Recently in Infectious diseases Category

For those who are following the XMRV-CFS-Mikovits story, science blogger John Timmer at ars technica provides a decent synopsis of the crazy soap opera/Greek tragedy.

Specifically Timmer outlines a complicated narrative in reasonably comprehensible (but not outstanding*) prose. The salient points:

• the rise and fall of data linking XMRV with the dubious CFS;
• researcher Judy Mikovits's refusal to abandon the idea that XMRV is associated with CFS, despite others' data indicating XMRV contamination;
• the symbiotic nexus between Mikovits and individuals with CFS, some of whom reportedly tried to undermine any investigation debunking the link between XMRV with CFS;
• Mikovits's subsequent unethical, and possibly criminal, behavior; and
• the overall integrity of the collective, collaborative scientific process (including nods to the DHHS and the "publishing system").

* One feels that Timmer's lengthy post could be a terrific short article with some professional editorial help.
CFS = chronic fatigue syndrome; DHHS = Department of Health and Human Services; XMRV = xenotropic murine leukemia virus-related virus.

The Nature News Blog and Retraction Watch provide the ongoing, head-torquing narrative of Judy Mikovits, the dubious or embattled (depending on your viewpoint) XMRV-CFS researcher who was fired in September from the Whittemore Peterson Institute in Reno, Nevada. The latest news: Mikovits was arrested last Friday in California (as a fugitive from Nevada, from what I can tell) for allegedly stealing property—eg, laboratory notebooks—from the Institute.

And while the jig certainly appears to be up for Mikovits regarding the validity of her past scientific claims about XMRV and chronic fatigue syndrome or a future career in legitimate science, to hold her without bail (especially while, elsewhere, an alleged serial pedophile is allowed out on $100,000 and no monitoring) seems terribly draconian and patently unfair.

Forbes's Matthew Herper on Bill Gates on vaccines and pharma: There's sufficient ink for undeniably venerable ideas and acts, but an "unimpressed" Gates disparages Novartis's Gleevac, a molecule that has completely revolutionized the treatment of CML.

“There’s always this divergence between what’s financially attractive and what has dramatic profit and the number of life years that you really save...Do the math on [Gleevac] versus, says, preventing Parkinson’s or preventing Alzheimer’s. It’s in a different universe."

There are journalistic programs in which we (I) place more credit than others—possibly owing to their style, possibly owing to their length and supposed care with a subject, and possibly owing to the fact that they air on the Public Broadcasting System. "Frontline" is one such show.

However, credit afforded to news programs can be easily and permanently eroded when they showcase a subject of which we (I) know something about—like medicine—and present a terribly biased or outrightly incorrect view of an issue. This is presumably done for the sake of generating controversy and attention (irresponsibly) or, I can only guess, because the show's producers are lazy or stupid or both.

Last evening, "Frontline" aired a documentary of the FBI's investigation of the so-called anthrax attacks of 2001, a subject of which I know something about, at least on an amateur basis. The program, "The Anthrax Files," was heavily informed, it appears, by input from ProPublica, an amorphous collection of "independent" journalists, that partners with all sorts of more tangible news organizations like "60 Minutes"* and NPR. And from ProPublica, the format and theme of the program—that being, that USAMRIID scientist Bruce Ivins was not the perpetrator of the anthrax attacks—were heavily informed by ProPublica's curiously perpetually suited managing editor Stephen Engelberg.

As a recurrent talking head, Engelberg heavily insinuates in his program (and it really does appear to be his program) that Bruce Ivins was not the anthrax killer by first laying out the case of Steven Hatfill. Hatfill, an American physician and virologist, was the FBI's prime initial suspect as the anthrax killer, circa 2002, and the agency basically hounded the guy (for a number of reasons that are not explained in the "Frontline" program) to no success. Engelberg's prelude on Hatfill provides the basis for later suggesting that the FBI pushed another hapless suspect, Bruce Ivins, who was much more mentally brittle than Hatfill, to suicide when the agency pursued the USAMRIID scientist in the same harassing way as it did Hatfill. In other words, according to Engelberg, Ivins didn't commit suicide out of guilt of being the anthrax killer or fear of rightful criminal prosecution, but because the FBI drove him to it.

But here Engelberg's journalistic transgression is one of serious omission. Namely Engelberg utterly fails (and I can only conclude that he intentionally utterly fails) to include essential information from a 2009 court-authorized psychological review of Bruce Ivins. From this review, a 9-member panel concluded in March that "Dr. Ivins was psychologically disposed to undertake the mailings; his behavioral history demonstrated his potential for carrying them out; and he had the motivation and the means." So why wouldn't Engelberg include this important psychological review of Ivins in the "Frontline" program? The answer: Because it gets in the way of his controversy- and attention-generating themes—namely that Ivins wasn't the anthrax killer, and the FBI is an incompetent and/or pernicious government institution.

Engelberg also attempts to undermine the FBI's scientific evidence pointing to the "smoking gun" RMR-1029 flask at USAMRIID (for background on this flask, start here), over which Ivins had control. To my understanding, there were 16 domestic labs that had the RMR-1029 strain before the 2001 anthrax attacks; however, only one of these labs was located where the "federal eagle" envelopes (which were used in the attacks) were distributed and sold (in Maryland and Virginia). And this was the USAMRIID RMR-1029 flask over which Ivins had control. Engelberg completely fails (and again, I can only conclude that he intentionally fails) to provide the information about the envelopes in his "Frontline" program. The fact that the scientific evidence (meaning the genetic evidence implicating RMR-1029) does not solely support the fingering of Ivins is nothing new. It is the confluence of the 2 vital pieces of information—the genetic identification of RMR-1029 and the location of the envelope purchase that points to Ivins.

Engelberg also attempts to erode the FBI's allegations that 1) Ivins worked alone in lengthy late-night shifts during September 14-16, 2001, and from September 28 to October 5, 2001, before the rounds of the NY Post/Brokow and Leahy/Daschle letters were respectively mailed, and 2) Ivins, in highly disingenuous fashion, submitted "unusable" and false B. anthracis spores to the FBI for testing. Engelberg's attempted correction of the FBI's graph of Ivins's late-night hours during the fall of 2001, although less impressive than the FBI's original graph, still reveals a spike in Ivins's work hours during the time in question. And Engelberg doesn't negate the fact that Ivins submitted an unusable sample of B. anthracis to the FBI, but that Ivins also submitted at least 2 workable samples to the agency at some point during their investigation.** Last Engelberg fails to include any information about the 2002 contamination of Ivins's laboratory with B. anthracis spores, outside of the proper containment facility, and Ivins's failure to report the incident.

Whatever easy agenda Engelberg is pushing to some receptive sector of the American population in "The Anthrax Files" (the FBI is a terrible organization—?), it is, in the case of the anthrax attacks and Bruce Ivins, nothing other than irresponsible and, in my view, only serves to undermine the credibility of ProPublica and "Frontline."

* Speaking of a news program in which we (I) have no confidence.
** Apparently because he had no choice but to do so.

Public domain photograph of Daschle "anthrax" letter from Wikipedia.

As demonstrated by grad student Abbie Smith at her ERV blog.

Smith's post heard 'round the Web—which is a major, career-devasting bust to researcher Judy Mikovits—shows how Mikovits clearly used the same Western blot data to describe two different experiments, both of which made the now highly dubious link between XMRV and chronic fatigue syndrome.

Although Smith acknowledges that she was not the first to recognize the identical nature of Mikovits's Western blot images (one of which was published in Science in 2009 and the other of which was presented at a recent conference in Ottawa), she should get credit for the worldwide disclosure.

Snap.

A Presidential commission, charged with investigating the US-funded VD experiments on Guatemalan prisoners and mental patients in the mid-1940s, revealed some of its shocking findings this week to the press (for background on this story, start here). The experiments, performed without subjects' consent, were discovered and reported by a Wellesley medical historian, Susan Reverby, last fall, and President Obama shortly thereafter apologized to the Guatemalan government for the unethical studies and ordered a commission to investigate them.

The commission's official report will reportedly be available in early September (tomorrow?), but a few highly disturbing details of the investigation were made available to the AP this week. Among them:

• 1300 Guatemalan soldiers, prisoners, prostitutes, or mental patients were intentionally exposed to the microbes that cause syphilis or gonorrhea
• Only about 700 (53%) of the exposed individuals received some sort of treatment (presumably penicillin*)
• 83 people in the study died, although it's not clear if death was due to intentional infection
• The research provided "no useful medical information"
• 7 women with epilepsy, residents of Guatemala's Asilo de Alienados (Asylum for the Insane), were injected with Treponema pallidum at the base of the skull, as a hopeful cure; all developed bacterial meningitis, probably as a result of unsterile technique
  
• A female patient with syphilis and an unknown terminal illness received an inoculation of gonococci in the eyes "and elsewhere"; she died 6 months later

Notorious US physician John C. Cutler, MD (right), who oversaw the PHS's Tuskegee syphilis experiment, led the American-funded human experimentation in Guatemala.

Guatemalan authorities are evidently conducting their own fact-finding investigation of the matter, but official reports have been delayed on more than one occasion. According to the AP, the Guatemalan report should be completed by November. (It should be remembered that Guatemalan authorities were complicit in the PHS experiments, according to Reverby.)

* The described rationale for the program was to determine the preventive benefit of penicillin.

Portrait of PHS physician John C. Cutler, MD, August 25, 1942, from the National Library of Medicine.

A rare and poorly understood form of pediatric epilepsy, head-nodding syndrome is spreading in the new nation of South Sudan,* reports Meredith Wadman of Nature. CDC experts on site remain stumped about the cause of the apparent seizure disorder, which is associated with malnutrition, subclinical seizures, and focal brain atrophy or gliosis (aka scarring of brain tissue) in some cases. A link to endemic river blindness, or infection with Onchocerca volvulus, is tenuous, and genetic susceptibility provides only a partial explanation as to the origin of HNS.

The disease, locally called kifafa,** was first recognized in the early 1960s in Tanzania (in the East African territory of Tanganyika) by Dr. Louise Jilek-Aall (right), who founded the Mahenge Epilepsy Clinic (link to a youtube video).

For more background on HNS, click here for a 2008 article.

HT: American Academy of Neurology.

* Capital, Juba, "Jeopardy!" fans.
** Swahili for epilepsy.

On Friday, the CDC reported the growing resistance of Neisseria gonorrhoeae, the bacterium that causes (not surprisingly) gonorrhea, to the class of antibiotics called cephalosporins. This is concerning because, as the CDC stressed, "No other well-studied and effective antibiotic treatment options or combinations currently are available." Most recently the CDC had recommended dual antibiotic therapy for the treatment of gonorrhea in the United States, consisting of ceftriaxone (the most-effective cephalosporin for the venereal disease) and azithromycin or doxycyline. This recommendation has changed slightly on the basis of data from the CDC-sponsored Gonococcal Isolate Surveillance Project (GISP).

According to GISP, ceftriaxone-resistant N. gonorrhoeae in the United States increased threefold, from 0.1% in 2000 to 0.3% last year. And while the CDC continues to recommend ceftriaxone as part of effective therapy for gonorrhea, the agency appears to be bracing for growing antibiotic resistance—like that seen with N. gonorrhoeae and fluoroquinolones at the turn of the century. The CDC recommends that the other half of currently recommended therapy for uncomplicated gonorrhea should now consist of azithromycin (not doxycycline) because of the sensitivity/resistance patterns of the latest cephalosporin-resistant N. gonorrhoeae isolates.

The history of antibiotic-resistant N. gonorrhoeae is nearly as old as the history of antibiotics. Before the advent of antimicrobial drugs, gonorrhea was treated in a haphazard way with various concoctions, delivered either systemically or locally. One such treatment, prescribed to a victim of Elixir of Sulfanilamide, called for a mixture of zinc sulphate, lead acetate, colorless hydrastis (the herb goldenseal), and bismouth subnitrate, which was to be injected by way of a penis syringe.

Sulfanilamide was the first widely available antibiotic shown to be effective against the venereal disease (see Dees JE, Colston JAC. The use of sulfanilamide in gonococcic infections. J Am Med Assoc. 1937;108:1854-1858). But sulfonamide resistance was reported as early as the mid-1940s, and preferred therapy for gonorrhea became penicillin, until N. gonorrhoeae resistance to this mainstay emerged in the 1960s (see here, here, and here for example) and grew throughout the 1970s. Tetracycline-resistant N. gonorrhoeae emerged in the 1980s (see here for example), and fluoroquinolone-resistant bugs (eg, to ciprofloxacin, ofloxacin) showed up in Hawaii in the mid-90s.

Gram stain showing N. gonorrhoeae diplococci from the CDC/M. Rein (1978).

Where: Mostly Germany (concentration in northwest Germany), with about 30 cases in Sweden, 12 in Denmark, and a handful in various other European countries. The CDC has reported 4 suspected or confirmed cases of infection in the United States (3 with HUS), and Canada has reported 1 suspected case (without HUS).

Given the not-inconsequential risk of PML with Tysabri (natalizumab) use in multiple sclerosis—particularly with prolonged use—neurologists have taken the unproven track of intermittently stopping the drug in an effort to reduce that risk. And although noone really knows if this measure leads to the intended result (ie, a reduced risk of PML), it almost certainly increases the risk of MS disease activity. But when the risk of disease activity returns and to what extent has been unknown—until now.

In an assessment of 1866 patients enrolled in pivotal Tysabri clinical trials* who stopped the drug (owing to the voluntary removal of the drug from the market in 2005), O'Connor et al found that disease activity** returned shortly after Tysabri was discontinued. Then disease activity peaked between 4 and 7 months but, importantly, did not "rebound" beyond baseline levels.

The study authors concluded,

These data indicate that a return of disease activity to pretreatment levels should be anticipated soon after natalizumab treatment is interrupted, underscore that the consequences of reucrrent MS disease activity should be weighed against potential benefits of PML risk reduction, and should motivate the search for suitable alternatives to a mere treatment interruption.

How to address the interruption of Tysabri therapy (which is taken, rightly or wrongly, as a given to reduce the PML risk) will be answered to some extent by the ongoing RESTORE study. This Biogen-sponsored multicenter US study, in which Tysabri therapy will be interrupted for 24 weeks, is designed to assess 1) how quickly the immune effects of Tysabri disappear; 2) when MS symptoms return; 3) if other immunomodulatory drugs (eg, interferon beta) can control MS symptoms; and 4) how quickly the effects of Tysabri return after resuming therapy. The estimated primary completion date of RESTORE is December of this year, and the estimated study completion date is December of 2012.

* The AFFIRM, SENTINEL, and GLANCE studies.
** As measured by the annualized relapse rate (ARR) and gadolinium-positive lesions on MR images.

PML = progressive multifocal leukoencephalopathy.