September 2011 Archives
Suffice it to say that the Hitchcockian thriller Anthony Zimmer (2005) works where its American remake, The Tourist (2010), does not, because the story's essential Everyman—you know, the pedestrian guy caught up in extraordinary circumstances—is played by a passably attractive, unknown* actor and not Johnny Depp—who can never be an Everyman. The former movie, a French product, also prevails because of some unexplainable tolerance we, as American viewers, have for unbelievable premises in foreign films—which we would otherwise laugh at in Hollywood vehicles. Or maybe, in the case of Anthony Zimmer versus The Tourist, the actors, or the execution, or just all of it is simply better in the former picture.
* That is, unknown to most American viewers. The Everyman actor in Anthony Zimmer, Yvan Attal, also has this curious right
By way of Nature Medicine's blog, A Spoonful of Medicine:Now 4 clinical trials with human embryonic stem cells (hESCs) have been launched; although 3 of these trials are from the same company (Advanced Cell Technology [ACT]) with the same hESCs (retinal pigment cells) for similar diseases (Stardgardt's disease, an inherited form of macular degeneration, and dry age-related macular degeneration [AMD]).
Here's the timeline (derived, in part, from a previous post):
1. In July 2010, the FDA lifted its regulatory hold* on Geron's clinical trial program for hESC-derived oligodendrocytes in subacute spinal-cord injury. The company announced this week that it has now enrolled 4 patients in the study. The "landmark" trial was featured in last week's SF Chronicle. The first unidentified enrollee was profiled by the Washington Post in April.
2. In November 2010, the FDA approved ACT's first trial of retinal pigment cells in patients with Stardgardt's disease (which affects only about 30,000 Americans but is an important disease model for dry AMD—which is much, much more prevalent). The first enrollee was treated in July at UCLA.
3. In January 2011, the FDA gave another nod to ACT to begin its hESC trial in patients with dry AMD. The first enrollee was treated in July at UCLA.
4. The UK Medicine and Healthcare products Regulatory Agency just gave approval to ACT to also conduct a trial of its retinal pigment cells in patients with Stargardt's disease at Moorfields Eye Hospital in London.
The Nature blog adds that ACT is in "late-stage talks" with other global regulators to conduct similar trials elsewhere around the world. News of these advances in clinical development of hESC treatment appears to have already been built into both companies' share prices—which are in the penny range.
* The hold was originally placed owing to preclinical concerns about the development of epithelial cysts at the site of injury.
Transverse section of the thoracic spinal cord from Gray's Anatomy (1918).
Seventy-four years after the US Elixir of Sulfanilamide tragedy, we're still trying to figure out exactly how diethylene glycol (DEG) damages the kidneys. And 74 years later, we are, in fact, closer to understanding the solvent's toxicity, thanks to continuing investigative work at the Louisiana State University Health Sciences Center in Shreveport. In July and August, researchers from the Department of Pharmacology, Toxicology, and Neuroscience published important sequential studies on DEG toxicity (for access to these articles, go to Besenhofer et al and Landry et al).What has been known is that DEG becomes toxic after it is metabolized to 2-hydroxyethyoxyacetic acid (HEAA) and diglycolic acid (DGA) and that fomepizole, a DEG antidote, inhibits this metabolism. HEAA has generally been fingered as the primary toxicant of DEG poisoning and the cause of associated kidney dysfunction. But a new animal study and in-vitro work suggest that DGA is an important instigator of renal failure (specifically proximal tubular necrosis) in DEG poisoning.
By administering various doses of DEG, with or without fomepizole, to Wister rats, Besenhofer et al determined that the primary DEG metabolite in blood is HEAA after high DEG doses, and that HEAA is probably responsible for the anion gap and low bicarbonate levels seen in DEG poisoning. However, concentrations of HEAA and DGA were similar in renal and hepatic tissues of rats at 48 hours, with a 100-fold "concentrative uptake of DGA" by the kidney. Renal concentrations of both HEAA and DGA correlated with kidney damage, indicating that DGA (as well as HEAA) is a significant contributor to renal injury in DEG poisoning (at least in rats). Importantly fomepizole blocked the formation of both HEAA and DGA, thereby inhibiting renal toxicity.
These animal data are supported by an in-vitro experiment from Landry et al, who incubated human proximal tubule cells with DEG, HEAA, and/or DGA in culture. What the researchers found, to their relative surprise, was that the DEG metabolite HEAA did not produce cell death. However, DGA produced dose-dependent cell necrosis. And on the basis of additional experiments, Landry et al suggested that DGA uptake and its renal accumulation is probably mediated by a cell-based transporter mechanism.
There's a lot of Facebook-generated schadenfreude in the aftermath of Michael Vick's concussion during yesterday's game between the Philadelphia Eagles (Vick's current team for you non-football fans) and the Atlanta Falcons (Vick's former football team). And while it's certainly nobody's duty to cheer for Vick or wish him well or even forgive him for his notorious animal cruelty, to celebrate his concussion as some kind of karmic payback is both inappropriate and nonsensical in a game where everyone (regardless of their off-the-field morals) is at risk. In a world of bizarre happenstance (of which American football is an important microcosm), narcissistic assholes can finish first,* and shit happens to decent people. Just ask Mike Utley.
As far as Vick returning to play, I suspect it will be soon, given a review of the videotape footage. It was a lateral helmet-on-helmet blow (with his own teammate!), followed by a bit of quick head torquing to the left—the latter of which is what probably rang Vick's bell.
* And given the bounty of narcissism in the NFL, it is probable that narcissistic assholes will finish first.
As far as Vick returning to play, I suspect it will be soon, given a review of the videotape footage. It was a lateral helmet-on-helmet blow (with his own teammate!), followed by a bit of quick head torquing to the left—the latter of which is what probably rang Vick's bell.
* And given the bounty of narcissism in the NFL, it is probable that narcissistic assholes will finish first.
The Big Combo (1955) is a B-grade noir thriller that broaches grade-A status, primarily owing to the sinister charisma of Richard Conte, as ruthless mob boss Mr. Brown. There's also the bland charm of Cornel Wilde (as Brown's cop nemesis), a blindingly platinum Jean Wallace (as Brown's seriously mixed-up girlfriend), and a young Lee Van Cleef and an even younger Earl Holliman—who pair up to form Brown's subtly (or not so subtly) homosexual thug-enforcers.A number of online references credit The Big Combo with informing elements of Quentin Tarantino's Reservoir Dogs—specifically Tarantino's use of color surnames and the "ear-torture" scene with Michael Madsen (I'm not sure how else to describe it). There are identifiable elements in The Big Combo that Tarantino may have ripped-off or embellished or otherwise paid homage to (pick your diplomatic or not-so-diplomatic descriptor), but the list of his film influences is miles long. And The Big Combo is sufficiently entertaining, without a contemporary reference to Tarantino or his work.
Blanche Fury (1947): As deliciously melodramatic as the title suggests, but very thoughtfully composed by DPs Guy Green and Geoffrey Unsworth and director Marc Allegret. In fact, the look and feel of this richly saturated film implies input from "The Archers," aka Michael Powell and Emeric Pressburger, and a quick check shows that Unsworth worked as a cameraman on several Powell-Pressburger projects, before rising to the status of cinematographer.The breathtaking story, reportedly based on a real-life Victorian-era scandal, concerns the ambitions of a high-minded, parentless young woman, Blanche (Valerie Hobson), who is invited by her uncle to work as a governess for the heir of his grand estate. At odds with the estate's owners and, initially, Blanche herself, is the estate's hunky steward and horse lover (Stewart Granger), the illegitimate son of the home's original owner, Simon Fury. Conflicts arise over control over the estate—conflicts which erupt in all the good stuff: lust, murder, and betrayal, as well as the ultimate fulfillment of family legend (through the specter of the Furies' Barbary ape...don't ask).
Amyloid-related imaging abnormalities of edema/effusion, or ARIA-E.
[Insert snarky X-Files/Roswell quip here.]
It's what Alzheimer experts are now calling the brain edema associated with the administration of Pfizer/JNJ's bapineuzumab, and other investigational anti-amyloid compounds, according to an article in last week's Neurology Today. The write-up also highlighted that ARIA-E occurs more frequently than previously thought—in about 17% of bapineuzumab-treated patients (36/210). But about three quarters of these re-examined cases, detected via MRI, were asymptomatic. Risks for the potentially adverse phenomenon were APOE4 homozygosity, a known risk for Alzheimer disease, and a higher dosage of bapineuzumab (more amyloid, more drug).
The Neurology Today report also described the results of a bapineuzumab extension trial, in which the rate (or risk) of ARIA-E declined after the third dose of medication. The lead investigator, Stephen Salloway, presented an unusually cheery picture of the drug's safety (and, by association, brain edema): "The majority of cases of ARIA are asymptomatic and almost all resolve by holding the dose," he was quoted as saying, along with, "Overall, bapineuzumab was generally well tolerated and adverse effects tended to be mild to moderate. Importantly, there were no new safety signals with exposure over five years of treatment." But there were questions among interviewed experts about the high drop-out rate of patients in bapineuzumab trials—a fact suggesting that the drug is not easily tolerated (or is ineffective, or both).*
Image from alzforum.org (reproduced in Neurology Today) showing development and remission of brain edema, aka ARIA-E, on MR images in bapineuzumab-treated patients. Credit given to Stephen Salloway and Reisa Sperling.
The question of bapineuzumab's safety is irrelevant if the drug doesn't improve cognition—which it doesn't seem to, at least not across the board in established Alzheimer disease. Salloway suggested, in an end-quote, that bapineuzumab might have a niche in earlier stages of dementia. But the general subtext of the article (or that of any transmission attempting to mitigate safety concerns about a marginally beneficial compound) is THIS DRUG IS A DEAD DUCK. And the scary generalization from this all-caps inference (and see the N.B. for support) is that all anti-amyloid compounds for Alzheimer disease are in serious jeopardy.
* The results of both of these described studies were presented in July at the Alzheimer’s Association International Conference in Paris.
N.B.—The cause of ARIA-E is unknown but has been entertained frequently at this blog and elsewhere. In the NT article, Dr. Reisa Sperling, suggested that the phenomenon is caused by "transient increases in vascular permeability—leaky vessels—due to mobilization of amyloid from plaque and into vessels and clearance of vascular amyloid." She added further, "I do think the leaky vessel problem will affect the whole class [of amyloid-modifying drugs], but it's manageable." That's one helluva qualified endorsement.
[Insert snarky X-Files/Roswell quip here.]
It's what Alzheimer experts are now calling the brain edema associated with the administration of Pfizer/JNJ's bapineuzumab, and other investigational anti-amyloid compounds, according to an article in last week's Neurology Today. The write-up also highlighted that ARIA-E occurs more frequently than previously thought—in about 17% of bapineuzumab-treated patients (36/210). But about three quarters of these re-examined cases, detected via MRI, were asymptomatic. Risks for the potentially adverse phenomenon were APOE4 homozygosity, a known risk for Alzheimer disease, and a higher dosage of bapineuzumab (more amyloid, more drug).
The Neurology Today report also described the results of a bapineuzumab extension trial, in which the rate (or risk) of ARIA-E declined after the third dose of medication. The lead investigator, Stephen Salloway, presented an unusually cheery picture of the drug's safety (and, by association, brain edema): "The majority of cases of ARIA are asymptomatic and almost all resolve by holding the dose," he was quoted as saying, along with, "Overall, bapineuzumab was generally well tolerated and adverse effects tended to be mild to moderate. Importantly, there were no new safety signals with exposure over five years of treatment." But there were questions among interviewed experts about the high drop-out rate of patients in bapineuzumab trials—a fact suggesting that the drug is not easily tolerated (or is ineffective, or both).*
Image from alzforum.org (reproduced in Neurology Today) showing development and remission of brain edema, aka ARIA-E, on MR images in bapineuzumab-treated patients. Credit given to Stephen Salloway and Reisa Sperling.
The question of bapineuzumab's safety is irrelevant if the drug doesn't improve cognition—which it doesn't seem to, at least not across the board in established Alzheimer disease. Salloway suggested, in an end-quote, that bapineuzumab might have a niche in earlier stages of dementia. But the general subtext of the article (or that of any transmission attempting to mitigate safety concerns about a marginally beneficial compound) is THIS DRUG IS A DEAD DUCK. And the scary generalization from this all-caps inference (and see the N.B. for support) is that all anti-amyloid compounds for Alzheimer disease are in serious jeopardy.
* The results of both of these described studies were presented in July at the Alzheimer’s Association International Conference in Paris.
N.B.—The cause of ARIA-E is unknown but has been entertained frequently at this blog and elsewhere. In the NT article, Dr. Reisa Sperling, suggested that the phenomenon is caused by "transient increases in vascular permeability—leaky vessels—due to mobilization of amyloid from plaque and into vessels and clearance of vascular amyloid." She added further, "I do think the leaky vessel problem will affect the whole class [of amyloid-modifying drugs], but it's manageable." That's one helluva qualified endorsement.
The Big Clock (1948): In a heated argument, a dictatorial, time-obsessed publisher (Charles Laughton) kills his girlfriend and then tries to pin the murder on her unknown date for the evening—who just so happens to be his overworked crime editor (Ray Milland). This black-and-white noir pick is notable for the commendable execution of rapid-fire, overlapping dialog—the kind that might be expected in a earlier Howard Hawks or much later Robert Altman movie. Ray Milland's delivery, in particular, is effortless.With Maureen O'Sullivan as the editor's put-upon wife; Harry (Henry) Morgan as the publisher's thug-enforcer; and Elsa Lanchestor (Laughton's wife in real life) as a ditsy, comical artist.
