bmartin: October 2010 Archives
If Mad Love (1935), starring Peeeeter Lorre, is any indication, these are the bad-news rules in spooky movie-land.
- Brilliant surgeons are kah-razy.
- They don't perform mundane operations, like appendectomies.
- They invariably transplant body parts.
- They don't tranplant kidneys.
- They do transplant limbs.
- The transplant donor is typically insane, a criminal, or both.
- The transplanted body parts behave according to the donor's, not the recipient's, will.
The good news in spooky movie-land: Graft rejection is simply not an issue.
Poster for Mad Love, starring Peeeeter Lorre, from Wikipedia and reproduced under fair use law.
The rising interest in brain injury among American football players has spilled over into Sports Illustrated. In the November 1 issue, out today, writer David Epstein profiles a complex study conducted by Purdue researchers, who fitted 11 Indiana highschoolers' helmets with impact sensors. Using the NFL-endorsed ImPACT neurocognitive test and fMRI, the researchers determined, to their surprise, that repetitive nonconcussive* head blows are not without consequence. The visual memory scores of some players who sustained these types of hits,** usually frontal and often exceeding 100 Gs, dropped significantly and appeared to correlate with changes in fMRI brain activity (in the dorsolateral prefrontal cortex).
The disturbing finding: On the sidelines and off the field, these players were clinically asymptomatic, at least by crude measures. They could carry on conversations, did not demonstrate memory impairment, and appeared to be fine by their parents' observations.
The reassuring finding: These players' ImPACT scores returned to baseline off-season.
The remaining uncertainty: No one really knows what the long-term toll of repetitive, nonconcussive, frontal head blows is, season after season. The Purdue researchers hope to follow up their subjects throughout their high school athletic careers and perhaps into college.
In addition to SI coverage, the Purdue study was published in the peer-reviewed Journal of Neurotrauma last month.
fMRI = functional MRI.
* Meaning, not impairing consciousness.
** Frontal head blows can be distinguished from the brainstem-torquing side blows associated with concussion.
Clint Eastwood's new movie, Hereafter, the profile of a psychic (Matt Damon), is evidently an excuse for the WSJ to feature an ongoing near-death study that was publicized 2 years ago. While the WSJ article, written by Melinda Beck, is most certainly not news, it is generating lively reader comments and a bunch of Facebook thumbs-up "likes."
These are the evident new priorities of the world's leading business and financial newspaper. Bravo. I'll take my hypercarbic, hypoxic afterlife show now.
While in shower, actor Matt Damon telepathically convinces reporter Melinda Beck to write movie-promoting fluff piece. (Photo courtesy of Warner Bros. Pictures, Inc.)
From the whimsically mundane (crystallized soy sauce) to the obligatory (Drosophila compound eye) to the just plain weird (I'm still trying to figure out the mosquito heart), scientists from the big Earth coned down on animals, vegetables, and minerals with light microscopes in Nikon's Small World Photomicrography Contest.
My favorite from this year's recognized pics: trazodone, alpha-estradiol 7256a (100X under polarized light) as a tiny Godzilla. The "Image of Distinction" is from Dutchman Lars Bech, who's evidently been photographing pharmaceutical products on a microscopic scale since at least the mid-1990s. Bech won the contest in 1996 with his museum-worthy abstraction of doxorubicin.
The deadline for next year's entries: April 30, 2011.
Kiss Me Deadly(1955): Film noir in the atomic age.
Mickey Spillane's Mike Hammer (Ralph Meeker) investigates the murder of a barefoot hitchhiker (Cloris Leachman in her screen debut), who—in some barely explainable turn of events—had the skinny on a box of hissing, radioactive stuff...or junk...or something. The fate of Hammer and his blatantly exploited Gal Friday (Maxine Cooper) is highly ambivalent in 2 alternate DVD endings. In addition to a 20-something Leachman, the sharp eye will catch a 30-something Strother Martin.
Praise the Lord and pass the loot, an alternative to warfarin is now available. Yesterday the FDA approved dabigatran (Pradaxa; Boehringer Ingelheim), a direct thrombin inhibitor, for the prevention of stroke and other systemic embolic events in patients with a-fib. The pill's approval comes exactly 1 month after an FDA advisory panel unanimously (9-0) endorsed the drug. The pill's main advantage is that its use does not necessitate the neverending chore of anticoagulation monitoring (eg, repeated protime assessments)—unlike treatment with the old-as-dirt warfarin.
Dabigatran's approval for the a-fib indication is based on the mammoth (N = 18,113) unblinded RE-LY trial,* in which the drug, at 2 dosages (110 and 150 mg BID), was either comparable or superior** to warfarin. What's confusing about yesterday's approval, however, is that a 75-mg dosage, not a 110-mg pill, got an FDA nod, in addition to the 150-mg BID regimen. Why the 110-mg pill is not available in the United States (but is available in Europe) is a bit of a mystery. According to heartwire, the 75-mg pill, BID, is available for "a small subset with severe renal impairment." One forum post at heartwire indicates that the 75-mg dosage was studied in early pharmacokinetics trials. Cardiologist Sanjay Kaul told heartwire, "The 110-mg dose, while associated with reduced bleeding, had a 12% higher incidence of ischemic stroke. In my opinion, it would not offer much of an advantage over warfarin and would likely be an ineffective alternative."
Data on US-based costs for Pradaxa are currently elusive. According to PharmacyChecker.com, a 1-month supply of 110-mg capsules ranges from $258 to $394 and some change. While warfarin, including brand-name Coumadin, is much, much cheaper, BI will no doubt consider the avoided direct and indirect costs of anticoagulation monitoring with warfarin and the reduced burden of prevented strokes when justifying its US price for Pradaxa.
N.B. Boehringer Ingelheim is a privately held German company.
RE-LY = Randomized Evaluation of Long-term Anticoagulant Therapy.
* RE-LY used the increasingly popular PROBE protocol, a prospective, randomized, open-label, blinded endpoint evaluation.
** 35% stroke risk reduction with 150 mg BID. The absolute stroke risk reduction was 1.69% - 1.11% = 0.58%. Rates of major bleeding and mortality were similar with the 2 treatments. The annual rate of hemorrhagic stroke was lower with dabigatran 150 mg BID (0.10% vs 0.38% with warfarin; P < .001).
Yesterday the FDA publicly released its redacted letter* to Austin "Jack" Decoster, notorious owner of the notorious Quality Egg of Galt, Iowa. The ironically named shell-egg facility is suspected to be at least one source (if not the source) of a recent egg-borne salmonella outbreak that has sickened more than 1000 Americans. Decoster and his manager son, Peter, were publicly tarred and feathered last month at a Congressional Subcommittee hearing on the outbreak.
The FDA's warning letter, sent by the agency's Kansas City District Director last week, alleges violations of the Prevention of Salmonella Enteritidis in Shell Eggs During Production, Storage, and Transportation regulation (21 CFR 118); the Public Health Service Act (42 USC §264(a)); and the Federal Food, Drug, and Cosmetic Act (21 USC 342(a)(4)).** The FDA demands "prompt and aggressive actions to eliminate the Salmonella Enteritidis contaminations and the observations described." Futhermore the letter appears to lay grounds for potential criminal proceedings against Decoster by the US government, in addition to explicitly threatening "seizure and/or injunction."
* Although it's not clear where the redactions were made.
** The cited portion of the FDCA identifies adulterated food by the following: "if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health."
As of October 12 (last Tuesday), the number of confirmed, probable, or suspect cases of pertussis in California is 5658. The pertussis caseload has grown by 40% in 1 month (from 4017 on September 14) and has now surpassed the number of pertussis cases that were recorded in the state during the mid-1950s. The latest pertussis incidence rate is 14.5 per 100,000. The death tally remains at 9 (all infants).
According to the California Department of Public Health (CDPH), pertussis cases peaked in 1950, at 6613, and the highest incidence of pertussis in the state was 16.1 cases per 100,000 in 1959.
In an attempt to stymie the spread of pertussis, the CDPH recommends, in addition to the routine schedule for DTaP during childhood, Tdap for 1) women of childbearing age, 2) persons who are in close contact with infants, 3) healthcare personnel, and 4) individuals with wounds. Tdap is similar to the standard tetanus-diphtheria booster (Td) received by adolescents and adults every 10 years, with an important exception. The Tdap vaccine also boosts immunity against pertussis. According to the CDC, a "single dose of Tdap is recommended for adolescents 11 or 12 years of age, or in place of one Td booster in older adolescents [or] adults age 19 through 64."
DTaP = diptheria, tetanus, and acellular pertussis.
Photo of symptomatic child with pertussis from pertussis.com.
No longer a fanciful abstraction, the use of hESC-derived cells in humans has begun in a phase 1 clinical trial. The specific hESC-derived cell line, called GRNOPC1 and licensed to the California-based Geron, will be injected into the spinal cords of patients with subacute thoracic injury. The first enrollee got a shot of 2 million hESC-derived oligodendrocytes yesterday at the Shepherd Center in Atlanta. The story is carried by the LA Times, and Geron's press release can be found here.
The company has selected 6 other medical centers for the trial, including the primary site of Northwestern University in Chicago, which is currently open for enrollment. The trick or trickiness of enrolling patients will be to identify individuals who have sustained complete (ie, grade A) spinal injury at the thoracic level (T3-T10) and are within 1-2 weeks of injury onset. However, the anticipated number of enrollees is small: 10.
The human clinical trial represents the expected quantum step from animal studies of GRNOPC1, which demonstrated improved locomotion in spinally injured rats and histologic evidence of cellular function. The development of epithelial cysts at the sites of cord injury in animals stalled a go-ahead from the FDA in 2009 to begin human trials. But the regulatory hold was lifted in July of this year, after Geron performed additional preclinical studies.
Oligodendrocytes, the myelin-producing cells of the central nervous system, are expected to facilitate signal conduction in a damaged cord. However, hESC-derived cells may also express important neurotrophic factors that promote the survival or regeneration of injured axons.
hESC = human embryonic stem cell.
Transverse section of the thoracic spinal cord from Gray's Anatomy (1918).
Shortages of influenza vaccine due to a limited supply of chicken eggs may soon be a quaint memory of last year's H1N1 epidemic. The use of fertilized chicken eggs to cultivate the virus was a major bottleneck in vaccine production during 2009 (and particularly because the unusually fastidious, novel H1N1 required 2 eggs instead of the typical 1 to reach sufficient titers).
The use of cell-generated virus to mass produce vaccines is a top priority for the US government, and the European Union has already approved a cell-derived influenza vaccine, Novartis's Optaflu (way back in 2007). Ten months ago, Novartis opened its cell-cultured vaccine facility in Holly Springs, NC, the construction of which was supported by a big federal grant. Mass production of vaccine is expected in 2011 or 2012, according to the latest estimates from HHS Secretary Kathleen Sebelius.
But will the cell-produced vaccine be as efficacaious as the old-school injection? Confirming the EU's approval, the clinical answer appears to be yes. New results from a large, international placebo-controlled trial, conducted during the 2007-2008 flu season, showed that Optaflu was as efficacious and as well tolerated as Agrippal, Novartis's egg-based vaccine. And both inactivated vaccines were better at protecting against influenza than placebo.
Six-month efficacy against all circulating influenza virus strains were 69.5% and 63.0% for Optaflu and Agrippal, respectively, and the immunogenicity of both exceeded CBER's licensing criteria. The rates of confirmed influenza in subjects were 1.25% with Optaflu, 1.54% with Aggripal, and 3.96% with placebo—resulting in an approximately 70% risk reduction of infection with Optaflu vaccination.
The conclusion of the industry-sponsored study: "Both vaccines can be considered for annual influenza vaccination campaigns."
CBER = Center for Biologics Evaluation and Research.
HT: MedPage Today.
There are chameleons, like Streep and Michael Sheen, who transform into entirely distinct characters on film, and then there are movie stars, who portray minor shades of the same charismatic personality in every movie. Such is the case with Lee Marvin and Burt Lancaster, who tweak their familiar images into former soldiers of the Mexican Revolution and munitions experts for hire in The Professionals (1966).
Here now is the story of a Western A-team—led by Marvin, of course, and hired by oil baron Joe Grant (Ralph Bellamy) to rescue his kidnapped wife from a south-of-the-border rebel and former compatriot of Marvin and Lancaster, Jesus Raza (Jack Palance). Richard Brooks, best known for his screenplay work (eg, Key Largo), directs his own words, which include better-than-average dialogue about the allegience to political ideals and romantic love.
Novartis appears to be taking a cue from Sarah Lawrence and every other college or university in the nation, which uniformly charge exorbitant tuitions and then provide almost everybody some kind of financial break.
That is to say: Novartis is tempering its boing-inducing sticker price of Gilenya, the first disease-modifying pill for relapsing-remitting multiple sclerosis, by offering monthly copays, writes Bloomberg. Consequently the $4000-a-month (that's wholesale) drug, which launched this week, will cost as little as (as little as!) $3200 for some non-Medicare patients. That's because Novartis will provide as much as $800 in monthly copayments to Gilenya users. It's also reported that the company will "help patients navigate testing and monitoring recommended by US regulators," by paying as much as $600 for these expenses (for background on these expenses, go here).
In the age of the dying blockbuster, Gilenya is nevertheless expected to be one (if not on the basis of sale volume). A Bloomberg-cited analyst predicts that the drug will fetch $3 billion annually, which easily exceeds Avonex's revenue for last year ($2.3 billion). Members of at least one very large health insurer will have immediate access to the drug, in top-tier fashion. The highest monthly out-of-pocket cost for Gilenya in this case would total $250.
Bloomberg also cites a nifty, online drug-purchasing resource, destinationrx.com. According to this website, monthly costs for the injectable disease-modifying drugs for MS are the following*:
- Avonex, $2941.92
- Betaseron, $6196.61
- Rebif, $2809.91
- Copaxone, $3267.05
Gilenya is not yet in the database.
* I have no idea why the cost of Betaseron is so high.
Photo of some building at Sarah Lawrence College, which charges $43,556 for tuition and "fees."
In characteristic fashion, freelance writer Robert Lowes, reporting for Medscape, is all over any novel Medicare legislation. He notes that a new bill, introduced this week by Senate Democrat Blanche Lincoln of Arkansas, would repeal the controversial and much-despised SGR formula, which dictates dramatic cuts in Medicare reimbursement to physicians.
Implementation of the SGR-defined cuts in Medicare payments has been perpetually and repeatedly delayed by Congress, while the legislative body has failed to repeal the formula. (For reasons why, go here.) Congress's latest kick-the-can measure postpones a 20-something-percent cut in Medicare reimbursement to December 1st.
Blanche's proposal calls for use of the Medicare Economic Index, or MEI, which correlates reimbursement to escalating physician-practice costs rather than the less-steep general inflation rate. According to Lowes, the Congressional Budget Office has not yet published an estimate of how much Lincoln's bill will cost, but previous SGR-repealing bills added more than $200 billion to the deficit.
"While it is unlikely that Sen. Lincoln's bill will come up for a vote before year's end," Lowes writes, "her proposal may spark a Congressional debate on a permanent doc fix early next year." Otherwise Congress is expected to convene a lame-duck session after the November elections to pass critical legislation, which possibly includes another stay to the SGR-defined cut in Medicare payments.
SGR = sustained growth rate.
Photo of weathered can from magannie at Flickr.
Friday's unsettling news that physicians with the Public Health Service (PHS) attempted to inoculate Guatemalan prisoners with syphilis in the 1940s* prompts more in-depth reading on the subject. In her online article, groundbreaking medical historian Susan Reverby also writes about similar and poorly known human experiments on American prisoners, which were funded by US tax payers.
In 1944, PHS investigators attempted to inoculate Neisseria gonorrhoeae into prisoners at the Terre Haute Federal Penitentiary. The experiments were abandoned, however, given the difficulty of transmitting the VD bacterium by penile-inoculation methods. Results of the failed experiment were not cloistered, however. They were written up by Mahoney et al ("Experimental gonococcic urethritis in human volunteers") and published in the now-long-defunct American Journal of Syphilis, Gonorrhea and Venereal Diseases (1946;30:1-39).
In 1953, PHS physicians conducted another inoculation study, this time with Treponema pallidum, the cause of syphilis, at New York's notorious Sing Sing Prison on 62 imprisoned "volunteers." The 1940s Guatemala studies informed the inoculation methods attempted in the Sing Sing experiments, writes Reverby; although a published medical report of the NY prison study in 1956 failed to mention the PHS's foundational work in Guatemala.
Reverby calls out John C. Cutler, MD, a coauthor of both US prison studies, as leading the American-funded human experimentation in Guatemala. Cutler is notorious for overseeing the PHS's Tuskegee syphilis experiment. But Reverby distinguishes the US prison and Guatemalan studies of the 1940s and 50s from the decades-long Tuskegee study by noting that the latter did not employ inoculation techniques or offer penicillin treatment, whereas the former trials did.
* Which has prompted apologies to the Guatemalan government from President Obama, as well as the Secretary of State and the DHHS Secretary (despite the fact that the Guatemalan government was complicit in the PHS experiments at the time, according to Reverby).
Portrait of PHS physician John C. Cutler, MD, August 25, 1942, from the National Library of Medicine.
The Damned United (2009): Few Americans are familiar with Brian Clough, the outspoken UK football (read, soccer) manager, but the guy's a legend in his home country. An American correlate would be somebody like the NY Yankees' Billy Martin: a personality in danger of overshadowing the players, the owners—even the sport itself. So when BBC Films and Left Bank Pictures wanted to back the filmic version of Clough's controversial 44-day tenure at Leeds United in 1974, based on a bestselling novel by David Pearce, the natural choice to play Clough was Michael Sheen.
Sheen, known for his portrayals of Tony Blair (The Queen) and David Frost (Frost/Nixon), has—like a budding Meryl Streep—developed a reputation for pulling off virtuoso impersonations. And like Streep playing Julia Child in the woefully misdirected Julie & Julia, Sheen carries The Damned United when the film has trouble sustaining itself or knowing its direction. Is The Damned United a study of a single character, manager rivalries, the marital-like bond between professional collegues, or the relationship between coach and team? Director Tom Hopper and screenwriter Peter Morgan weren't sure, it seems. But one thing is clear: they had a most valuable player. Sometimes that's all that's needed to prevail.
The timeline for the next act in the stem-cell legal drama is now in place. An appeal to overturn an August 23rd injunction against federally funded research on human embryonic stem cells (hESCs) will begin in 2 weeks with a volley of briefs in the US Court of Appeals for the DC Circuit.
On October 14, the appellants' (DoJ's) brief is due, and 2 weeks later, the appellees (the original plaintiffs, Sherley et al) should submit their brief. Then wait another week for the government's reply brief (on November 4). Oral argument will take place "on the first appropriate date following completion of briefing."
In so far as it may be relevant, the federal appeals court judges are a Catholic (Kavanaugh), a Mormon (Griffith), and someone whose political views appear to meet in that weird nexus of extreme left- and right-wing ideology (Brown).
Should be interesting.
Thanks once again to the Great Beyond Blog for easy access to relevant court docs.