Avandia (rosiglitazone) for Rat Alzheimer's Prophylaxis?!

I'm sure it's too late to buy stock in GlaxoSmithKline today, but it might be worth shorting it when disappointment sets in.

This FuturePundit article describes a rat study demonstrating that a "PPAR delta agonist" prevents progression of rat Alzheimer-disease like dementia. Sounds like they're talking about Rosiglitazone (Avandia), a Thiazolidindione class drug [1] that's alleged to work in diabetes by stimulating PPAR Delta receptors and thus enhancing intracellular glucose uptake.

The theory is that defects in insulin uptake into neurons play a role in the development of Alzheimer's disease, and the plaque and tangles we see are secondary processes arising in glucose starved brain cells. Improve uptake is alleged to slow disease progression.

I follow this domain casually, and this "type 3 neuro-diabetes" theory of Alzheimer's seems new to me, but of course being middle-aged I've probably forgotten about earlier readings.

Interesting for sure. In the unlikely event it actually worked GlaxoSmithKline would have hit the jackpot and the US debt bomb would be defused. Anyway, if it's really promising we'll know within the year.

[1] All of this stuff is pleasantly new to me, I'm getting far enough removed from medical practice I actually get to read about new physiology periodically. That's fun.

PS. I've always been suspicious that exercise really helped prevent Alzheimer's disease. It would fit with this though, if exercise had some global effect on insulin response and glucose uptake ...

PPS. All members of this class of medication cause weight gain ... Isn't that a deliciously nasty choice? You can be thin and demented, or hefty and not demented ...

Update 4/21/2010: Didn't do so well in human trials!

The Hall of Shame: 6 Democrats join

Histories Hall of Shame will include the Bush administration and all but two every GOP Senators in office today. It will also include six democrats. Five are anonymous drones, but it is astonishing how far Lieberman has fallen. This was a man who once had a reputation.

10/2/06: Correction: Lincoln Chafee opposed and Olympia Snowe did not vote. My apologies to these two.

What DeLong reads

DeLong responds to yet another decrepit journalist decrying the blogosphere. Those articles are both ridiculous and boring, I'm surprised DeLong has the energy to respond.

Along the way, he tells us what the reads. He rates the FT and the WSJ (news only, not the rabid and demented editorial pages) above the Economist, then runs through his blogs. Happily, I read at least half of them. DeLong is more avidly political than I, so my list leans more to science, technology and OS X than his. Still, I'm pleased to read at least half his favored set!

Now I need to start reading the Finacial Times ...

Guardians of the Enlightenment: Join SEFORA, promote the rationalist bill of rights

SEFORA is special interest group -- for scientists, engineers, and rationalists. Non-partisan, but it's obvious what's inspired them. My spouse and I have joined, even though we didn't make the illustrious first thousand. SEFORA (Scientists and Engineers for America) asks candidates to endorse a rationalist bill of rights -- and promotes candidates that sign up:

SEFORA

# Federal policy shall be made using the best available science and analysis both from within the government and from the rest of society.

# The federal government shall never intentionally publish false or misleading scientific information nor post such material on federal websites.

# Scientists conducting research or analysis with federal funding shall be free to discuss and publish the results of unclassified research after a reasonable period of review without fear of intimidation or adverse personnel action.

# Federal employees reporting what they believe to be manipulation of federal research and analysis for political or ideological reasons should be free to bring this information to the attention of the public and shall be protected from intimidation, retribution or adverse personnel action by effective enforcement of Whistle Blower laws.

# No scientists should fear reprisals or intimidation because of the results of their research.

# Appointments to federal scientific advisory committees shall be based on the candidate’s scientific qualifications, not political affiliation or ideology.

# The federal government shall not support any science education program that includes instruction in concepts that are derived from ideology and not science.

# While scientists may elect to withhold methods or studies that might be misused there shall be no federal prohibition on publication of basic research results. Decisions made about blocking the release of information about specific applied research and technologies for reasons of national security shall be the result of a transparent process. Classification decisions shall be made by trained professionals using a clear set of published criteria and there shall be a clear process for challenging decisions and a process for remedying mistakes and abuses of the classification system.

I can't imagine any Republican who could sign up for this, so SEFORA will inevitably be supporting Democrats.

We knew what was happening. The Fall of America, part VII.

If you’re a Chinese high school student of 2018 reading this as part of your essay on “how did 21st century America betray its ideals”, you should not believe that bunk about “regular Americans didn’t know what was happening”. If Americans didn’t “know” what was happening, it was because they chose not to look.

So don’t buy it. Guilty we are. We did not deserve the legacy we inherited. I hope your China will find a better path …

Antiterrorism Bill on Detainees, Geneva Conventions - Rushing Off a Cliff - New York Times,

….These are some of the bill’s biggest flaws:

Enemy Combatants: A dangerously broad definition of “illegal enemy combatant” in the bill could subject legal residents of the United States, as well as foreign citizens living in their own countries, to summary arrest and indefinite detention with no hope of appeal. The president could give the power to apply this label to anyone he wanted.

The Geneva Conventions: The bill would repudiate a half-century of international precedent by allowing Mr. Bush to decide on his own what abusive interrogation methods he considered permissible. And his decision could stay secret — there’s no requirement that this list be published.

Habeas Corpus: Detainees in U.S. military prisons would lose the basic right to challenge their imprisonment. These cases do not clog the courts, nor coddle terrorists. They simply give wrongly imprisoned people a chance to prove their innocence.

Judicial Review: The courts would have no power to review any aspect of this new system, except verdicts by military tribunals. The bill would limit appeals and bar legal actions based on the Geneva Conventions, directly or indirectly. All Mr. Bush would have to do to lock anyone up forever is to declare him an illegal combatant and not have a trial.

Coerced Evidence: Coerced evidence would be permissible if a judge considered it reliable — already a contradiction in terms — and relevant. Coercion is defined in a way that exempts anything done before the passage of the 2005 Detainee Treatment Act, and anything else Mr. Bush chooses.

Secret Evidence: American standards of justice prohibit evidence and testimony that is kept secret from the defendant, whether the accused is a corporate executive or a mass murderer. But the bill as redrafted by Mr. Cheney seems to weaken protections against such evidence.

Offenses: The definition of torture is unacceptably narrow, a virtual reprise of the deeply cynical memos the administration produced after 9/11. Rape and sexual assault are defined in a retrograde way that covers only forced or coerced activity, and not other forms of nonconsensual sex. The bill would effectively eliminate the idea of rape as torture.

There is not enough time to fix these bills, especially since the few Republicans who call themselves moderates have been whipped into line, and the Democratic leadership in the Senate seems to have misplaced its spine. If there was ever a moment for a filibuster, this was it.

We don’t blame the Democrats for being frightened. The Republicans have made it clear that they’ll use any opportunity to brand anyone who votes against this bill as a terrorist enabler. But Americans of the future won’t remember the pragmatic arguments for caving in to the administration.

They’ll know that in 2006, Congress passed a tyrannical law that will be ranked with the low points in American democracy, our generation’s version of the Alien and Sedition Acts.

Update 9/28: I bolded the part about the "spineless democrats", but on reflection this is a perfect Rovian trap. The man has no limits. If only we were better than Rove knows we are, but I fear his low opinion is justified. He's right that Americans will fall for his trap. Perhaps Democrats can do nothing but remain silent and vote against the bill.

Update 9/29/06: There's some "law" of the Internet that forbids comparisons to the Nazi era. Is there an appeal process by which one can obtain exemption from the law? I think we should invoke it. Really, though, I'm not sure the Nazis went in for this kind of Orwellian process. It's not even clearly Soviet. Maybe more tinpot dictatorship ...

FolioViews and ICD-9: a billion dollar tale never told

The more decrepit one becomes, the more "odd stories never told" one accumulates. This is one of those stories, a tale of a seemingly minor technical decision made 20 years ago -- with vast economic, social and scientific consequences that almost nobody recognizes today. It's a story about what happens when data moves into software and how proprietary data formats can shape a world -- unrecognized by anyone. It's a story of the mutability and immortality of software, and about data lock. It's boring, obscure, and I really don't know it all -- but I'm one of the few people that can guess some pieces of it. So, I'll tell it now, and hope corrections in the comments section.

In the 1980s a company named Folio Corporation produced a DOS information management software packaged called "FolioViews". They called it an InfoBase, and it was one of several semi-structured information managers that, in today's terms, were a cross between a database, a textbase, a content management system and and ontology editor. I was quite fond of that class of software, the most famous of which was probably Lotus Agenda. There were several similar, immensely powerful, and long forgotten applications on Mac Classic.

I remember that product because I used to write software reviews for the Journal of Family Practice in the 80s, and I wrote on FolioViews/DOS. (Back then JFP was still a scientific journal, not a throwaway.) FolioViews made a rocky transition to Windows 3.x, I wasn't as impressed with the Windows version, but, oddly enough, I have all the manuals. The software is gone.

That's where I thought the story ended, around 1993. It didn't though.

FolioViews was picked up by a number of governments, government contractors, publishers, CD-ROM vendors and legal firms around the world. It became a vertical market product. Somewhere along the way it was purchased by NextPage and buried (a search on their web site yields nothing about FolioViews). It probably lives a zombie existence there as a potential source of software patent litigation; many of these 1980s software packages implemented designs and ideas that were later patented independently, the old software can invalidate later patents.

Ahh, but what about the economic implications? That's a twisted tale. Somewhere along the line FolioViews became the standard means of editing and publishing ICD-9 and ICD-10, which started life as data sets used by epidemiologists and healthcare researchers. (For all I know it's used for CPT also, but that's murkier.) Here's the catch. ICD-9, in the US at least, became, by default, the only "standard" way to talk about diseases, disorders, and patient conditions. It became the flawed foundation of health care payment rules (along with CPT, DRG, etc etc), clinical decision support systems and EHRs (including one I helped create).

ICD-9 is the primary source of everything we know about what health issues Americans have, a fundamental constraint on the accuracy and capabilities of decision support systems, and a major obstacle to smarter/better healthcare systems. ICD-9 is also built and maintained in FolioViews -- but it's not distributed that way. It's distributed as a paper book (or a PDF, same difference). Fragments of ICD-9 are also published as database-like tables -- but that's only a fraction of it. The complete ICD-9, which exists only in FolioViews, is a rich and baroque mixture of classification, ontology and document -- mostly we don't have it.

Fundamentally, ICD-9 is locked away in the FolioViews Infobase somewhere in the offices of a federal contractor. My 1990s FolioViews manual tells me FolioViews can export wordprocessing documents or the proprietary "Folio Flat File" -- but that's it. Data Lock. Big time. FolioViews had its own peculiar and powerful way of managing data, and even if FolioViews had some sort of useable export facility it would be a non-trivial job to recreate it. It's not clear that there's an equivalent modern software environment that could recreate FolioViews. It might be easier to hire people to translate the WordPerfect output into a purpose-built environment -- except that really we need to dump ICD-9 and ICD-10 and do a SNOMED-derivedICD-11 (but that's another story).

So here we are, twenty years later, living with the consequences of a modest decision made when DOS was king. In a sense, a large portion of American healthcare is a captive of FolioViews, software who's fundamentals, including file formats and data structures, are lost in the mists of ancient computing. Something to think about the next time you wonder why software vendors struggle mightily to produce reliable and interoperable systems to support both clinical practice and financial obligations. The reasons may be more mysterious than you can imagine ...

References:

• A 2003 PDF marketing document about FolioViews
• The Fien Group
• Canadian Legal FolioViews InfoBase review
• QuickerWit database entry on FolioViews
  

Update 12/13/06: Interesting twist. A renamed descendant of Folio Views is used by the Mormon church (LDS) to distribute census/genealogy data. FolioViews was indeed a groundbreaking piece of software in its DOS incarnation, so unique it cannot be quite killed. Incidentally, I found this usenet discussion as a side-effect of how I track my usenet postings and follow-up. I add the semi-unique string 'jfaughnan' as metadata to my postings, and I have standard google query embedded in a my news page that retrieves postings. Since 'jfaughnan' appears in the URL for this blog, my standing query turned up the usenet posting referencing the blog. A very new age sequence of circumstances.

Answering the stupid question: what would YOU do in Iraq

Apparently in right wingnut circles and spineless journalists there's a call for "democrats" (meaning rationalists in this context) to come forward with their "solutions" to the Bush/GOP catastrophe in Iraq.
Shrillblog amplifies a Kevin Drum response. In brief, this is the GOP's Vietnam. There isn't a fix any longer, there are only less bad alternatives. The less bad alternatives are basically versions of retreat under fire, possibly with a continued presence in the north. It appears that Iran has won, the US lost an immense amount of money and thousands of lives, and the Iraqi people lost much more. If there are better options they will need to come from the Iraqi people and with an internationalized support rather than direct US support.

Politically, the sad truth is that the American people are not ready to hear this. A recent MN opinion poll show that less than 50% believe that the Iraq war was bungled. The numbers are a large increase from a year ago, but that's still not enough.

Given the impossibility of being frank, and the hopelessness of the GOP and the Bush administration, a non-suicidal rationalist politician will say relatively little. (Betty McCollum, our local representative, is rather honest -- but her seat is so safe I think the GOP opposition might be on the lam somewhere).

The irritating thing here is not the GOP ploy -- it's a perfectly reasonable ploy. It's the spineless journalists who play along with it ...

The Fall of Microsoft?

I've proclaimed the Fall of Microsoft before. The last time was OS/2 3.x, which was so clearly superior to both Win 98 and Win NT that it seemed sure to succeed. That's when I learned a lasting lesson about business strategy (including the Black Arts) vs. technical excellence. (I think of OS/2 every time my XP box slows to a grinding halt, tied up by its utterly lousy multitasking engine.)

Now I'll do it again. No, it's not Vista. Sure Vista will be a massive turkey, but we know about that. It's Word and Outlook/Exchange.

Word I've written about. It's fundamentally awful when used as anything but a sophisticated typewriter. Yeah, the help files and the grammar/spelling checking are good -- but that's about the end of it.

In some ways though, the Outlook/Exchange combination is even worse. Word I can work around the bugs, but Outlook/Exchange is just nasty. I got my latest jolt today when performance and reliability issues (sync errors with Exchange) forced me to switch to cached mode -- which is far faster. Except that my Sent folder had vanished, and I had several cryptic/worthless Outlook sync error messages that pointed to dead addresses.

No harm done of course. I keep my data in non-synched offline PST files and past experience had taught me to backup my Sent folderm, and anything else that's synched with the Exchange server, prior to switching modes. So I didn't really lose any data.

The point is though, that Outlook/Exchange and Word are two of Microsoft's core money spinners. Over the years they keep getting worse, not better. Microsoft can't seem to fix it. They've moved into a parasitic mode, siphoning the juices of the corporate customers who can't escape data lock. That mode will work for a long time, but it's a Faustian bargain. Once a corporation, or an organism, becomes a parasite, reversion to free range existence is very rare.

This time, the Fall may be for real ...

Brer Clinton: the rage returns

Incredibly, for it's surely suicidal, right wingnuts are allegedly trying to resurrect the shade of William Clinton. This is a bit like having your enemy sick a dog on you -- except its your dog. Maybe we should call him Brer Bill 'Briar Patch' Clinton.

Or perhaps it's not incredible. Maybe it's 'suicide by cop'. The wingnuts know they're destroying the nation, so they're asking us to stop them before they kill again.

Not that I'm a Clinton fan. Through some terrible strain of self-destructive arrogance he gave his enemies the perfect weapon, and they used it to put Vlad Bush in office. That was a historic failure. Still, to remember a competent president with a competent administration ...

David Brin, expanding on Russ Daggatt, provides a minor demonstration of what a potent weapon the wingnuts have handed the forces of reason.

Grief

A mother's son dies at war. She tells the story of her grief. It is in grief that we are most akin.

System failure: No Contact orders in Minnesota

Another story of a women killed by boyfriend/husband. The sad story didn't suggest much that could be done differently, until near the very end ...

Two slayings renew calls for vigilance

... The Minnesota Legislature this year increased the penalties for violating no-contact orders, making repeated violations a gross misdemeanor. Kluz said that Lee is the 15th woman to be killed in Minnesota this year in a domestic violence situation.

Huh? A gross misdemeanor? Repeat required? That was an increase?!

Why is it that the noteworthy part of any article is always about 3/4 of the way to the end?

Most of the time there doesn't seem to be any obvious response to tragedies like this one, but the "gross misdemeanor" suggests an obvious fix. Maybe a GM at the judge's discretion on the first violation, but otherwise a felony and arrest.

Not your father's immunology - and odd implications thereof

Nor your father's definition of the human.

In the past few weeks we've read of toxic viral payloads in sometimes commensal bacteria, we're read of viral infections that are a critical part of placental formation in at least one mammal, and we've read about T-Reg cells, such as:

• mice without T-Regs developed a fatal inflammatory bowel disease -- not due to autoimmune attacks on bowel cells, but rather due to immune attacks on normally tolerated bowel bacteria
• the best response (mice again) to some parasite infections is to keep a few of the buggers around so the immune system stays tuned. T-Regs help with that.
• T-reg activity may increase in pregnancy in some women to manage tolerance of the foreign fetus
  

This must be starting to at least make its way into medical school infectious disease lectures, and of course there are lots of implications for a range of auto-immune diseases (Is ulcerative colitis an auto-immune attack on GI bacteria, why do parasite infections seem to suppress UC, what's the relationship between cutaneous T-Reg cells, vitamin D, sunlight exposure and multiple sclerosis, etc).

Eventually we'll change the way we treat infections, and probably abandon the idea (still persisting) that patients need to take all their antibiotics to kill all the pathogens. We may eventually move to the long mooted concept that managing infections is about managing the "human" (meaning nuclear DNA, mitochondrial DNA, bacterial DNA, Viral DNA, a few prionic forms and lord knows what else) superorganism and its ecology rather than the traditional view of an attacking "pathogen".

Hmmm. What could this approach imply about managing terrorism?

Why do humans lose their childhood memories?

One of the curiousities of human memory is that childhood, for most people, is largely lost. I think I'm not atypical in having a few memories I suspect are genuine, another set based on what I've been told, and mostly no memory at all.

The assymetry between parent and child is one of the more poignant aspects of parenting; one party remembers much of a rather important relationship, the other remembers little.

Why do adults not retain childhood memories? Is there an adaptive advantage to forgetting, or is it simply a side-effect of the way the human brain develops?

Protecte expensive checked gear, fly with a gun

Well, ok, a starter pistol. The pistol means your checked gear qualifies for weapons handling. It's safe from theft and abuse, and it'll arrive with you.

If we end up having to check our laptops and cellphones starter pistols will be commonplace on planes (well, in the locked secured gun case actually).

Safari must die.

I love Safari. I love the elegance, the performance, the efficiency, the security, stability and features of Safari. I love the Cocoa services and the beautiful UI and the excellent printing. It's a great product from a great team.

Safari must die.

I've known that for months, years maybe. Still, I held out hope. Hope died when I created a Gmail account for my wife last night. There's a button to click to test username availability; in Firefox it updates the page, in Safari it does nothing. I became so frustrated by the process I quit and did it using Firefox.

Safari was the right choice in its time. Back in the day was no way Apple could rely on IE, and Phoenix (later Firefox) was either unborn or unproven. Apple was right to start work on their own browser. Then came Google, and Ajax and, painfully, slowly, widespread support of Firefox as well as IE.

Now Safari is wrong. Being smaller, faster, better, more standards compliant is not enough. The best man doesn't always win the race. Safari cannot contend against Google, Yahoo, and every up and coming Web 2.0 solution. Most of all, Safari cannot defeat Google.

Gates, in his robber-baron heyday, had one great gift even I admired. He would shoot the horse he'd ridden when it faltered. He shot OS/2 (in the back), he shot pre-web MSN, he shot a lot of things. When he stopped shooting Microsoft went into decline.

Jobs shot the Newton (in the forehead). He can shoot Safari.

Maybe keep Webkit for Apple products, but use Firefox's Gecko engine and identify to websites as Mozilla/Firefox. We've got Camino and soon Firefox/Cocoa; Apple should work to make Apple's branded browser the best Firefox there is. Make it beautiful, make the printing work, make it Rendezvous and Keychain and spotlight and Cocoa and Webkit and Photocasting and Address Book friendly. Above all, make it Firefox/Mac -- even if you still call it "Safari".

Death to Safari. Long live Safari/F.