, which PTC refused to pursue. 

By my read, Judge Martini bases his opinion in favor of the Gunvalsons primarily on whether PTC created some kind of legal obligation to provide PTC124 to Jacob. The judge refers heavily, on this issue, to the affidavit of the patient's mother, Cherie Gunvalson, and what was said and/or promised to her by PTC employees, specifically Hirawat. However, Hirawat's statements, as quoted by the judge, provide an important caveat to clinical-trial enrollment that is overlooked (in my opinion) by the judge. For example,

I informed Mrs. Gunvalson that Jacob's non-enrollment in the phase 2a trials would not by itself preclude him from participating in all of PTC's anticipated future clinical trials, for PTC 124, assuming he satisfied the eligibility requirements for those trials [emphasis added].

It is also important (at least to me) that this statement does not promise enrollment in the 2a extension trial specifically (although some may consider this point too fine to care about). In addition, the accurate quotation of other statements allegedly made to Jacob's mother are suspect, in my mind. For instance, PTC chief medical officer Langdon Miller is claimed to have promised unqualified access to PTC124, a dubious proposition: "[O]nce positive results were back from the [phase 2a] trial, Jacob will get PTC124."

Lawyers Jim Beck and Mark Hermann, over at the Drug and Device Law Blog, dissect some of the legal issues in the case—such as the advisability of communications between company representatives and patients and the nontrivial nature of opening a compassionate-use program for an individual patient. They also make a lot of decent-sounding arguments for why Judge Martini's opinion is a raw deal for any company that develops drugs for hopeless conditions. 

* A previous post discusses Jacob's enrollment in a phase 2b trial of PTC124; however, a footnote in Judge Martini's opinion dispels any notions that either party thought Jacob was or is eligible for enrollment in this trial (see opinion footnote, page 3).

Addendum: In its press release on Judge Martini's opinion, PTC writes, "The decisions made about prior trials were decisions made by the Gunvalsons or the principal investigator for that trial, and not based on any promises or assurances by PTC. In fact, medical records and emails from the Gunvalsons also indicated that Jacob was ineligible for our Phase 2a trial because of the specific nature of his medical condition."

Evidently Richard Finkel, MD, principal investigator of the 2a trial of PTC124, believed that Jacob had BMD on the basis of a record review. A diagnosis of BMD would have disqualified Jacob from PTC's 2a trial, according to Finkel (see page 7 of Martini's opinion). However, another principal investigator, Brenda Wong, MBBS, MRCP, believed that Jacob had DMD. The judge conferred greater weight to Wong's diagnostic opinion.

Physicians have been arguing about pharma's influence on postgraduate medical education for at least 50 years, reveal Scott Podolsky, MD, and Jeremy Greene, MD, PhD, in last week's JAMA. The Harvard physicians' commentary, "A Historical Perspective on Pharmaceutical Promotion and Physician Education," is intended to provoke cautionary thought about the future of medicine, given industry's longstanding involvement in and financial support of the dissemination of drug information.

However, the fact that a 50-year argument on the subject goes on merely indicates this: There's still no tangible evidence that pharma's potential influence on continuing medical education (CME) alters physician competence or patient outcomes—for better or worse.

In the closing of their JAMA commentary, Podolsky and Greene quote advertising executive Pierre Garai from 1963: "We know what the doctors are today. What will they be tomorrow?" This originally rhetorical question cannot be answered, of course, for today's physicians; but it can be addressed for physicians who were practicing during the early 1960s.

Therefore we can ask, what untoward healthcare event has occurred during the last 45 years as a result of pharma's influence on CME?

The only event that comes to mind (to which Podolosky and Greene also allude) is the overuse or misuse of antibiotics, ostensibly as a result of pharma marketing injected into industry-funded CME. However, a search of the medical literature does not support this contention (although an exhaustive search, for the purposes of this blog post, cannot be guaranteed).

On the other hand, a survey of Georgia pediatricians, discussed in a 1999* issue of Pediatrics, indicates that the decision to prescribe antibiotics for children is influenced by 1) diagnostic uncertainty (ie, Is the illness viral or bacterial?); 2) sociocultural and economic pressures (eg, consideration for time-strapped working parents); 3) fears of malpractice litigation; and 4) parental expectations. While the surveyed physicians may have been reluctant to admit to the influence of pharma-funded CME on their prescribing behavior, it seems unlikely that this potential influence would supersede the practice considerations cited by the surveyed physicians.

So the debate will continue, until there is compelling evidence that pharma's influence on CME—influence that has clearly been moderated during the last several years—has caused some undeniably beneficial or untoward healthcare outcome. 

* Arguably the height of pharma's influence on CME, before the institution of stricter firewalls between pharma marketing and CME.

Photo of the pop duo Sonny & Cher, who charted with the 1967 hit "The Beat Goes On," from Wikipedia.

Addendum: Some may cite the exuberant use of off-label fen-phen in the 1990s as an example of the adverse influence of pharma-funded CME. However, the fen-phen mess doesn't seem to be easily distilled to a single factor. Nevertheless, I am certainly receptive to any evidence that Wyeth funded CME activities in which the drug combination and supportive studies were discussed. 

In a welcome study of poorly regulated dietary supplements, investigators in Boston report the presence of toxic heavy metals—namely lead, mercury, or arsenic—in one fifth of US- or Indian-made Ayurvedic products. Results of a metal survey of these Internet-sold drugs were published in the latest issue of JAMA.

Among 199 of 230 randomly selected Ayurvedic medicines available for web-based purchase,* nearly 21% contained metals per x-ray fluorescence spectroscopy, wrote the authors, with no appreciable difference between US- and Indian-made products. Rasa shastra drugs—which combine herbs with metals, minerals, and gems—were significantly more likely to contain metals than non-rasa shastra products (41% vs 17%) and contained significantly higher median concentrations of lead (11.5 vs 7.9 µg/g) or mercury (20,800 vs 34.5 µg/g).

The amount of metals detected in metal-containing products consistently exceeded one or more standards for acceptable daily intake. These drugs were much more likely to be sold at US web sites (Table), and 75% claimed Good Manufacturing Practices, wrote the authors. In some cases, products were specifically recommended for pediatric use.

Product(s)	Manufacturer	US Web Site	Metal(s) Detected†
Prana-Breath of Life	Ayurherbal Corporation	By the Planet	Lead and/or mercury
AyurRelief, GlucoRite	Balance Ayurvedic Products	Balance Ayurvedic Products	Lead
Mahasudarshan	Banyan Botanicals	The Ayurvedic Institute	Lead
Kanchanar Guggulu, Shilajit	Banyan Botanicals	Banyan Botanicals	Lead
Acnenil, Bakuchi, Brahmi, Chairata, Cold Aid, Trifala Guggulu, Heart Plus, Jatamonsi, Kanta Kari, Licorice, Praval Pisti, Prostate Rejuv, Sugar Fight, Tagar, Yograj Guggulu	Bazaar of India	By the Planet	Lead, mercury, and/or arsenic
Energize	Bazaar of India	Bazaar of India	Lead
Hingwastika	Bazaar of India	Herbal Remedies	Mercury
Lean Plus, Neem Plus	Tattva's Herbs	Tattva's Herbs	Lead

These findings are consistent with those of a previous report, in which 20% of 70 Ayurvedic products made in South Asia and sold in Boston contained higher-than-regulatory amounts of lead, mercury, or arsenic. Scores of clinically symptomatic cases of heavy-metal intoxication due to the ingestion of Ayurvedic drugs have been reported since 1978.

* One web-based supplier of Ayurvedic products refused to fill an order for 14 products after recognizing that the purchasers were authors of a previous study.

† Measurement greater than reporting levels for x-ray fluorescence spectroscopy (ie, lead, ≥5 microg/g; mercury, ≥20 microg/g; arsenic, ≥10 microg/g).

A cautionary note to gray panthers: take it easy on the denture cream. Zinc in the grippy goo may lead to copper deficiency and associated neurologic illness.*

In this week's Neurology, physicians from the University of Texas Southwestern Medical Center report 4 patients with neurologic abnormalities in the setting of copper deficiency (hypocupremia) and high zinc levels (hyperzincemia). All presented with clinical myeloneuropathy, and all demonstrated low levels of serum copper and high levels of serum zinc. 

Neurologic symptoms followed the excessive use of denture cream, 2 or more tubes per week for several years. In samples of Fixodent (P&G) or PolyGrip (GSK) denture cream, the authors found zinc levels that ranged from 17 to 34 mg/g and identified no other plausible source of zinc or reason for copper deficiency.

Moreover, in the 3 patients who discontinued the use of denture cream, serum zinc levels dropped. Copper supplementation normalized copper levels in all 4 patients and was associated with mild clinical improvement in 2 patients.

The neurologic conditions in these patients are believed to be due to zinc-induced copper deficiency. Excess zinc—either unintentionally or intentionally swallowed by the denture-cream user—acts as a functional copper chelator, by upregulating the production of copper-binding metallothionein. (The metallothionein-copper complex is excreted in the feces, thereby causing copper deficiency.)

Removal of zinc from denture creams may be problematic, because the saliva-activated adhesive is generally a calcium-zinc polymer. Replies to e-mail inquiries sent to P&G and GSK, asking for comment on the Neurology case reports, are pending.

* Clinically similar to subacute combined degeneration associated with vitamin B12 deficiency.

Photo: iStockPhoto.

Addendum: In a formulaic-type e-mail, GSK, maker of Poligrip products, writes, "When someone uses Super Poligrip for their dentures, the vast majority of the zinc in the product remains in the adhesive and is not released into the mouth. Absorption through the gums, if any, is minimal. This is because the pH level of saliva [generally weakly acidic to neutral] in the mouth prevents the zinc from being released." GSK adds, "Swallowing small amounts of denture adhesive when used as directed is not harmful," and notes that there are Poligrip products that do not contain zinc.

9/11/08 addendum: At last, a response from P&G, or really "Fixodent," or really Ruth...

Thanks for contacting Fixodent, Barbara.

We appreciate your patience while we researched. Our products and their ingredients undergo rigorous scientific evaluations and safety testing before going to market. They are manufactured and packaged in accordance with FDA's good manufacturing practices. We meet all local laws and regulations where we sell Fixodent. We also continually monitor the safety of our products once in market.

Fixodent does not contain harmful ingredients and is safe when used as directed. Zinc is essential to good health. The amount of zinc an average denture adhesive user would ingest from daily usage of Fixodent is less than the amount of zinc in a daily multi-vitamin; less than 6 oysters (fried or raw); comparable to 6 oz. beef tenderloin.

I hope this information is helpful.

Ruth

P&G Team

In a more complete account of last week's "anthrax" science briefing by the FBI, USA Today describes how the incriminating flask of Bacillus anthracis at USAMRIID, RMR-1029, became so genetically distinctive.

RMR-1029 started out as spores from an original Ames strain isolate, which was obtained from a dead Texas calf in 1981. At the US Army's Dugway Proving Ground, 13 production runs were initially conducted with this Ames isolate. Then USAMRIID scientist Bruce Ivins ran another 22 runs, to produce 164 liters of spores in 1997. Later Ivins concentrated the spore collection, called at this time RMR-1029, to 2 flasks in 2001 and then one 1-liter flask in 2004.

Because RMR-1029 had therefore been produced from so many generations of B. anthracis (Paul Keim of Northern Arizona University estimated that one spore colony might represent up to a trillion generations, wrote the paper), subpopulations of spores in the collection harbored distinctive mutations.* Four of these mutations were used by investigators to trace the letter spores back to RMR-1029.

*Strains of B. anthracis are usually highly genetically conserved, because spores in the wild typically remain dormant in the soil for such a long period of time before growth in an infected animal.

Scanning electron micrograph of spores of Ames strain of B. anthracis from CDC/Janice Haney Carr.

Addendum: USA Today, unlike other media outlets, also provided the FBI's list of scientific publications that relate directly to the anthrax investigation.

• Read TD et al. Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis. Science. 2002;296:2028-2033.
• Cummings CA, Relman DA. Genomics and microbiology: microbial forensics—"cross-examing pathogens." Science. 2002;296:1976-1979.
• Read TD et al. The genome sequence of Bacillus anthracis Ames and comparison to closely related bacteria. Nature. 2003;423:81-86.
• Whiteaker JR et al. Quantitative determination of heme for forensic characterization of Bacillus spores using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Anal Chem. 2004;76:2836-2841.
• Easterday WR et al. Specific detection of Bacillus anthracis using the TaqMan mismatch amplification mutation assay. Biotechniques. 2005;38:731-735.
• Beecher DJ. Forensic application of microbiological culture analysis to identify mail intentionally contaminated with Bacillus anthracis spores. Appl Environ Microbiol. 2006;72:5304-5310.
• Van Ert MN et al. Strain-specific single-nucleotide polymorphism assays for the Bacillus anthracis Ames strain. J Clin Microbiol. 2007;45:47-53. (Discussed in a previous post, here.)
• Brewer LN et al. Forensic analysis of bioagents by X-ray and TOF-SIMS hyperspectral imaging. Forensic Sci Int. 2008;179:98-106.

Young and Innocent (1937): a not-terrifically-well-known-but-still-terrific Hitchcock joint, in the style of The 39 Steps.

A constable's daughter (Nova Pilbeam) comes to champion the innocence of a young writer (the nicely coiffed Derrick de Marney) in a starlet's murder. The film version of Westlake Entertainment's DVD could stand some audio and visual restoration, though nothing can be done about a swing band in wince-inducing* black face. Ouch.

* Ha. Watch the movie, and you'll realize that's kind of a double entendre.

Poster image (NB: The Girl Was Young was the US title) from Wikipedia and reproduced under fair-use law.

At last count, the number of Americans who had contracted measles this year was 127. Now add 4 more cases.

This week, the CDC's MMWR reports a total of 131 cases of the highly contagious infection in 15 US states and the District of Columbia from January 1 to July 31 (Table). The overwhelming majority of these cases were imported* (13%) or linked to imported disease (76%). (It is important to note that the number of imported measles cases in the United States has not changed appreciably over the years, but that the number of importation-associated cases accounts for this year's dubious record.) A large percentage (81%) of measles cases were related to 7 outbreaks (≥3 cases). Fifteen individuals, including 4 children younger than 15 months, were hospitalized for disease; however, there have been no deaths—yet. 

Most important, however, is the fact that a whopping 91% of cases occurred in individuals who had not received vaccination or whose vaccination status was unknown. Among these 112 patients, 85% were eligible to receive vaccination, but 66% had declined because of "philosophical or religious beliefs." 

Location	Measles Cases
Illinois	32
New York	27
Washington state	19
Arizona	14
California	14
Wisconsin	7
Hawaii	5
Michigan	4
Arkansas	2
DC	1
Georgia	1
Louisiana	1
Missouri	1
New Mexico	1
Pennsylvania	1
Virginia	1

The MMWR highlights outbreaks in 2 locations, Washington state and Illinois, in which affected children had not been vaccinated on the basis of personal-belief exemptions. A sizable portion of these children were home schooled, which obviates the vaccination requirement for traditional-school enrollment.

In an editorial note, the CDC advises that the current national vaccination rate for measles is adequate to prevent the "sustained spread of measles," but that importation-associated outbreaks are likely to continue as long as there are geographic clusters of unvaccinated individuals. Unfortunately this information will probably be used by parents who forego vaccination to maintain their behavior.

Most affected by the deferral of measles vaccination are immunocompromised children and children younger than 12 months of age, who rely on adequate herd immunity. It appears to be a mere matter of time before a measles outbreak will cause a known, severe complication of the disease, like encephalitis or death, in the United States. Such an event has already occurred in the United Kingdom.

* Genetically or epidemiologically linked to cases in Italy, Switzerland, Belgium, India, Israel, China, Germany, Pakistan, the Philippines, and Russia.

Photo of child with measles rash from the CDC.

While sympathies for anyone with an untreatable and ultimately fatal condition—like Duchenne muscular dystrophy (DMD)—are undeniable, the right for such a person to access an experimental, proprietary therapy is not clear. There's the issue of unproven safety (not to mention efficacy) and the violation of numerous clinical-trial protocols (on which evidence-based medicine rests) that control important variables—like an enrollee's health status, the double-blind process, and randomization of treatment.

Nevertheless, a New Jersey federal judge ruled yesterday that a 16-year-old boy with DMD, Jacob Gunvalson, should have access to PTC124, a drug in clinical-phase development by PTC Therapeutics. According to PTC's web site, a phase 2b trial of the drug is being conducted in ambulatory DMD patients with a nonsense mutation. PTC124 is an orally administered, small molecule that targets this particular mutation type.

It has not been reported if Gunvalson even harbors a DMD nonsense mutation (if not, the use of PTC124 would be, well, nonsense). Also photographs in news reports suggest that the teenager, shown in a wheelchair, is not sufficiently ambulatory at his age to qualify for the PTC trial. Confirmed particulars of the case, expected to be available in the judge's forthcoming written order, should answer these and other issues* that may have implications for anyone seeking access to experimental treatments.

According to the NYT, PTC Therapeutics plans to appeal the decision, and federal regulators must still approve Gunvalson's application to use PTC124.

* For instance, will Gunvalson even be considered an enrollee in the phase 2b trial, should he receive PTC124?

Thanks to insomnia and NBC's late-night/early-morning coverage of the Beijing Olympics, BMX racing now has at least one more fan.

真牛!

Photo of BMX race crash: Carl de Souza/Getty Images.

How and when the potentially fatal contaminant oversulfated chondroitin sulfate wound up in lots of Baxter's Chinese-made heparin remain unknown. The synthetic contaminant, probably introduced at the workshop level, is believed to have caused more the 80 deaths and hundreds of adverse reactions in Americans during the last year. However, the longstanding process of producing heparin from pig intestines—a process susceptible to the introduction of infectious and foreign substances—may be threatened in the long term.

The laboratory production of heparin was reported Monday by Robert Linhardt, PhD, from the Rensselaer Polytechnic Institute at the ongoing meeting of the American Chemical Society in Philadelphia. At a press briefing, Linhardt described investigators' small-scale production of synthetic heparin by using the bacterial strain Escherichia coli K5. The bacteria naturally produces the polysaccharide backbone of heparin, heparosan,* which can be modified by recombinant mammalian enzymes and cofactor recycling to create a substance that is identical to the USP form of heparin.

The chemical production of heparin from E. coli, however, is presently limited to mg quantities (the current world market consumption of heparin is 100 metric tons per year), and Linhardt advises that the next step is to ramp up synthetic heparin production to the kg level during the next 5 years to enable preclinical and clinical study. He anticipates that the biggest hurdles to the large-scale production of heparin will relate to the downstream modifications of the polysaccharide backbone. Peer-reviewed details of the production process will be presented in an upcoming issue of the Journal of the American Chemical Society.

Linhardt admitted to interest from pharma and biotech companies in the production of synthetic heparin but warned that commercial entities are awaiting further development—ostensibly because heparin produced by current methods is so cheap.

* The only other organism, outside of animals, that is known to produce heparosan is the pathogen Pasteurella multocida.

Image of heparin chemical structure from Wikipedia.

HT: MedPage Today 

Yesterday's FBI press briefing on the 2001 "anthrax" letter attacks was intended to rectify a few erroneous pieces of information in press reports and to bolster confidence in the science linking Bruce Ivins to the mailed Bacillus anthracis spores. However, several media outlets (eg, NYT) and Senator Tom Daschle, a target of one of the anthrax letters, continue to express skepticism that the FBI undeniably had its man. Specifically, to highlight the FBI's ineptitude, much is being made of an initial, unusable spore sample that was provided by Ivins to the FBI in 2002 and later destroyed by the agency.*

In an opening statement at the press briefing, Vahid Majidi, PhD, Assistant Director of the FBI's Weapons of Mass Destruction Directorate, clarified that the mailed spores had not been "weaponized" with silicon—contrary to numerous, previous reports. Specifically Joseph Michael, PhD, at the Sandia National Laboratories (who was present at the briefing), concluded that silicon had been naturally incorporated into the spores after examining them with transmission electron microscopy. Majidi also further outlined the genetic investigation that led to the RMR-1029 flask of B. anthracis at USAMRIID (as graphically presented in a recent post).

An initial, preliminary analysis of the letter spores at the CDC revealed a mixture of several phenotypes. This discovery led to the extraction of DNA from these phenotypic variants at Northern Arizona University and full sequencing of the DNA samples at The Institute for Genomic Research (TIGR). Majidi further advised that additional scientific information would be available in peer-reviewed publications and asked the audience to "respect the integrity of this process." He also acknowledged the FBI's inability to quell all suspicions related to the FBI's case against Ivins and added, "There's always going to be a spore on a grassy knoll," wrote the NYT.

Other panel scientists at the briefing included FBI Laboratory Director Chris Hassell, PhD; Paul Keim, PhD (Northern Arizona University); James Burans, PhD (National BioForensic Analysis Center); Rita Colwell, PhD (University of Maryland; Johns Hopkins Bloomberg School of Public Health), Claire Fraser-Liggett, PhD (University of Maryland); and Jacques Ravel, PhD (University of Maryland).

Meanwhile, Slate blogger Glenn Greenwald—evidently forsaking all other evidence—believes the FBI's case against Ivins is completely undermined by the agency's inability to pinpoint exactly when Ivins drove from USAMRIID in Fort Detrick, Maryland, to Princeton, NJ (160 miles), on 2 occasions to mail the anthrax letters postmarked 9/18 and 10/9 of 2001.

* However, Paul Keim's lab at Northern Arizona University reportedly kept a sample of these spores for later analysis.

Additional source: ScienceNOW Daily News.

Scanning electron micrograph of spores of Ames strain of B. anthracis from CDC/Janice Haney Carr.

The percentage of childless American women aged 40-44 years doubled during the last 30 years—from 10% to 20%—according to 2006 survey data released yesterday by the US Census Bureau. The survey also revealed that women of this age group had an average of 1.9 children, which is below "replacement level," and 13.5% had never married.

Childless women were more likely to be 40-something non-Hispanic whites (22.5%), be native born (21.4%), and have a graduate or professional degree (27.4%).

Not sure what any of this has to do with the price of tea in China—other than 1) it might provide you're-not-alone solace to 40-something childless women and 2) it might signal the time to learn Mandarin or Spanish.

Despite the discovery in 1993 of the altered gene that causes Huntington's disease (HD), treatment for this dismal illness remains purely symptomatic and supportive. In the United States, medical therapy for HD chorea has been limited to traditional dopamine-receptor-blocking neuroleptics; however, these medications are associated with a high incidence of extrapyramidal side effects (eg, Parkinsonism) and irreversible tardive dyskinesia.

On Friday, the FDA approved tetrabenazine (Xenazine; Prestwick Pharmaceuticals), a well-known dopamine-depleting agent, for the treatment of HD chorea. The drug, which was granted "orphan drug status," is the first medication approved in the United States for the movement disorder; although tetrabenazine has been in use for HD chorea in Canada, Europe, and other parts of the world. The agent, which probably has limited dopamine-receptor-blocking properties at therapeutic dosages, has not been associated with the development of tardive dyskinesia.

Tetrabenazine was approved for HD chorea on the basis of a multicenter, prospective, double-blind, placebo-controlled study of ambulatory patients with HD (N = 84). Randomly assigned tetrabenazine* was associated with a 3.5-unit relative reduction of the chorea score (Unified HD Rating Scale) at 12 weeks. Five tetrabenazine-treated patients withdrew from the study, and 5 serious adverse events—drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer—were reported with treatment. Nevertheless, another controlled study (industry sponsored) and open-label studies support the drug's use in HD.

With the approval of tetrabenazine, the FDA requires a company-supplied Risk Evaluation and Mitigation Strategy (REMS) to manage any serious risks associated with the drug.

* Titrated up to a maximum of dosage of 100 mg/d.

Public-domain photo of American folk legend Woody Guthrie, who died of complications due to HD in 1967.

Affecting a w-for-r accent,* Sir Alec Guinness is an unassuming banker who attempts a bullion heist in The Lavender Hill Mob. The movie climaxes in (or degenerates into, depending on your viewpoint) a farcical police chase. Oh, cwazy English bobbies wunning awound! How dwoll!

P.S. Don't blink or you'll miss Audwey Hepbuwn.

* Or is that just Alec Guinness?

The techniques used to trace the Bacillus anthracis spores from the 2001 "anthrax" letter attacks to the USAMRIID laboratory at Fort Detrick, Maryland, weren't particularly novel, according to a report in this week's Science. By using documents released by the DoJ last week and expert speculation, writer Martin Enserink proposes the series of events that led to the source of the B. anthracis (Ames strain) that killed 5 people.

The first major task was to genetically distinguish the letter spores on the basis of phenotypic differences in cultured bacterial subpopulations, if at all possible.

The second task was to match the letter spore makeup to known, available Ames strain samples.

The FBI likely identified the USAMRIID lab as the source of the letter spores given that it was the only lab within the area where the "federal eagle" envelopes used in the attacks were distributed and sold. Although this very sound conclusion does not completely rule out the possibility that the spores came from another lab, it is the confluence of evidence (including Ivins's alleged submission of sabotaged or false B. anthracis samples to the FBI) that indicts the former USAMRIID scientist.

SNPs = single nucleotide polymorphisms.

* Sequencing work was likely performed by scientists at Northern Arizona University and The Institute for Genomic Research (TIGR) in Rockville, Maryland.

08/18/08 update: According to ABC News, 8 of the positive samples originated from 2 US labs. One is presumed to be USAMRIID, and the other is not named. The original (2002), "unusable" sample of B. anthracis provided by Bruce Ivins to the FBI—a portion of which was retained by Paul Keim at Northern Arizona University—later tested positive for the 4 "letter" mutations.

The use of cardiac death (as opposed to brain death) to obtain organs for transplantation has been accepted practice for more than a decade in the United States.* According to various protocols, cardiac death in the context of organ harvesting is defined as asystole for 2 or more minutes after the withdrawal of life support. The criterion is based on the fact that autoresuscitation has not been observed after 65 seconds of asystole. However, a logical problem arises when considering the transplantation of a heart after cardiac death.

As ethicist Robert Veatch writes in this week's NEJM, it should be impossible to transplant a heart after the irreversible cessation of cardiac function. If the heart can be restarted in the graft recipient, then the donor could not have been dead in the first place on the basis of cardiac death. Moreover, the very act of removing the "restartable" heart from the donor is equivalent to killing the donor by means of organ removal. Veatch concludes that it is therefore impossible to legally harvest a heart in the setting of cardiac death and proposes 2 ways by which the paradox can be resolved.

One is to alter laws to permit heart removal from living donors. In such cases, however, strict scenarios—such as terminal illness or previous consent—would have to be explicitly defined. The other is to redefine brain death as the loss of higher cortical function (ie, consciousness), which may have popular support. Until then, Veatch argues, "[A]ny successfully transplanted heart cannot have come from a person who was declared dead on the basis of irreversible stoppage of the heart."

Veatch's editorial appears in the same NEJM issue in which Denver physicians report their experience with cardiac transplantation in 3 infant recipients following cardiac death in pediatric donors.

* Although the management of end-of-life care, especially if left to transplant surgeons, can go horribly wrong—for example, as in the case of Ruben Navarro.

Update: Further debate on the controversy of heart donation after cardiac death, particularly in the case of infants, was explored by The Washington Post. Veatch further defined the procedure as "homocide," according to the paper, but a Denver cardiologist involved in the pediatric transplantations called Veatch's assertions "fussy semantics." 

Asked on behalf of mothers everywhere, given Michael Phelps's crazy calorie consumption.

HT: NY Post by way of the WSJ Health Blog and every other conceivable media outlet.

Taking a break from identifying the women they love, the editors at Esquire have decided that the magazine's September cover will feature an animated, black-and-white electronic image—evoking the moving pictures in Harry Potter's newspaper, The Daily Prophet. But some say the distinctive cover, made possible by E-ink,* is a misguided gimmick.

* Which is used in Amazon's Kindle.

The stereotypical expressions of pride and shame after athletic competition are probably biologically hardwired, say behavioral researchers. Their conclusion, published in the latest issue of PNAS, is based on an assessment of physical displays among sighted, blind, or congenitally blind athletes who just won or lost judo matches at the Olympic or Paralympic Games in 2004.

The investigators found that both sighted and blind athletes from a wide range of cultures consistently showed the prototypical pride display after winning—back head-tilt, smile, arms out or raised, hands in fists, chest expanded, torso pushed out—and shame-consistent behaviors after losing—chest narrowed, shoulders slumped. These data suggest that spontaneous pride and shame behaviors are unlikely to be culturally determined, given their consistent presence in athletes from different nations and in congenitally blind competitors who cannot model their behavior on visual cues.

One curious note, however, is the observation of a weaker shame display among sighted athletes from Western European or North American countries. The authors conjecture that characteristic shame behaviors are suppressed in these individuals "in accordance with cultural norms that stigmatize the display of shame and emphasize asserting oneself and maintaining a high quality of life."

The observed pride display in humans is similar to that of other victorious primates (eg, a chimpanzee who has defeated a rival) and may be evolutionarily advantageous by increasing one's apparent physical size. Conversely a shame display, by conveying the acceptance of another's superiority, averts energy-consuming and potentially injurious conflict.

For numerous examples of the universal pride display, just visit the NYT's Winner's Spotlight for the 2008 Summer Olympics.

HT: NPR

Photo of Man Zhong winning the gold medal at the 2008 Summer Olympics: Daniel Dal Zennaro/European Pressphoto Agency.

It may not have occurred to the WSJ Health Blog that surgeons throw instruments in fits of pique, but this type of behavior is nothing new to those in healthcare. Finding a medical trainee who's observed verbal or threatened physical abuse from surgeons in the OR is the act of finding a medical trainee.

For the young and relatively uninitiated, the tolerance of bad behavior from medical superiors toward nurses and other healthcare workers has been taken as a matter of course in the stiffly hierarchal world of medicine. And in some cases, the tolerance of abuse serves as a license for trainees to mirror the behavior. But this misguided tolerance is finally waning, and rightly so—even if it means losing the lucrative business of surgical specialists.

The Boston Globe reported Monday that Massachusetts hospitals, like the North Shore Medical Center and Saint Vincent Hospital, are adopting a kind of 3-strikes rule for physician outbursts, before some kind of discipline is implemented. Of course, intervention after 1 or 2 strikes should be considered by any hospital administration, depending on the behavior.

Another deterrent is to publicize the names of those who exhibit the alleged bad behavior: like orthopedic surgeon Peter J. Mulhern, who reportedly threw 2, 10-pound limb-stabilizing sand bags in the Saint Vincent OR, hitting a nurse's foot; or orthopedic surgeon Murray J. Goodman, who reportedly flung dull scissors in the North Shore OR, just missing a nurse's head.

While doctors' bad behavior may be explained (or excused) by the high-stress environment in the OR and the fact that "[s]urgeons hold patients' lives in their hands," the sand-bag incident with Mulhern occurred in the context of 2 delayed surgeries for carpal tunnel syndrome, wrote The Globe—hardly a life-in-the-balance condition.

The Globe also reported that Mulhern was suspended by Saint Vincent in 2002 and moved his practice to Fort Oglethorpe, Georgia.* Goodman is evidently still affiliated with the North Shore Medical Center in Massachusetts.

The Massachusetts hospitals' disciplinary actions are presumably in line with recommendations from the Joint Commission, which released an alert last month requiring that "all accredited hospitals create a code of conduct that defines acceptable and unacceptable behaviors and...establish a formal process for managing unacceptable behavior," beginning January 1, 2009.

* Which is sufficient punishment in my mind.

Photo of piece of surgeon's arsenal: iStockPhoto

At Saturday's Olympics, the black, vaguely calligraphic design on the shoulder of volleyballer Kerri Walsh most certainly prompted the following question in a range of languages: What the hell is that?

A few curious Web posters thought it might be a fierce tattoo. But no, NBC's Olympics coverage says it's black Kinesio tape on Walsh's right shoulder, which was surgically treated last winter. One commentator said the tape eases pain, stabilizes joints, increases circulation, and reduces lymphedema. If so, that's some tape.

The official web site for the product emphasizes the benefits of the tape—it's particularly elastic and sticky—and the all-important taping method—which accounts for the funky design on Walsh's shoulder. The 4-inch-wide tape can be cut lengthwise for "Y" applications (which are designed to stabilize muscle or prevent its contraction or otherwise do something nice), like that along Walsh's scapular spine and posterior deltoid (see graphic below). In Walsh's case, another Y application was applied to her middle deltoid, along with uncut tape that crisscrossed the joint. Kinesio tape evidently comes in a variety of colors, which (as far as I can tell) are for fashion purposes alone—or in the case of black, to intimidate.

The Kinesio web site claims that taping "alleviates pain and facilitates lymphatic drainage by microscopically lifting the skin. The taped portion forms convolutions in the skin, thus increasing interstitial space. The result is that pressure and irritation are taken off the neural and sensory receptors, alleviating pain. Pressure is gradually taken off the lymphatic system, allowing it to channel more freely." Nice-sounding words to the medically uneducated, and bullshitty to the rest of us. Moreover, I'm not entirely sure how one would even go about proving these physiologic effects.

Evidently only one randomized clinical trial has been conducted to evaluate Kinesio taping for any musculoskeletal condition. A quasi-double-blind* study, published just last month in the Journal of Orthopaedic and Sports Physical Therapy, assessed the short-term self-reported effects of Kinesio or sham taping in 42 young adults with rotator-cuff conditions. The investigators observed immediate improvement in pain-free shoulder abduction with Kinesio taping but no other statistically significant benefit (range of movement, pain, or disability) over sham taping during a 6-day treatment period. The authors suggest why Kinesio taping may improve immediate pain-free movement (gate-control theory, anyone?) but acknowledge their complete speculation on the subject.

* One author was blinded to the taping methods used, and taping methods were different between Kinesio and sham subjects.

A US biostatistician, who testified for runner Mary Decker in a 1997 doping hearing, believes that doping tests among athletes are inherently flawed. In the latest issue of Nature, Donald Berry cites a lack of validated sensitivity and specificity data for individual doping tests—data which are necessary to know the accuracy of positive tests.

Berry argues that, even when a test has a very high specificity (eg, 95%), the false-positive rate in a non-doper who provides 8 different urine samples remains remarkably high (eg, 34%).* A comparable false-positive rate would also apply to the large number of samples assayed by a particular doping laboratory. Invariably some percentage of these tests in non-dopers would turn up positive and, consequently, ruin careers. Berry concludes that doping labs "must prospectively define and publicize a standard testing procedure, including unambiguous criteria for concluding positivity...and validate that procedure in blinded experiments."

The flip side of Berry's argument, the reliability of negative doping tests, was explored recently by Danish investigators, who showed that the detection of recombinant human erythropoietin (rHuEPO) in intentionally doped volunteers was astonishingly inconsistent within and between official doping labs.

* 1 – 0.95 to the 8th power = 1 – 0.66 = 0.34.

Photo: iStockPhoto

Among the compromises reached by the Massachusetts legislature last week in its health-code bill is the stipulation that drug companies will report any physician gifts exceeding $50 to the state's Department of Public Health. The bill now awaits the signature of Governor Deval Patrick, but 5 trade groups* are attempting to persuade the governor not to sign by way of a full-page ad in The Boston Globe.

In addition, PhRMA senior vice president Ken Johnson wrote yesterday in a press release that the public disclosure of gifts "could chill ongoing clinical research in the commonwealth." Johnson proposes, "Physicians and other healthcare providers who do not want such personal information disclosed may decide to no longer work with the pharmaceutical research companies sponsoring the clinical studies." He adds, "Public disclosure of a pharmaceutical company's arrangements with the principal investigators of its clinical trials also would reveal sensitive, proprietary business information to a company's competitors. This could erode the independent decision-making of companies trying to bring science from research facilities to patient care settings."

However, it seems unlikely that Massachusetts physicians would forego pharma research grants for clinical study given 1) the nature of this particular "gift" and 2) the fact that grant information is already publicly available through the NIH database at clinicaltrials.gov (although the size of the grant, to my knowledge, is not provided).

As far as public disclosure revealing "sensitive, proprietary business information," PhRMA's Julie Corcoran tells Pharmalot that, according to the bill, companies "shall disclose...the value, nature, purpose, and particular recipient of any fee, payment, subsidy or other economic benefit"—which, she argues, is subject to overly broad interpretation. But again, in the case of clinical grants, the nature, purpose, and recipient of the funds are already available through the NIH registry.

* Biotechnology Industry Organization, Massachusetts Biotechnology Council, Associated Industries of Massachusetts, Massachusetts High Technology Council, Cambridge Chamber of Commerce, and PhRMA.

8/11 update: The Boston Globe reports that Governor Patrick signed the bill yesterday.

Kitty Foyle: A hypnotic melodramedy of women's liberation and class distinction circa 1940—which means not a whole lot of liberation and a substantial amount of class distinction. Starring a remarkably versatile Ginger Rogers.

Poster image from Wikipedia and reproduced under fair use law.

Although observational studies suggest that specialty care leads to better inpatient outcomes for certain conditions—like ischemic stroke—than general care, these studies have been confounded by prognostic differences among admitted patients. In a recently published retrospective study, investigators at UCSF found that, when adjustments were made to avoid a selection bias for specialist-versus-generalist admission, the rate of in-hospital mortality after ischemic stroke was not significantly lower with primary neurologic care.

When assessing the outcomes of 26,925 inpatients with ischemic stroke in a database of 113 US academic hospitals (1997-1999), Gillum and Johnston attempted to avoid confounding by applying a grouped-treatment analysis, which is used to evaluate individual outcome differences associated with practice variability among hospitals. According to these investigators, this analysis has been previously applied to health-services research (McClellan M et al. JAMA. 1994;272:859-866).

In their assessment, the authors discovered 1760 (7%) in-hospital deaths and, in the univariate and multivariate analyses, a significantly lower risk of these deaths among patients admitted by neurologists. However, there was no difference in the mortality rates among hospitals admitting different proportions of patients with ischemic stroke to neurologists (ie, grouped-treatment analysis).

Analysis Type	Odds Ratio of In-Hospital Mortality With Neurologist Care	Significance
Univariate	0.32	P < .001
Multivariate	0.60	P < .001
Grouped-treatment	1.02	NS

The authors conclude that observed differences in ischemic-stroke outcomes between neurologists and generalists may be due to differences in initial prognosis, given that mortality was not lower at hospitals where patients were admitted more frequently to neurologists.

Image of reflex hammer from iStockPhoto.

Good lord almighty. I'm beginning to think that the ACCME should move to Cuba.

The council that bestows accreditation on organizations to provide CME is now proposing that independent physicians or writers who are involved in the production of any kind of promotional material for pharma cannot be involved in the development of content for CME. This would arguably prohibit any non-industry physician involved on a company's advisory board or speakers' bureau from participating in the production and delivery of CME. Likewise, any independent writer who produces promotional material for a company could not be involved in the creation of CME content about the same drug class. Yeesh, what's next, ACCME? Little Mao caps?

The ACCME's new proposal is evidently based on the following:

In May 2008, the Attorney's[sic] General of thirty US states won a judgment against a commercial interest that included the stipulation that a promotional speaker for the commercial interest could not also be a CME speaker, on the same class of drugs discussed in the promotion activity, in a CME activity that received funding from the commercial interest.

As Thomas Sullivan at the Policy and Medicine blog points out, the ACCME's characterization is not exactly accurate. In May 2008, Merck actually agreed to a multistate* settlement (it was not a judgment) regarding its Vioxx ads. With respect to the funding of CME, the settlement indicated that Merck will comply with the ACCME's Standards of Commercial Support (nothing particularly earth-shattering) and that any person acting in a promotional capacity for Merck shall disclose to CME participants this promotional relationship (again, nothing particularly earth-shattering). This settlement also indicated that Merck cannot fund a CME program, if it has foreknowledge that a CME speaker has been a promotional speaker for Merck during the last 12 months (a minor tremor, given that Merck could not recommend CME speakers anyway, according to the ACCME standards).

In addition, the ACCME cites a June report from the AAMC Task Force, which urged academic medical centers to discourage their faculty from participating in industry-sponsored speakers' bureaus. But the Task Force also wrote,

To the extent that academic medical centers choose to allow participation of their faculty and staff in industry-sponsored, FDA-regulated programs, they should develop standards that define appropriate and acceptable involvement.

1. Academic medical centers should require full transparency and disclosure by their personnel to the centers and when participating in such programs; and

2. Academic medical centers should require that payments to academic personnel be only at fair market value.

So the ACCME, given the full details of the Merck settlement and the AAMC opinion, is overgeneralizing and grossly overstepping its purview, IMO, by proposing that non-industry physicians limit their communication to other physicians, depending on the setting. Moreover, the ACCME's proposal would needlessly undermine opportunities for independent medical writers to earn a living.

Or to provide another free-speech comment: Blpppht.

AAMC = Association of American Medical Colleges; ACCME = Accreditation Council for Continuing Medical Education.

* Twenty-nine states and Washington, DC.

I'm not eager to recommend therapy to another MD, but I wouldn't mind if psychiatrist and fervent CME critic Daniel Carlat took up some kind of regular relaxation technique. Perhaps, simply deep-breathing exercises—particularly before posting at his blog.

The effort might otherwise prevent hasty, arguably emotion-driven, and inaccurate assumptions about those who dare to disagree with him on the subject of industry-supported continuing medical education (CME). I am specifically referring to his post yesterday, which referred to online critical comments of a recent BusinessWeek article ("Teaching Doctors—or Selling to Them?"). One of these online comments (which can be found here) was mine, and in addition, I cited the BW author, Arlene Weintraub, at this blog for failing to distinguish between overt pharma marketing and CME and her omission of relevant information about Zimmer Holdings.

What I and other online critics of the BW article apparently failed to do, Dr. Carlat implies, is reveal every darn thing about ourselves in the comment box as a show of transparency. (Of course, Dr. Carlat's focus on the article's critics diverts attention from what is actually justified criticism of the BW article.) Some of the critics, who did provide their names, are (gasp) affiliated with the CME business—which could be easily determined by your basic fall-off-a-log Google sleuthing. With respect to my comment, Dr. Carlat wrote the following:

But wait—there's more!

B. Martin criticizes Weintraub's "inability to differentiate between outright pharma marketing and the current status of industry-funded CME." She does not disclose that she is Barbara Martin, who, on her Pathophilia website, identifies herself as a "formerly practicing board-certified neurologist" who is now a full time writer in the "intriguing world of pharmaceutical marketing and pharma-supported continuing medical education (CME)." I guess that means her job is dependent on industry support of CME.

For perspective, here's my actual comment at the BW site:

B. Martin, MD
Aug 6, 2008 5:24 PM GMT
In addition to Ms. Weintraub's inability to differentiate between outright pharma marketing and the current status of industry-funded CME, she also neglects to indicate that Zimmer's move away from funding MECC-sponsored CME is likely related to the company's Deferred Prosecution Agreement with US Attorneys: http://bmartinmd.com/2008/08/businessweek-engages-in-sloppy.html.

So what I did do was provide a link to this blog, which Dr. Carlat failed to notice or inform his blog readers. For an online comment, at least in my opinion, that's as transparent as cellophane. I would also correct Dr. Carlat's interpretation of my About page. I am indeed a formerly practicing neurologist, and I was employed, after my clinical experience, in pharma marketing and, later, in the CME business (which accounts for my knowledge of CME). Today, I am a full-time, freelance writer; however, it is inaccurate to say that my current job is "dependent on industry support of CME."

There. Deep bloody breath.

By now everyone has seen MAD Magazine's on-target political-movie posters for McCain and Obama. This is merely a note to enjoy the fine print—eg, "A Post Traumatic Stress Production," etc, etc.

While we wait for confirmation and further explanation from the scientific community (and I suspect specifically from Northern Arizona University's Paul Keim) about the forensic evidence that ties Bruce Ivins to the 2001 anthrax attacks, we can comb the documents released today by the DoJ. At least from my perspective, the evidence against Ivins is very compelling.

Among the presented information is the fact that the Ames strain of Bacillus anthracis contained in the mailed letters can be directly linked to a single spore batch, called RMR-1029. This identification was accomplished by the detection of 4 characteristic genetic mutations, which are otherwise not described in the DoJ documents; however, it is possible that these mutations refer to the use of highly mutable single nucleotide repeat (SNR) markers described in a previous post here on the subject.

Of the 16 domestic labs that had RMR-1029 before the 2001 anthrax attacks, only one—the USAMRID facility in Fort Detrick, MD—was located where the identified "federal eagle" envelopes used in the attacks were distributed and sold (Maryland or Virginia).

At Fort Detrick, RMR-1029 was stored in the B3 biocontainment suite in Building 1425, to which Bruce Ivins had "unrestricted access." Moreover, Ivins had been "the sole custodian of RMR-1029 since it was first grown in 1997."

Because the B. anthracis spores in the letters sent to the Post and Tom Brokaw (postmarked 9/18/2001) were physically different* from those contained in the letters to Senators Leahy and Daschle (postmarked 10/9/2001), the investigators concluded that the spore batches were created from the RMR-1029 flask at Fort Detrick on two separate occasions. This conclusion is supported by the presence of a B. subtilis contaminant in the Post/Brokaw letters, which could not have been derived from the Fort Detrick flask.

On the basis of nighttime work records at Fort Detrick, the DoJ proposes that Ivins produced the Post/Brokaw B. anthracis during September 14-16 and the Leahy/Daschle spores sometime from September 28 to October 5. It is important to note that Ivins worked alone during these late-shift periods, and that his work time differed considerably from those of other Fort Detrick researchers with access to RMR-1029.

Probably most damning is the allegation that Ivins stalled the genetic identification of the RMR-1029 batch at Fort Detrick by submitting possibly sabotaged or false samples to the FBI for analysis. Initial samples provided by Ivins in 2002 were unusable, according to the DoJ documents, and a second sample of RMR-1029 from Fort Detrick did not contain the characteristic 4 mutations. In 2004, the FBI seized the RMR-1029 flask, which subsequently indicated a genetic match to the B. anthracis contained in the letters. 

A final note of curiosity is the return address provided on the Senators' letters: "4th Grade, Greendale School, Franklin Park, NJ, 08852." Former person of interest Stephen Hatfill had been loosely linked to the fictitious address, owing to erroneous media reports that he lived near a "Greendale Elementary School" while in Zimbabwe. The DoJ documents suggest that the return address may be an indirect reference to the Greendale Baptist Academy in Wisconsin and a related suit filed by the ultra-conservative American Family Association against the Wisconsin Department of Public Services, which was investigating the corporal punishment of a 4th-grade student at the Academy. The DoJ notes that "Mr. and Mrs. Bruce Ivins," who were practicing Catholics, made several donations over the years to the AFA and received the organization's newsletter, which would have referenced the suit.

* Genomic sequencing, however, revealed that the B. anthracis spores in all 4 letters were identical.

Scanning electron micrograph of spores of Ames strain of B. anthracis from CDC/Janice Haney Carr.

In a recent BusinessWeek article, writer Arlene Weintraub demonstrates a very poor understanding of the differences between outright pharma marketing and the current status of industry-funded, certified continuing medical education (CME). Several online comments to the article, which features the usual high dudgeon of CME critic Daniel Carlat, rightly indicate that Weintraub describes a dated version of industry-funded medical education. For example, MCM's Lew Pinsker wrote,

It's unfortunate that a reporter for a major business periodical would indict a billion-dollar industry without doing due journalistic diligence in researching her subject. As has been pointed out in previous comments, her use of the term "marketing companies" when describing accredited medical education companies ignores the significant changes which have been taking place for more than a year. Organizations which develop certified CME cannot in any way be "marketing companies".

In her article, Weintraub cites two companies, Pfizer and Zimmer Holdings, as having recently suspended their funding of CME produced by medical education communications companies (MECCs). In fact, Zimmer—an orthopedic device company—suspended funding of all CME activity, Weintraub reports, and will identify an "independent third party," like a professional medical society, to produce the CME activities that the company supports financially.

However, Weintraub fails to note that Zimmer's move away from funding CME is likely related to fallout from a Deferred Prosecution Agreement in September of last year with the US Attorney's Office in New Jersey. The Indiana company settled with federal prosecutors as a result of an investigation into the company's financial relationships with consulting orthopedic surgeons. As part of the agreement, Zimmer will pay a civil fine of $169.5 million* and agreed to an 18-month oversight by a federal monitor appointed by the DOJ and a 5-year Corporate Integrity Agreement with the Office of the Inspector General (OIG). The company, however, did not admit to any wrongdoing.

In April of this year, Zimmer announced "comprehensive changes in its corporate compliance model," which "is designed to aggressively reduce potential or perceived conflicts of interest inherent in consulting relationships between industry and healthcare professionals." The changes are intended to "meet and exceed the requirements of its September 2007 resolution agreements with the US government," the company wrote in its press release. 

* According to Yahoo, Zimmer's net income for 2007 was $773.2 million.

Adjunctive, transdermal estradiol significantly reduces the positive and general psychopathologic symptoms of acute or chronic schizophrenia in women of childbearing age, according to a clinical study published in this month's Archives of General Psychiatry. The assessment of supplemental estrogen in schizophrenia is based on long-term observations of the delayed onset of disease in women, improved symptoms during pregnancy, and postpartum deterioration.

In the double-blind Australian study, women with acute or chronic schizophrenia (inpatients, 29; outpatients, 73) received randomly assigned transdermal estradiol 100 µg (n = 56) or transdermal placebo (n = 46) for 28 days, in addition to standard psychiatric treatment. Estradiol effects on symptoms were assessed weekly with the standard Positive and Negative Syndrome Scale (PANSS). Despite improved positive symptoms (eg, hallucinations) at 28 days, there was no effect on the negative symptoms (eg, avolition) of schizophrenia.

Larger and longer studies are necessary to confirm these short-term study results and to assess the risk of the known adverse events of estrogen in a population that routinely smokes and is treated with dopamine-blocking antipsychotics. Moreover, stratifying results on the basis of disease state (acute vs chronic) is needed, given the differential effect of short-term estrogen on positive symptoms in this study. Whether estrogen supplementation is worthwhile in men with schizophrenia is a trickier prospect for obvious reasons.

Image of estradiol patch from Mylan.

Our understanding of fear responses in mammals improved last week, thanks to 2 rodent studies published in the latest issue of Nature (see here and here). In a combined analysis of the work, Australian scientists Pankaj Sah and Frederick Westbrook provide an overview of the circuitry now implicated in fear conditioning. Fear conditioning is a process whereby a normally innocuous stimulus (eg, a flashing light) is paired with a noxious, fear-producing stimulus (eg, an electric shock) to produce a fear response after exposure to the innocuous stimulus alone.

The rodent studies indicate that fear conditioning is the result of sensory input from both the innocuous and noxious stimuli into so-called fear neurons of the basolateral portion of the amygdala. (The amygdala is a bilateral, deep-seated collection of neurons within the medial temporal lobes, which can be thought of as the brain's Grand Central Station of emotional reactions.) These fear neurons then activate neurons in another part of the amygdala, the central nucleus, which sends its output to the hippocampus and brainstem to produce a behavioral fear response.

Extinction of the fear response, which occurs after repeated exposure to the innocuous stimulus alone, is the result of activation of intercalated neurons within the amygdala, either directly from the prefrontal cortex or by way of so-called extinction neurons within the basolateral nucleus of the amygdala. These intercalated neurons then inhibit the fear neurons and their input into the central nucleus. Likhtik et al showed that toxic lesions of the intercalated neurons in mice resulted in deficient extinction that correlated inversely with the number of surviving cells.

The renewal of the fear response, which occurs when the innocuous and noxious stimuli are re-paired, is the result of input from the hippocampus, which activates inhibitor neurons in the basolateral amygdala. These inhibitor neurons, in turn, suppress the activity of extinction neurons.

Paj and Westbrook indicate that specific neuronal receptors* within this fear circuitry are likely to become targets for investigational treatments of anxiety and panic disorders in humans.

* The chief transmitter of major inputs into the amygdala is glutamate, and the central nucleus contains inhibitory gamma amino-butyric acid (GABA) receptors, which are potentiated by benzos.

Image of transparent brain from underneath (ventral aspect) showing bilateral amygdalae (red) from Wikipedia. 

Get Carter

: Michael Caine is smokin' hot as a ruthless hitman who investigates his brother's murder. There's still plenty of England's Swinging Sixties in this 1971 film—micro-minis, sexual promiscuity, bad teeth...no paisley, though.

Poster image from Wikipedia and reproduced under fair use law.

Yesterday, the Massachusetts House and Senate reached anticipated compromises on a widely discussed pharma-code bill, reports the Boston Globe. The drafted bill, which is expected to be approved and sent to the state governor this weekend, now requires the following:

1. Companies will report any physician gifts exceeding $50 to the state's Department of Public Health, and the DPH should post this information online for public access.
2. The DPH will adopt something like the recently unveiled, voluntary PhRMA code, which bans branded trinkets and out-of-office meals with reps.
3. A $5000 fine will be levied for each violation by pharma or medical-device companies.

Two new cases of Tysabri-related progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) were reported yesterday by comarketers Elan and Biogen. In both cases, the diagnosis was established by the detection of JC virus DNA in spinal fluid, along with clinical and MRI findings. The patients had received Tysabri monotherapy for more than a year. These new cases can be added to 2 cases of PML in MS patients who received Tysabri with Avonex (interferon beta-1a; Biogen) and 1 case in a patient with Crohn's disease given Tysabri monotherapy.

Reports of these new PML cases follow the publication in this week's Neurology of the long-term risk-versus-benefit of the agent in patients with relapsing-remitting MS. By assessing quality-adjusted life years (QALYs), investigators from the University of Rochester concluded that the PML risk with Tysabri would have to increase more than 7 times to reduce the drug's net benefit below that of interferon beta. This result is mostly due to the superior reduction of relapses with Tysabri.

	QALYs With Tysabri	QALYs With Interferon Beta-1a
Natural history	8.70	8.70
Health gains
Delayed progression	0.08	0.06
Reduced relapse rate	0.78	0.37
Health losses
Non-PML	–0.002	–0.003
PML	–0.055	0
Net effect	9.50	9.12

The positive analysis notwithstanding, the news of the latest PML cases with Tysabri hit Elan and Biogen hard, with share prices dropping substantially.