June 2009 Archives

Middlemarch (1994): If you can't get through the book (I'm talking to you, English majors), then watch the BBC mini-series—a highly faithful adaptation of George Eliot's novel (written by Andrew Davies of Pride and Prejudice fame).

Dorothea Brooke believes that life's purpose can be found in marriage to a fussy academic, the elderly Reverend Casabaun, while she cultivates a sympathic friendship with his disinherited cousin, the fetching Will Ladislaw (Rufus Sewell). The parallel lives of two other couples (the earnest Dr. Lydgate and his spoiled wife; a ne'er-do-well aristocrat and his long-suffering country sweetheart) are intertwined for the obligatory contrast and comparison.

Delivering chemotherapy to brain tumors is particularly challenging because of the blood-brain barrier (BBB), the collection of tight junctions between endothelial cells in cerebral blood vessels. When intact, these protective junctions prevent the passage of a number of substances—including chemotherapeutic molecules—from the systemic circulation into the brain tumor bed. The key to effective, targeted therapy of brain tumors is to 1) selectively disrupt the BBB to allow the entry of cancer-killing drugs and then 2) reestablish the BBB so that chemotherapeutic agents are retained within the tumor bed.

Biomed engineers at Duke have constructed a prototype of an intravascular catheter, which can deliver BBB-busting hyperthermia* and provide real-time 3D imaging of brain tumors. The thin, flexible catheter is intended to be snaked through the internal jugular vein (which obviates the need for invasive cranial surgery) and manipulated into the dural venous sinuses. The investigators' proof-of-concept experiments, performed in dogs, was published in this month's issue of Ultrasonic Imaging.

The investigators concluded that their next-generation device must be smaller and more flexible than the prototype, to negotiate the curves of the cerebral vasculature. The long-term plan for the catheter is to obtain fluoroscopic-guided access to brain tumors through the venous sinuses, administer BBB-disrupting heat, which would then trigger the release of chemotherapeutic agents to the tumor bed.

* A temperature rise of approximately 5 degrees C.

Depiction of dural sinus system from Gray's Anatomy.

Thanks to vigilant laboratory testing (at least in part) for H1N1, the number of swine flu cases worldwide has increased by nearly 90% in the last 11 days.

The World Health Organization reports a total of 52,160 cases of H1N1 disease (up from 27,727) in 99 countries (up from 74), with a large bulk of new cases reported in the United States (3594) and Chile (1190). The number of deaths stands at 231 (up from 141), for an overall mortality rate of 0.44%.* Swine-flu-related deaths have now affected 11 countries.

Country	Cases	Deaths
Australia	2436	1
Costa Rica	149	1
Dominican Republic	93	1
Guatemala	208	1
United Kingdom	2506	1
Colombia	71	2
Chile	4315	4
Argentina	1010	7
Canada	5710	13
United States	21,449	87
Mexico	7624	113

* Which is slightly less than the previously calculated mortality rate of 0.5%. 

The Damned Don't Cry! (1950): A 40-something Joan Crawford still rocks a body as a ruthless, faux socialite. Nothing—and I mean nothing—detracts from Crawford, thanks mostly to a B-movie supporting cast. Still it's a brave star who's willing to receive an on-camera beating from one of those second-string actors.

When it debuted in 1991, Billy Bathgate—based on the novel by E. L. Doctorow—was generally faintly praised (Vincent Canby) or soundly panned (Roger Ebert). Perhaps the lukewarm reception had something to do with overblown expectations and rumors of production troubles on director Robert Benton's set. But the film is notably sustained by a young Loren Dean as the titular street kid. Dean (Mumford, "Bones"), who never quite developed the career that this movie would have forecasted, strikes a nice reactive-proactive balance as the protege of gangster Dutch Schulz (Dustin Hoffman) and the protector of his boss's mistress (Nicole Kidman).

While drugmakers create a vaccine against the currently pandemic swine-flu virus (H1N1 S-OIV 2009), neurologists are advised to monitor the safety of such inoculations, should they be implemented. The caution is founded on a higher-than-expected rate of Guillain-Barre syndrome (GBS) in vaccine recipients during the 1976 immunization campaign against swine flu, reports Neurology Today.

More than 30 years ago, soldiers at Fort Dix, New Jersey, experienced an outbreak of swine flu. Fearing a recurrence of the 1918 influenza epidemic, US government officials implemented a widespread vaccine campaign in which more than 40 million Americans were immunized. However, the drive was aborted after 3 months when reports of GBS in vaccinated individuals emerged. Although GBS surveillance data for the time period are sketchy, evidence suggests that vaccine recipients were significantly more likely to develop the condition within several weeks after inoculation.*

At present, leading neurologists do not anticipate a government-led vaccine campaign against H1N1 S-OIV 2009, given the low mortality rate (0.5%) of the current swine-flu pandemic and the historical risk of GBS with inoculation.

* The typical background rate of GBS is about 1.5 per 100,000 individuals.

After forecasting a swine flu pandemic for a good month or so, the World Health Organization (WHO) has now given the H1N1 virus official level 6 status. What this means is nothing particularly new: A pandemic occurs when a novel influenza virus causes several, simultaneous epidemics worldwide, according to WHO. In the case of H1N1, the virus is spreading in at least 2 regions, reports the BBC; specifically, rising numbers of cases are being observed in the United Kingdom, Australia, Japan, and Chile.

As of yesterday, 74 countries had reported a total of 27,727 cases of swine flu, the majority of which have occurred in Mexico and the United States. But the virus has caused only 141 deaths, for an overall mortality rate of about one half of 1%.

Country	Cases	Deaths	Mortality Rate, %
Mexico	5717	106	1.9
United States	13,217	27	0.2
Canada	2446	4	0.2
Chile	1694	2	0.1
Dominican Republic	91	1	1.1
Total	23,258	141	0.6

Swine flu in humans first emerged in Mexico last April; although Oxford scientists estimate that the H1N1 virus could have been transmitted from pigs to people as early as August of last year, writes the AP.

The comedy and gravity of global espionage are explored in Our Man in Havana (1959), Carol Reed's adaption of the Graham Greene novel. A humble vacuum cleaner salesman in prerevolutionary Cuba, Jim Wormold (Alec Guinness) adds to his income by exploiting the pyramid structure of British intelligence. With its uneven tone, the movie's never quite what it could be; but Greene shows off a blithe cynicism in the story's fantasy-to-reality turnabout. With Burl Ives, Ernie Kovacs, and a-not-particularly-well-cast Maureen O'Hara.

Although the gene responsible for Huntington's disease (HD), a dominantly inherited neurodegenerative disorder, was detected more than 10 years ago, the mechanism of its brain-specific pathology has remained elusive. Now investigators at Johns Hopkins reveal, in an elegant series of cell-line experiments, how the genetic disorder preferentially affects the corpus striatum, despite the fact that the mutant protein is found in cells throughout the body. Their findings are available in the journal Science. 

But first some necessary background...

HD is characterized by the expansion of a 3-nucleotide repeat section in the gene that encodes for the protein huntingtin (Htt). Neurotoxicity in HD is related to the cellular solubility of the mutant form of Htt, or mHtt. Protein aggregates of mHtt appear to be neuroprotective, whereas soluble mHtt is associated with cytotoxicity. It is also important to note that the mutant protein is sumoylated—meaning that it is covalently bound to a small ubiquitin-like modifier (SUMO)—which reduces neuroprotective protein aggregation.

Investigating Rhes protein...

The Hopkins investigators chose to examine the relationship between mHtt and the protein Rhes, because the latter is very selectively expressed in the corpus striatum. By using striatal (mouse) cell lines that overexpressed Rhes or that were Rhes deficient, investigators determined that Rhes binds "robustly" to endogenous Htt—but much more so to mHtt than to wild-type Htt. Moreover, overexpression of Rhes, in particular, profoundly affected the survival of cells that expressed mHtt (but not those expressing wild-type Htt). Specifically they found that the cytotoxic effect of overexpressed Rhes was concentration dependent. And in a final set of experiments, investigators determined that overexpressed Rhes augments the sumoylation of mHtt, thereby causing the disaggregation of mHtt and cell death.

So...it appears that striatal Rhes promotes localized neuronal degeneration in HD by enhancing the sumoylation of mHtt. Drugs that block the interaction between Rhes and mHtt may have therapeutic potential in HD, the authors conclude.

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

In the National Review, conservative journalist Mary Claire Kendall questions the influence that the private Josiah Macy, Jr, Foundation has on the nonprofit Institute of Medicine (IOM). At stake, evidently, is the Foundation's interest in removing all sources of commercial funding for physicians' continuing medical education (CME)—funding which is argued (without supporting evidence) to adversely influence physician practice and, consequently, patient outcomes.

Kendall highlights the possibility that the Foundation itself, a private philanthropy established by the descendant of merchant seamen, is unduly influencing the IOM by funding various IOM committees that are concerned with medical education. The possibility that the Foundation is buying off the IOM to push its own predetermined, but unfounded, idea that commercial support of CME is bad is implicit in the Foundation's support of the IOM's Conflict of Interest Committee ($75,000) and the IOM's upcoming ad-hoc Committee on Planning a Continuing Health Care Professional Education Institute ($428,177). The ad-hoc committee, Kendall notes, will include representatives from the Association of American Medical Colleges and the Institute of Health Policy—both of which have received a cumulative $738,000 from the Macy Foundation.

"What is damning is that they [the Macy Foundation] are dedicated to pushing private industry out of CME in the name of an entirely self-serving definition of 'bias' that reaches predetermined conclusions," Kendall writes. What is also damning and, moreover, ironic is the fact that the IOM has failed to provide detailed evidence of its funding sources, despite a united call for transparency in CME to uncover possible conflicts of interest.

HT: Policy and Medicine

Citalopram (Celexa; Forest), the model SSRI, is no better than placebo for improving general behavior and reducing repetitive behaviors in children with autism or related disorders.* This conclusion is based on a multicenter, NIH-sponsored 12-week trial of the antidepressant in 149 pediatric volunteers (age range, 5-17 years; mean age, 9.4 years) with at least moderate disease. Results of the study were published in the June issue of the Archives of General Psychiatry.

Rates of general improvement (measured with the Clinical Global Impressions, Improvement subscale) were similar with citalopram (32.9%) and placebo (34.2%), and scores for OCD-like behaviors were similarly reduced with either treatment. Adverse event data suggest that citalopram is more likely to be associated with undesirable behaviors—like impulsiveness, decreased concentration, hyperactivity, stereotypy, and insomnia.

The mean dosage of citalopram administered in the study was 16.5 mg/d, with a maximum dosage of 20 mg/d. (The initial starting dosage in adults is 20 mg/d, which is typically increased to a maintenance dosage of 40 mg/d.) Citalopram has not been FDA approved for use in the pediatric population, and the label includes the general "black box" for SSRIs, which warns of suicide risk in minors.

NIH = National Institutes of Health; OCD = obsessive-compulsive disorder; SSRI = selective serotonin-reuptake inhibitor.

* Including Asperger disorder and unspecified pervasive development disorder.

Another study, published in the latest issue of Neurology, supports the use of statin therapy* after a first-time ischemic stroke to reduce the risk of recurrent stroke. Moreover, data support the use of post-stroke statin therapy to reduce the risk of long-term mortality.

In a retrospective, observational study of the Athenian Stroke Registry (N = 794), the risk of a second stroke was reduced by 46% (absolute risk reduction, 16.3% - 7.6% = 8.8%; P = .002) with statin therapy during a 10-year period.** The risk of death during follow-up was also significantly reduced with the use of post-stroke statins: 11 deaths among statin-treated patients vs 213 among non-statin-treated patients. These data remained consistent after adjustments were made for blood-pressure control and 12-month lipid levels—suggesting that statin-related neuroprotection is achieved independently of lipid control. (Other independent predictors of mortality after a first-time stroke included a history of coronary and peripheral artery disease, atrial fibrillation, heart failure, and stroke severity.)

In most cases, statin therapy was continued after the first stroke; although some patients initiated statin therapy after their first stroke. Medication adherence rates were estimated at about 70%. Subanalyses of data on the basis of statin type or dosage were not performed owing to their limited statistical power.

Approximately 30% of the 700,000 strokes that occur each year in Americans are recurrent strokes.

* Simvastatin 10-40 mg/d (34%); atorvastatin 10-40 mg/d (26%); pravastatin 20-40 mg/d (22%); or fluvastatin 40-80 mg/d (18%).

** There was no significant difference in the time of second stroke in the 2 treatment groups: 21 vs 19 months.

CT brain image showing massive right hemispheric infarct with midline shift; from Wikipedia.