June 2010 Archives

The recuperating blogger's method of easy blogging: Link to another story.

For today: A report from the NY Times, which revisits the dubious idea of stenting jugular veins in patients with multiple sclerosis. According to the paper, interest in the unproven procedure remains fueled by unknown numbers of desperate, logged-on MS patients and a few rogue physicians—some of whom market, in cringe-inducing fashion, a "liberation package."

Oh my ugh.

But neurologist Stephen Hauser of UCSF correctly tells the NYT that evidence for the procedure "is quite scanty" and that its "biological plausibility is low."

Previous posts at this blog highlight 1) a conclusion from US neurologist John Corboy that the small drop in pressure provided by these jugular-vein procedures is unlikely to be pathologically significant; and 2) the correct decision by Stanford to shut down the jugular-stent program of a vascular surgeon until well-controlled data are available to support the treatment.

Image of neck veins from Gray's Anatomy (1918).

Killer's Kiss

(1955): Stanley Kubrick deserves full credit or blame for nearly everything in this low-budget noir with neorealistic tendencies.* Waiting for a train out of the Big Bad Apple, a washed-up boxer (Jamie Smith) contemplates his brief relationship with a taxi dancer (Irene Kane) and her oppressive boss (Frank Silvera).

The final scene between boxer and villain (which presumably takes place somewhere near the Garment District) evokes the climax in The Lady From Shanghai (1947), with female mannequins substituting for mirrors. It's clear here that Kubrick was in love with the compositional possibilities.

* Given the on-site filming.

Jamie Smith and mannequins in still from Killer's Kiss.

Having recently survived a 4-day stay at a local university-affiliated hospital, I can only conclude that today's nursing care should be represented by the clackety-clack of a keyboard and the reflected glow of a computer monitor. Despite its intent to streamline work and possibly prevent medication errors,* the nurse's ever-present mobile computer workstation (left) merely appears to serve as an attention-sucking barrier between nurse and patient—an imperial scutum against professional empathy for the sickest of the sick.

* And has anyone demonstrated this?

Image of Infologix's ST7 Mobile Workstation.

Ball of Fire

(1941): Screenwriter Billy Wilder anticipates the urban dictionary in this sublime meeting of a mob-connected singer (Barbara Stanwyck), a monkish grammarian (Gary Cooper), and his 7 professorial mates. There's so much that's great in this movie, it's hard to keep up: Wilder's dizzying dialogue; Stanwyck's and Cooper's effortless timing; DP Toland's camera magic*; director Howard Hawks's typical break-neck pacing; and...ladies and gentlemen, Gene Krupa on the drums!

* One dazzling gem: Toland captures Stanwyck's reflection in a nightclub table while Gene Krupa plays "Drum Boogie" with matchsticks.

Okay, maybe it's a cloying move by Pfizer to protest the absurdity of government oversight. But it's also kind of funny.

The world's largest drug company is advising US physicians who visit its exhibit booth at the ongoing ASCO meeting that they will have to swipe their registration cards if they want a freebie latte, reports Reuters. And oh no, you di'int: MDs from Minnesota and Vermont can't have one at all, thanks to their state laws that prohibit all swag—no matter how trivial.

Moreover, if you do accept a latte from Pfizer, the company may provide your name to US regulators and post the fact that you received caffeinated remuneration at its disclosure website. God knows, you could end up scribbling scores of prescriptions for Aromasin during your 20-minute Pfizer-propagated caffeine buzz.

At least the oversight measures are keeping somebody employed...and amused.

ASCO = American Society of Clinical Oncology.

"angry latte" by Chris Barkeley at Flickr.

06/10/10 addendum: It's hard to keep up, but Vermont recently amended its existing, relevant law to allow the "provision of coffee and other snacks or refreshments at a booth at a conference or seminar." The bill became effective on March 27th (without the governor's signature, according to the FDA Law Blog).

An expert panel of the American Academy of Neurology (AAN), the flagship organization of US neurologists, confirms the 1995 criteria for establishing brain death and has little to add on the basis of the interim literature. The panel's assessment is available in the latest issue of Neurology.

Among the findings:

1. There have been no published reports of neurologic recovery once brain death has been diagnosed by using the 1995 criteria.
2. There is insufficient evidence to define a minimal observation period for diagnosing brain death, once brain function has ceased.
3. Complex, spontaneous movements, like facial myokymia, and ventilator triggering can be seen in brain death.
4. The various tests for determining apnea have not been compared—so one test has not been shown to be preferable.
5. Data supporting the use of newer ancillary tests, like MR angiography, to confirm brain death are not sufficiently compelling.

The steps to determining brain death include the prerequisites (eg, excluding the use of CNS depressants and neuromuscular blockers, establishing a normal core body temperature and blood pressure), the clinical evaluation (eg, documenting a lack of responsiveness, assessing brainstem reflexes, performing an apnea test), and ancillary tests (eg, performing an EEG or imaging study). A useful appendix checklist is provided in the article.

In addition, the AAN web site provides a Q&A with one of the panel members, Eelco Wijdicks of the Mayo Clinic, regarding the reassessment of brain-death criteria. In addition to discussing clinical and other parameters, Dr. Wijdicks provides all-important guidance for communicating the diagnosis of brain death to the victim's family. (In my experience, a particularly difficult concept for many family members to understand is the idea that brain death equals death, both functionally and legally. Conveying this information firmly and compassionately can be a challenge.)

After the diagnosis of brain death is made, the attending physician should meet with the family, accompanied by nursing staff and, often, hospital clergy. Considerable time for conversation and a quiet place to sit are needed. The family members are told that their loved one has passed on and that the medical staff deeply regrets the loss. The family members will have ample time to say their good-byes. The medical staff will be available for support. The family, however, will have to make a decision about possible organ donation and is invited to speak with an organ donation agency. The medical staff is keeping the rest of the organs working with medication and the mechanical ventilator, and if there is no wish for organ donation, the staff will stop the ventilator and other treatments.

Let's make no mistake: Disclosing potential pharma-related conflicts of interest among healthcare professionals, when possible, is desirable. But the idea that a few thousand pounds, Euros, or whatever from Roche or GSK led any WHO-advising expert to recommend the government stockpiling of Tamiflu and Relenza (the only drugs that exist to treat influenza symptoms), stretches credulity.

Nevertheless, that's what Deborah Cohen and Philip Carter would evidently like us to entertain in their BMJ "investigative" piece of last week. The writers also float the idea that WHO-advising physicians should have no industry ties whatsoever—a both unrealistic and unwise proposal. In such cases, WHO would be basing its recommendations for the planet on the thoughts of physicians who are actually less knowledgeable about proprietary drugs.

In an ABCNews report on the BMJ article, John Treanor, a vaccine expert from the University of Rochester essentially concurred: "[I]ndividuals with the greatest experience and insight into these interventions will almost always either be employees of industry or individuals paid by industry to conduct studies."* Likewise, John Bartlett of Johns Hopkins said, "[T]he people in medicine who know most about flu are often conflicted because they also are advisors to pharma and often do the big trials that are funded by pharma."

Let's also remember that Cohen and Carter are in the cushy position of being able to make their anti-WHO criticisms in the aftermath of what was a mild influenza pandemic.** Would they have had any problem lambasting WHO for a lack of preparedness if the pandemic had been far worse and the supplies of anti-influenza drugs had been limited? Probably not.

This specter of journalistic duplicity was echoed by ABC's quoted experts:

Treanor: "I think even [Cohen and Carter] would have to agree that there really was no choice here but to prepare for a pandemic. If there had been a severe pandemic and there had been no preparations, the outcome (and the outcry) would have been far worse."

John Barry, author of The Great Influenza: "This is a classic case of 20-20 hindsight, with some witch hunting thrown in." 

Last, biosecurity expert Donald A. Henderson concluded about Cohen's and Carter's angle: "WHO is a handy whipping post. I would characterize this focus on WHO as a 'cheap shot.'" 

* Treanor also acknowledged that a lack of industry ties doesn't necessarily remove bias. Researchers "will always view the product they do work on in a positive light, even if they weren't paid by industry," he said.

** At least as of now.

06/09/10 addendum: Responding to the BMJ accusations, WHO Director-General, Margaret Chan, denies that commercial interests were considered in WHO's decision-making process "for one second," reports Canada's Globe and Mail. "The bottom line...is that decisions to raise the level of pandemic alert were based on clearly defined virological and epidemiological criteria. It is hard to bend these criteria, no matter what the motive," Chan rebutted. (The full text of Chan's letter to the BMJ can be found here.) 

Chan also responded that the continued anonymity of 3 members of WHO's "emergency" committee is to protect them from undue influence, including undue commercial influence. It is reported that their identities will be revealed once their service is complete.

In the meantime, an independent committee is reviewing WHO's handling of the 2009 H1N1 pandemic.

Classe Tous Risques

(1960): Rough translation, Weigh All Risks (but released in the United States with the very noirish title, The Big Risk).

The end of the road for Abel Davos (Lino Ventura), a career thief with 2 young sons, is told in a cinematic nexus of hard-boiled noir, existentialism, and lingering ideas of social responsibility. Put that in yer film-class paper.

Preliminary data

from the CDC's Emerging Infections Program* (EIP) suggest a small, but statistically significant, increased risk of Guillain-Barre syndrome (GBS) with receipt of the 2009 pandemic H1N1 vaccine. However, the risk, 0.8 excess cases per 1 million vaccinations, is comparable to that seen with other seasonal flu vaccines and is much lower than the observed risk of GBS during the 1976 swine-flu vaccination program (~10 excess cases per 1 million vaccinations). The excess risk of GBS with the 2009 pandemic H1N1 vaccine is also much lower than the risk of hospitalization or death due to illness with the virus itself (222 and 9.7 per 1 million).

Within EIP's surveillance area, there were 326 cases of GBS (meeting case criteria) between October 1, 2009, and May 10, 2010. Among these patients, 27 received documented vaccination against the 2009 pandemic H1N1 virus during the 42 days preceding their illness, and 274 did not (the vaccine status of 25 was unknown or "pending ascertainment"). Consequently the estimated age-adjusted rates of GBS were 1.92 and 1.21 per 100,000 person-years among vaccinated and unvaccinated persons, respectively. These data led to an attributable excess risk of GBS with vaccination of 0.8 per 1 million vaccinations.

Once again, it's important to remember that association does not mean causation. For instance, many of the vaccinated persons (59%) also reported illness symptoms during the 42 days before GBS onset, which is consistent with many cases of non-vaccine-related cases of GBS. Vaccination, in these cases, could have been completely incidental to the development of neuropathy. Moreover, there was no temporal clustering of GBS onset after vaccination (eg, at 2 weeks), suggesting that vaccine was not causally related to illness. Vaccinated persons with GBS were not sicker, nor did they suffer worse outcomes, than unvaccinated individuals with GBS.

The CDC advises that the final assessment of the EIP data will be available in the fall of this year. Other safety databases, like the Vaccine Safety Datalink, have not shown an association between GBS and receipt of the 2009 pandemic H1N1 vaccine.

* A collaboration among the CDC, state health departments, and academic centers in 10 states. Surveillance covers about 45 million individuals.

Corexit, the chemical dispersant being used by BP to break up its massive and growing oil spill, is not the cause of physical symptoms among cleanup workers, says the product's manufacturer, Nalco.

Several news sources, including the NYT, are reporting today that the Naperville, Illinois-based company is defending the safety of Corexit, "when used as directed," although Nalco advises that BP's direct application of Corexit to the spewing oil well is "unprecedented." The Naperville Sun Times says that 993,000 gallons of Corexit have been sprayed or dumped in the Gulf of Mexico as of yesterday. In May, the EPA asked BP to back off on its use of Corexit in the Gulf spill.

So what's in Corexit? It's hard to know exactly, because part of the formula is proprietary. According to the material safety datasheet for Corexit 9500, the "clear, hazy, amber" liquid contains

• 10%-30% hydrotreated light petroleum distillates (a mineral spirit-type solvent, as far as I can tell);
• 1%-5% propylene glycol (a widely used solvent and chemical cousin of ethylene glycol); and
• 10%-30% "organic sulfonic acid salt," which is proprietary (the EPA evidently has the full formula, according to the NYT).

For humans, Corexit appears to be merely a short-term irritant; it is not defined as hazardous or toxic by EPA standards. Safety precautions (eg, gloves, splash goggles) are intended to keep the product away from the skin and eyes. Filter masks are recommended when air concentrations are expected to reach a certain threshold.

Today's PubMed search for "Corexit" returns 59 articles, dating back to 1974. No article pertains to human safety, and 37 articles concern the product's effect on sea life. A search for "Corexit 9500" returns 22 articles, dating back to 1996; 12 pertain to animal or plant effects.

The upshot: Products like Corexit 9500 are very effective oil dispersants, but they may increase (at least temporarily) the concentrations of toxic polycylic aromatic hydrocarbons (PAH) in oil-contaminated water, presumably through their dispersant effects. And there are evidently A TON of variables to consider when deciding to use dispersants—like, the concentration of the crude oil, the "weathered" condition of the oil, water salinity, oil-exposure conditions (eg, whether declining or continuous), and the myriad, myriad, myriad species at risk and their life cycles. 

Singer et al (1996). Comparison of acute aquatic effects of the oil dispersant Corexit 9500 with those of other Corexit series dispersants. Corexit 9500 was found to be similarly "toxic" to other Corexit products on early-life stages of the red abalone and kelp forest mysid. The authors, from the University of California, Santa Cruz, wrote that Corexit 9500 is a "reformulation of a long-time industry 'standard,' Corexit 9527, to allow use on higher viscosity oils and emulsions."

George-Ares and Clark (2000). Aquatic toxicity of two Corexit dispersants. Two Exxon employees described the in-vitro "low to moderate toxicity" of Corexit 9500 and Corexit 9527 on "most aquatic species." They also described the variables affecting toxicity (such as species, life stage, duration of exposure, and temperature) and addressed environmental factors that inform the use of dispersants.

Pollino and Holloway (2002). The toxicity of testing of crude oil and related compounds using early life stages of the crimson-spotted rainbowfish (Melantotaenia fluviatilis). Australian academicians determined that Corexit 9500 and Corexit 9527 were less acutely toxic than naphthalene and crude oil-water-dispersant mixtures on the larvae of freshwater rainbowish.

Ramachandran et al (2004). Oil dispersant increases PAH uptake by fish exposed to crude oil. Canadian researchers concluded that the use of dispersants, like Corexit 9500, actually increases the exposure of fish to toxic crude-oil hydrocarbons.

Fuller et al (2004). Comparative toxicity of oil, dispersant, and oil plus dispersant to several marine species. Scientists at Texas A&M observed that crude oil with dispersant was equally or less toxic that crude oil alone on 2 fish and 1 shrimp species. "Unweathered" crude oil (dominated by "soluble hydrocarbon fractions") was more toxic than weathered oil (which was dominated by "colloidal oil fractions"). In declining exposure conditions, weathered and unweathered oil with dispersant were equally toxic to a standardly tested fish species, Menidia beryllina. Both media were dominated by the less toxic "colloidal oil fractions." The consistent finding in this variable-results study: declining-exposure conditions were less toxic than continuous-exposure conditions.

Couillard et al (2005). Effect of dispersant on the composition of the water-accommodated fraction of crude oil and its toxicity to larval marine fish. Researchers from the Canadian Department of Fisheries and Oceans concluded that Corexit 9500, when added to seawater-accommodated fractions of light crude oil, multiplied the concentrations of PAH and was associated with higher mortality rates in larval mummichog.

Liu et al (2006). Field investigation on the toxicity of Alaska North Slope crude oil (ANSC) and dispersed ANSC crude to Gulf killifish, Eastern oyster and white shrimp. Investigators at Louisiana State University found that Corexit 9500 was an effective oil dispersant and facilitated the rapid reduction of hydrocarbon concentrations. At testing conditions, most of the tested juvenile organisms (>83%) survived "well" after 24 hours of exposure. A crude oil concentration higher than 30 ppm was required for "any significant toxic effect."

Ramachandran et al (2006). Influence of salinity and fish species on PAH uptake from dispersed crude oil. Water salinity reduced PAH exposure (by reducing PAH solubility) and the efficiency of dispersants (but only at the highest tested salinity). The Canadian authors concluded that the risk of PAH exposure from dispersed oil will be greatest where salinity is lowest—that is, in coastal waters.

Anderson et al (2009). Preliminary investigation of the effects of dispersed Prudhoe Bay Crude Oil on developing topsmelt embryos, Atherinops affinis. Again, Corexit 9500 increased the hydrocarbon concentrations in water-accommodated oil fractions and this effect appeared to adversely affect the survival of topsmelt embryos, according to researchers of the University of California, Davis.

Jung et al (2009). Biochemical changes in rockfish, Sebastes schlegeli, exposed to dispersed crude oil. Korean investigators confirmed that oil dispersants, like Corexit 9500, increase the exposure of fish to oil hydrocarbons.

Lin et al (2009). Characterization of the metabolic actions of crude versus dispersed oil in salmon smolts via NMR-based metabolomics. Taiwanese scientists concluded that "dispersant treatment significantly decreased the lethal potency of crude oil to salmon smolts," and described several variable metabolic effects that may be useful for monitoring sublethal actions of dispersed oil on fish.

Duarte et al (2010). Acute effects of chemically dispersed crude oil on gill ion regulation, plasma ion levels and haematological parameters in tambaqui (Colossoma macropomum). Investigators in the Amazon reported that chemically dispersed crude oil impairs gill function (ie, ion regulation) in tambaqui to a greater extent than untreated crude oil or Corexit 9500 alone.

Video still of burning Deepwater Horizon rig from YouTube.

06/07/10 addendum: BP's use of 1 million or so gallons of dispersant may also confound the cleanup effort in the Gulf. It's certainly to BP's advantage to obscure the scope of the spill, and Admiral Thad Allen of the Coast Guard says that dispersants "have succeeded at fragmenting one giant spill into 'hundreds of thousands' of mini spills," reports today's Politics Daily. BP's use of dispersant directly on the wellhead is also likely to prevent crude oil from rising to the surface, where it is easier to spot and clean up.  

Despite the fact that it's already taken on the musty smell of ancient history-ness, a 2-month-old report that atrial fibrillation (AF) increases the risk of dementia, including Alzheimer disease, merits review (primarily because I just got around to reviewing it).

Investigators of the Intermountain Heart Collaborative Study examined the potential nexus between the 5-year rates of AF and those of dementia in a prospective cohort of 36,025 older* Utahans (ergo, 90% white). In all cases, the development of AF was associated with a greater likelihood of developing dementia generally or any subtype thereof.

Dementia Type (n = 1535)	AF (n = 10,161)	No AF (n = 26,864)	Statistical Significance
Nonspecified (n = 688)	3.3	1.3	P < .0001
Alzheimer (n = 347)	1.5	0.7	P < .0001
Senile (n = 321)	1.6	0.6	P < .0001
Vascular (n = 179)	0.9	0.3	P < .0001

The authors also found that, in patients who developed AF and dementia, AF occurred before (or possibly simultaneously with) dementia, suggesting causality. AF also portended an earlier cognitive decline among patients with dementia and an increased risk of death. Associations were stronger in younger patients (eg, ≤70 years)—an observation that supports the associations, since both conditions are also independently linked to advancing age.**

Mechanisms by which AF may increase the risk of dementia include the obvious: the occurrence of small silent strokes that add to the burden of neurodegenerative brain pathology. (However, imaging studies—and specifically MR imaging studies—were not uniformly available to examine this likelihood with any gusto.) Another possibility: both conditions are associated with an underlying systemic cardiovascular process, like widespread cardiovascular inflammation.

* Mean age, 60.6 years ± 17.9

** AF affects up to 9% of the population by the age of 80 years. The risk of Alzheimer disease increases from 0.6% in persons aged 65-69 years to 8.4% in persons aged 85 years or older.

Photograph: Atrophied brain from person with AD from the National Institute on Alcohol Abuse and Alcoholism.

A first-of-its-kind investigational vaccine prevents breast cancer in mice, according to a press release from Cleveland Clinic researchers. Results of their preclinical studies, which were published online Saturday in the journal Nature, lay the foundation for clinical development of the vaccine in women.

The new vaccine differs from the most notable cancer-preventing vaccine, Merck's Gardasil, in that it targets an autoantigen, alpha-lactalbumin, not a cancer-associated virus, like HPV. Alpha-lactalbumin is a breast-specific protein that is overexpressed in most breast cancers and during lactation, but not in normal breast tissue of nonlactating women. In transgenic mouse models of breast cancer, disease was prevented in all inoculated animals, while unvaccinated mice developed cancer. The vaccine also stymied the growth of existing tumors.

The excitement of the study's lead investigator, Vincent Tuohy, PhD, is palpable: "If it works in humans the way it works in mice, this will be monumental. We could eliminate breast cancer," he says in the press release. Tuohy proposes that the vaccine would be appropriate for women older than 40, when pregnancy (and lactation) is less likely and the risk of breast cancer rises.

Human trials of the vaccine may begin within the year, reports the Clinic.

HPV = human papillomavirus.