Gabapentin, Alzheimer's, fake science, and the National Library of Medicine

Gabapentin was developed as a focal seizure medication and has been found to be effective for neuropathic pain syndromes in diabetic neuropathy and postherpetic neuralgia.

Gabapentin is also widely used in America for a variety of pain syndromes including sciatica. The well done wikipedia article has a good overview of what we know about these uses. In general the benefits of gabapentin for many pain syndromes are not clear; as usual more research is needed. The evidence for nerve healing benefit is weak. I am confident we would almost never use gabapentin for chronic sciatic pain if opioids were not cursed by tolerance, dependence, dosage escalation, respiratory suppression, and diversion to recreational use. Without opioids we have acetominophen and ibuprofen and not much else.

In addition to doubts about efficacy some patients report significant persistent side-effects of somnolence and fatigue, sleep disruption, and a withdrawal syndrome that resembles benzodiazepine withdrawal. In my own life I've taken gabapentin for months for spinal stenosis* and I have not experienced either obvious benefits or problems, but I believe reports that some people have unpleasant withdrawal syndromes.

The combination of unclear benefit outside of diabetic neuropathy and idiosyncratic withdrawal syndromes would be enough to make gabapentin unpopular. Beyond that there's a significant group of chronic pain patients who feel they would do much better on opioids; they believe they are getting a defective substitute because of an excessive reaction to physician overuse of opioids in the 1990s. It's easy to see why gabapentin is not loved.

Which brings me to the point of this post. I have seen claims from the community of chronic pain patients who have legitimate suspicion about the value of gabapentin that "gabapentin causes Alzheimer's" based on an article published out of Taiwan - The association between Gabapentin or Pregabalin use and the risk of dementia: an analysis of the National Health Insurance Research Database in Taiwan. The authors conclude "Patients treated with gabapentin or pregabalin had an increased risk of dementia. Therefore, these drugs should be used with caution, particularly in susceptible individuals".

Long ago I was an academic family physician who did the tedious work of evaluating research publications. Back then I'd have had to point out that this is an outrageous conclusion to draw from data mining a health insurance data set. If all the right boxes were checked and procedures followed the most one could conclude from this type of study is that maybe there's some signal that should be researched in animal models and maybe one day in a range of increasingly expensive and complex studies. In those days that conclusion in an abstract would be the end of my interest in the publication.

Sadly, these days, we don't even have to look that deeply. We start with looking at where an article was published. Front Pharmacol is a pay-to-publish eJournal. That's why you can read their articles without paying - the authors paid for you to read it.

You can find the publishers of this article in www.frontiersin.org and read about them in a wikipedia article on Frontiers Media. Nobody, absolutely nobody, would publish in Frontiers if they could get through peer review anywhere else. Derek Lowe is the most publicly accessible writer about this class of publication, you can read two of his recent pieces here and here. The garbage output of these fake journals to qualify for academic promotion is so bad that even PRC academic centers are turning against them: "... January 2023, Zhejiang Gongshang University (浙江工商大学) in Hangzhou, China, announced it would no longer include articles published in Hindawi, MDPI, and Frontiers journals when evaluating researcher performance."

In short, in our broken modern world, we don't have to dig into the particulars of this article. We don't have to even look at the absurd abstract conclusion. All we have to know is that the authors of this article paid to get it published by an enterprise that is almost certainly fraudulent.

It's not impossible that any substance that interacts with the human body might in some way increase the risks of Alzheimer's dementia. That, I suppose, includes cosmic rays. But there's no particular reason to suspect gabapentin more than other medications. This is a bullshit result published in a bullshit journal.

So why, a reasonable person would say, was this crap indexed by the National Library of Medicine, a division of the National Institute of Health funded by the American tax payer? That's a damned good question. I can guess why the NLM is effectively promoting fraud, and I can suggest workarounds for the problems I'm guessing they have, but I honestly don't know. I am, however, angry. As you might guess. I'm sick of this academic fraud.

* I'm now post-decompression surgery. That's a story for another day.

The Trump I remember

It's Nov 6, 2020 and I believe Trump's presidency is ending. I look forward to forgetting him, but one day I'll be asked what all the fuss was about.

For that day, to remind me, here is what I know of him know:

1. The crimes for which he was impeached -- extorting a foreign power to attack a political opponent.
2. The crimes for which he was not impeached -- the collusion with Russia against HRC.
3. The obstruction of justice.
4. The personal corruption.
5. The corruption of government and of industry, including running a protection racket against businesses.
6. The casual racism.
7. The people who worked for him.
8. The anti-science -- from CO2 to COVID to the environment and beyond.
9. Inserting Christian fundamentalism into American government.
10. The constant lying. (He was paradoxically transparent however. An accusation was invariably a confession.)
11. His mockery of persons with disabilities.
12. The threats and the cruelty. Not least the separation of migrant children and parents.
13. The stupidity. He really didn't seem to know very much about anything beyond corruption and real estate.
14. The propaganda.
15. The destruction of the ACA without a replacement.
16. The complete disinterest in art, culture, and the humanities.
17. The destruction of government agencies.
18. A complete lack of honor, compassion, or decency.
19. COVID mismanagement.
20. QAnon.
21. The authoritarianism.
22. The pardons. (Remember Al Kinani)
23. The post-election conduct.
24. The record-breaking federal executions.
25. The Gallagher war crime pardon
26. The illegal destruction of government records. 

As of Nov 2020 McSweeney's has a list, NYT Magazine did an interactive summary, The Atlantic had many articles summarized in their Biden endorsement:

...he has divided our people; he has pitted race against race; he has corrupted our democracy; he has shown contempt for American ideals; he has made cruelty a sacrament; he has provided comfort to propagators of hate; he has abandoned America’s allies; he has aligned himself with dictators; he has encouraged terrorism and mob violence; he has undermined the agencies and departments of government; he has despoiled the environment; he has opposed free speech; he has lied frenetically and evangelized for conspiracism; he has stolen children from their parents; he has made himself an advocate of a hostile foreign power; and he has failed to protect America from a ravaging virus"

Was there anything he did that was good?

1. Accepting North Korea as a nuclear power. It was the only viable choice, but I'm not sure HRC could have taken it (esp. with a GOP Congress).
2. He understood the Left Behind -- the majority of Americans who will never be knowledge workers. I don't think my team gets this. He didn't know what to do for them, but he knew what they wanted.

Update 1/18/21 - adding Unthinkable from The Atlantic.

COVID-03 and COVID-19: influenza co-infection and multiple strains

I remember COVID-03 (Coronavirus disease 2003, known then as SARS) caused by Novel Coronavirus 1 (SARS-CoV-1). It was frightening and puzzling, especially in Toronto Canada (from 11/2003, emphases mine):

The entire SARS story puzzles the heck out of me. Why did so many nurses die, even in locations that should have had strong infection control? Why did the disease seem so contagious in some places, and not at all contagious in others? Did the virus attenuate? Was the epidemiologic behavior due to an unidentified cofactor infection that was common in some places and not in others? (eg. a second virus was needed to develop full fledged SARS).  

I can't believe that the infection control measures were so effective. The disease was loose in China for months. Why did it not spread in India at all?

A year later I wondered if there were multiple strains circulating, all mutually immunogenic, some more toxic than others. (There may be multiple strains of SARS-CoV-2 as well.) I wondered if that suggested a pandemic management strategy - a kind of "backburning"...

Create a contagious synthetic pathogen that's relatively benign, but induces immunity to the major pathogen -- and spread it actively. I say not entirely novel, because this is how Polio was suppressed. The oral vaccine was an active contagious pathogen that was excreted in stool. It immunized a vast number of persons -- but some became sick, disabled, or dead. When Polio was less of a threat we switched to a non-pathogenic inoculation. The difference is the successful Polio strategy was probably unintentional (I suspect some people understood even in the 1950s), but in the future we'd be deliberately exposing an entire population to an immunogenic pathogen that would almost certainly harm many people.

Now we are enjoying COVID-19, the bigger, uglier, brother. Again there's tremendous variability from place to place and time to time. Again India seems unbothered. Again young healthcare workers are vulnerable. Again I wonder if some of the sickest patients have multiple viral inflections or more aggressive strains. Perhaps as our seasonal flu finally fades so will the worst of COVID-19.

I hope this time we'll understand it better.

Warmer climate on the earth may be due to more carbon dioxide in the air. 1956.

Originally published in the NYT Oct 28, 1956 by Waldemar Kaempffert. Reprinted as Climate Science in 1956 and 2015 | HuffPost:

The general warming of the climate that has occurred in the last 60 years has been variously explained. Among the explanations are fluctuations in the amount of energy received from the sun, changes in the amount of volcanic dust in the atmosphere and variations in the average elevation of the continents.

According to a theory which was held half a century ago, variations in the atmosphere’s carbon dioxide can account for climatic change. The theory was generally dismissed as inadequate. Dr. Gilbert Plass re-examines it in a paper which he publishes in the American Scientist and in which he summarizes conclusions that he reached after a study made with the support of the Office of Naval Research. To him the carbon dioxide theory stands up, though it may take another century of observation and measurement of temperature to confirm it….

…. The atmosphere acts like the glass of a greenhouse. Solar radiation passes through to the earth readily enough, but the heat radiated by the earth is at least partly held back. That is why the earth’s surface is relatively warm. Carbon dioxide, water vapor and ozone all check radiation of heat.

Of the three gases that check radiation, carbon dioxide is especially important even though the atmosphere contains only 0.03 percent of it by volume. As the amount of carbon dioxide increases, the earth’s heat is more effectively trapped, so that the temperature rises.

... According to Dr. Plass, the latest calculations indicate that if the carbon dioxide content of the earth were doubled the surface temperature would rise 3.6° C and that if the amount were reduced by half the surface temperature would fall 3.8° C...

...Despite nature’s way of maintaining the balance of gases the amount of carbon dioxide in the atmosphere is being artificially increased as we burn coal, oil and wood for industrial purposes. This was first pointed out by Dr. G. S. Callendar about seven years ago. Dr. Plass develops the implications….

… Today more carbon dioxide is being generated by man’s technological processes than by volcanoes, geysers and hot springs. Every century man is increasing the carbon dioxide content of the atmosphere by 30 percent — that is, at the rate of 1.1° C in a century. It may be chance coincidence that the average temperature of the world since 1900 has risen by about this rate. But the possibility that man had a hand in the rise cannot be ignored.

Whenever the cause of the warming of the earth may be there is no doubt in Dr. Plass’ mind that we must reckon with more and more industrially generated carbon dioxide. “In a few centuries,” he warns, “the amount of carbon dioxide released into the atmosphere will be so large that it will have a profound effect on our climate.”

Even if our coal and oil reserves will be used up in 1,000 years, seventeen times the present amount of carbon dioxide in the atmosphere must be reckoned with. The introduction of nuclear energy will not make much difference. Coal and oil are still plentiful and cheap in many parts of the world, and there’s every reason to believe that both will be consumed by industry as long as it pays to do so.

I believe current predictions are on the order of 2C with doubling CO2 with longer term higher secondary increases. So bit less than 1956 model, but on the other hand the effects on climate have been obvious sooner than expected.

Overall, holds up quite well.

Attack of the Clones - New disease mechanism identified

First came CHIP - Clonal hematopoiesis of indeterminate potential (Jan 2018)

… a bizarre accumulation of mutated stem cells in bone marrow increases a person’s risk of dying within a decade, usually from a heart attack or stroke, by 40 or 50 percent. They named the condition with medical jargon: clonal hematopoiesis of indeterminate potential…

… Up to 20 percent of people in their 60s have it, and perhaps 50 percent of those in their 80s …

… large numbers of study participants had blood cells with mutations linked to leukemia — but they did not have the cancer. Instead, they had just one or two of the cluster of mutations…

… [mutations], especially those linked to leukemia, seem to give stem cells a new ability to accumulate in the marrow. The result is a sort of survival of the fittest, or fastest growing, stem cells in the marrow…

… researchers described a 115-year-old woman. Nearly her entire supply of white blood cells was generated by mutated stem cells in her bone marrow.

At the first she had developed just two mutated stem cells. But over time their progeny came to dominate her bone marrow. She lived about as long as a human can, nonetheless, and died of a tumor.

… Mutated blood cells began proliferating in the mice, and they developed rapidly growing plaques that were burning with inflammation.

“For decades people have worked on inflammation as a cause of atherosclerosis,” Dr. Ebert said. “But it was not clear what initiated the inflammation.”

Now there is a possible explanation — and, Dr. Ebert said, it raises the possibility that CHIP may be involved in other inflammatory diseases, like arthritis.

That was mindboggling. An entirely new mechanism of disease! It’s easy to speculate on relationships to unexplained disorders like osteoarthritis.

This week the clones are everywhere …

Researchers Explore a Cancer Paradox Oct 2018

… a large portion of the cells in healthy people carry far more mutations than expected, including some mutations thought to be the prime drivers of cancer…

… rogue cells spread out across the esophagus, forming colonies of mutant cells, known as clones. Although these clones aren’t cancer, they do exhibit one of cancer’s hallmarks: rapid growth.

“These mutant clones colonize more than half of your esophagus by middle age” …

… By examining the mutations, the researchers were able to rule out external causes for them, like tobacco smoke or alcohol. Instead, the mutations seem to have arisen through ordinary aging. As the cells divided over and over again, their DNA sometimes was damaged. In other words, the rise of these mutations may just be an intrinsic part of getting older…

It’s been a long time since we’ve had an entirely new class of pathophysiology. We may be entering a new and exciting era of medical research with near term clinical implications. Nobel prizes have been awarded for less.

Medical topic monitoring: PCOS topics added to my RSS feeds

I’ve been a fan of the National Library of Medicine’s medical literature service through MEDLARS to MEDLINE to Grateful Med (my fave) to the current PubMed.

I monitor a number of topics though RSS streams of search updates:

To create an RSS search feed:

1. Run a search in PubMed.
2. Click RSS located below the Search box.
3. You may edit the feed name and limit the number of items displayed [2], and then click Create RSS. If the number of citations retrieved is greater than the number of items displayed the feed will include a link to display the complete PubMed retrieval.
4. Click the XML icon to display the XML and copy and paste the URL into the subscribe form in your RSS reader. Web browsers and RSS readers may use different options to copy the feed.

Today I’m adding one for Polycystic Ovary Syndrome/Disorder (PCOS/PCOD) with a focus on exercise, metformin, and research (I may split searches after a while). I have similar searches on a variety of topics as shown in the table below. (If I remember I’ll come back and update this post over time.)

I read results in my RSS clients - Feedbin (RSS server and web client) and Reeder.app (iOS, I’m also playing with Lire.app). I save selected references to Pinboard, generally with a tag (when I remember). The Pinboard tags have feeds too.

Search	RSS	Pinboard stream
PCOS etiology	PCOS/etiology [1]	pcos
PCOS and exercise	PCOS and exercise	pcos
PCOS and metformin	PCOS and metformin	pcos
arthritis and tolerance induction	Arthritis and tolerance induction	arthritis

PS. My longstanding #1 feature wish for MarsEdit is native table support. Just saying.
PPS. I miss Google Reader’s ability to share sets of feed subscriptions

- fn -

[1] You can search on a MeSH heading/subheading pair but I couldn’t get the RSS to work that way. OTOH, Pubmed was flaky this morning. That’s quite rare. I hope I didn’t break it. I’m going to have to update this post another day with some of the other topics I follow.
[2] With a new feed only 10 articles are displayed. I suspect this is a Feedbin problem.

Save America. Vote GOP.

In the real world HRC is President and the GOP is beginning a painful reform process that will lead to a far better conservative party and a healthy American democracy.

In our consensus hallucination a walking tire fire is President, the GOP is further from reform than ever, and smart Dems are reading Josh Marshall’s advice. Oh, and the wake-up button isn’t working.

While we’re waiting for wakefulness we might as well come up with a plan or two. Plan one is to address the root cause of non-college misery. That will be useful if we survive (hint: avoid war with China) to get a sane government again.

Plan two is about getting a sane government. Towards that end we need to save the GOP from its addiction to the unreal. Unreality is a dangerous drug, after decades of abuse the GOP is in desperate need of rehab …

From Tabloids to Facebook: the Reality Wars (revised from my original)

I’ve been thinking about Russia’s successful hacking of the 2016 US election. It shouldn’t be seen in isolation.

It should be understood as part of the ancient human struggle with delusion and illusion — the reality wars.

In the US the reality wars were once bipartisan; each party struggled to separate fact from fantasy. Over the past few decades the GOP stopped fighting, they embraced the unreal. From Reagan to Gingrich to the Tea Party to Trump. By the 21st century we began seeing books like “The Republican War on Science”.

Unreality spread like a virus. AM talk radio was infested. Then came Drudge and Fox. Later Breitbart and finally the Facebook fake news stream. From the Clinton “murders” to birtherism to child pizza porn slaves.

This wasn’t bipartisan. The anti-reality meme, a core historic component of fascism, became concentrated in the GOP. Russia jumped on board, but Russia is more of a plague carrier than an intelligent agent. They lost their reality-war in the 90s. All their news is unreal now. Putin, like Trump, takes the fakes.

Trump’s victory is a triumph of the unreal. Of Will, I suppose. Now it threatens us all.

The rebellion against reason, against the perception of the real, is old. It’s a core component of fascism, but it’s much older than fascism. The Enlightenment was a setback for the unreal, but it wasn’t a final defeat. Now, in our troubled 3rd millennium, anti-reason is strong. It has taken over Russia. It has taken over the GOP, and Trump’s GOP has taken over America.

Somehow we have to rescue the GOP from it’s addiction to the unreal. That would be hard if it had been defeated. Now it seems impossible.

But there is a way. We need to vote GOP.

Vote GOP … in the primaries that is. In my home of Minnesota the Dem contenders are all pretty reasonable. I can send some money and volunteer to support the party, but my primary/caucus vote isn’t needed. On the other hand, the Minnesota GOP has lots of reality denialists running for office. I can use my primary vote to favor relatively sane GOP contenders.

If even half of Dems vote GOP in primaries we can ally with sane conservatives to pull the GOP back from the brink. Yes, there are a few sane conservatives. They are a dying breed, but there is room to ally with them here.

Then, in the election, we vote Dem. If America is lucky the Dems win. If America is unwise the GOP wins — but it’s a saner GOP. A setback, but not a catastrophe.

Work for a sane GOP. As a good Dem, vote GOP. 

Special relatively predicts the photon: Minkowski:Poincaré:Lorentz:Boosts from 2 assumptions & math.

From Backreaction: Dear Dr B: If photons have a mass, would this mean special relativity is no longer valid? I learn that while Einstein may have created Special Relativity with light in mind he could have done it in the dark.

To summarize …

1. Make time a coordinate rather than a parameter. That produces 4 dimensional space time.
2. Call that Minkowski space.
3. Require that laws of physics be the same for all observers moving at constant velocity in Minkowski space (inertial observers).
4. Mathematically, that means symmetry transformations are required. The group of these transformations is called the Poincaré group.
5. The Poincaré group (again, math) has two subgroups. One is translation — all space-time points have same physics. That one is not so interesting.
6. The other Poincaré group is called the Lorentz-group. It has rotations and boosts. Rotations in space aren’t so interesting, they just say all directions are the same. Boosts are rotations between space and time. Minkowski:Poincaré:Lorentz:Boosts give us length and time contraction and the like.

and so …

Deriving the Lorentz-group …  is a three-liner … it is merely based on the requirement that the metric of Minkowski-space has to remain invariant … the  boosts depend on a free constant with the dimension of a speed. You can further show that this constant is the speed of massless particles.

… if photons are massless, then the constant in the Lorentz-transformation is the speed of light. If photons are not massless, then the constant in the Lorentz-transformation is still there, but not identical to the speed of light…. 

Giving a mass to photons is unappealing not because it violates special relativity – it doesn’t – but because it violates gauge-invariance, the most cherished principle underlying the standard model. But that’s a different story and shall be told another time.

Perhaps (this is me writing) another way of thinking about this is that making time a coordinate, and requiring physics have inertial constancy, gives us, through math, the properties of a massless particle. So if we didn’t already have personal experience with photons, we’d know what to look for. When we found them we’d then say that our science made a great prediction…

I’m really looking forward to Dr. Hossenfelder’s explanation of Gauge-invariance.

PS. OS X insists in quietly auto-correcting photons to photos.

Phenazopyridine (pyridium, AZO) - yet another example of missing research

Phenazopyridine is an old drug, discovered in the 1930s. Chemically it’s classified as an “azo dye”, these chemicals are usually used to color clothing. Phenazopyridine will stain clothing orange. Another Azo dye was once used a seizure med. 

Two-thirds of a dose is excreted unchanged in the urine (and sweat and tears), the rest is metabolized to unknown substances. It has some sort of anesthetic action on the urinary tract, we don’t know how that works. “Trace amounts” may enter the cerebrospinal fluid. With prolonged use there is injury to both liver and kidney.

Historically phenazopyridine was prescribed for use in the very early stages of a bladder infection, before antibiotics did their job (since it’s older than antibiotics I suspect it was used heavily in the past). It’s over the counter now, to be used for one to two days.

Except some patients use phenazopyridine for longer than a few days. Interstitial cystitis is particularly nasty syndrome. Like many poorly understood disorders (osteoarthritis, autism, etc) it’s probably several different disorders that share common features. One pattern of interstitial cystitis causes severe sleep disruption; patients wake up to void every 10 to 60 minutes with very small volume urination. On bladder biopsy the protective lining of the bladder has been disrupted. 

Sleep deprivation is a well understood and effective form of torture, so it’s not surprising that IC patients get a bit desperate (you would too). Phenazopyridine may allow sleep when all else fails. So it’s used more than it should be, especially since it’s available without a prescription.

Since phenazopyridine has an anesthetic effect, we presume it interacts with the peripheral nervous system.  So what happens to the brain with large lifetime doses of phenazopyridine? I can’t see that this has ever been investigated, even in animal models.  Tartrazine, another azo dye used in food coloring, was associated with oxidative brain damage in one rat study.

Medicine is full of things like phenazopyridine. Medications that were adopted long ago, and have received minimal research review since. We could employ an army of scientists studying these drugs. But then we’d have to figure out how to pay for them…

Why Johnny can't make drugs any more ... we need better science from government.

I think of In the Pipeline’s Derek Lowe as a small ‘m’ marketarian. He has more confidence in the “invisible hand” of markets than I, but he’s not a believer in Rand’s Market Divine (the market that can do no evil, so long as government snakes are avoided). He combines critiques of big pharma CEOs with a robust defense of antibiotic development process.

Which may explain why he sort-off calls for more government funding of basic research — without quite getting there…

A Terrific Paper on the Problems in Drug Discovery | In the Pipeline

… Jack Scannell and Jim Bosley … “These kinds of improvements should have allowed larger biological and chemical spaces to be searched for therapeutic conjunctions with ever higher reliability and reproducibility, and at lower unit cost … in contrast many results derived with today’s powerful tools appear irreproducible; today’s drug candidates are more likely to fail in clinical trials than those in the 1970s … some now even doubt the economic viability of R&D in much of the drug industry [22] [23].

The contrasts ..between huge gains in input efficiency and quality, on one hand, and a reproducibility crisis and a trend towards uneconomic industrial R&D on the other, are only explicable if powerful headwinds have outweighed the gains [1], or if many of the “gains” have been illusory …

Shaywitz and Taleb wrote something similar about ten years ago (via Hensley, WSJ, emphases mine)…

… The molecular revolution was supposed to enable drug discovery to evolve from chance observation into rational design, yet dwindling pipelines threaten the survival of the pharmaceutical industry,” say consultant David Shaywitz and Nassim Nicholas Taleb, author of “The Black Swan: The Impact of the Highly Improbable.”

“What went wrong?” they ask in the opinion pages of the Financial Times. “The answer, we suggest, is the mismeasure of uncertainty, as academic researchers underestimated the fragility of their scientific knowledge while pharmaceuticals executives overestimated their ability to domesticate scientific research.”

When you get right down to it, Shaywitz and Taleb say, we still don’t understand the causes of most disease. Even when we think we do, because someone found a relevant gene, we’re not very good at turning the knowledge into a treatment. “Spreadsheets are easy; science is hard,” they tell Big Pharma.

I lived through this, including the 2nd failure of the genomic revolution. In retrospect the years from 1945 through the 1970s were a Golden Age of medicine. I did my medical science in 1982; for my generation the Golden Age was a baseline. We thought we understood so much …

By 2008 we all knew we had a problem. I’d been long out of practice and I was having to catchup on 7 years of medicine for my licensing exam. That turned out to be easier than expected. I wrote then about medications…

1. Lots of new combinations of old drugs, maybe due to co-pay schemes
2. Many new drugs have suicidal ideation as a side-effect.
3. Lots of failed immune related drugs re-purposed with limited focal impact on a few disorders.
4. Probably some improvements in seizure meds. Lots of new Parkinson’s and diabetes meds, but they’ve had limited value. (metformin was a home run, but that was more than 7 years ago).
5. Really lousy progress in antibiotics; there are fewer useful therapies now than 7 years ago. Actually, fewer every year.

With Lowe’s latest we learn what has come from 8+ years of digging into our research flail (emphases mine):

… this paper is also a great source for what others have had to say about these issues, too (and since it’s in PLoS, it’s open-access). But the heart of the paper is a series of attempts to apply techniques from decision theory/decision analysis to these problems …

 

… Let’s all say “Alzheimer’s!” together, because I can’t think of a better example of a disease where people use crappy models because that’s all they have. This brings to mind Bernard Munos’ advice that (given the state of the field), drug companies would be better off not going after Alzheimer’s at all until we know more about what we’re doing, because the probability of failure is just too high…

 

… I’ve long thought that a bad animal model (for example) is much worse than no animal model, and I’m glad to see some quantitative backup for that view. The same principle applies all the way down the process, but the temptation to generate numbers is sometimes just too high, especially if management really wants lots of numbers. So how’s that permeability assay do at predicting which of your compounds will have decent oral absorption? Not so great? Well, at least you got it run on all your compounds…

 

… there’s no cure for the physical world, either, at least until we get better informed about it, which is not a fast process and does not fit well on most Gantt charts. Interestingly, the paper notes that the post-2012 uptick in drug approvals might be due to concentration on rare diseases and cancers that have a strong genetic signature …

 

… in drug discovery, we have areas that where our models (in vitro and in vivo) are fairly predictive and areas where they really aren’t…

I think what Lowe is telling us that we need more basic science work because drug development has raced ahead of the science-road it runs on. On the other hand, being a believer in markets and enterprise, he doesn’t quite come out and say that government needs to fund this work, even though he knows pharma won’t.

 

Or perhaps he has such a low opinion of current US government funded research that he doesn’t think our NIH will help. I see his point.  So we need government, but we need better government science …

 

It’s a tough one.

 

But… I just did my board exams again. Seven more years have passed. This time I had to learn more things. Maybe, when we look back, we’ll say that genomics science began to pay dividends around 2010. I think that’s not enough though. If the US is ungovernable, maybe we need to look for others to lead…

See also:

• Rebooting medical research - the world needs Canada 2/2016
• Why did medical progress slow after 1984? 12/2010
• Challenges to medicine and science – medication invention hits a brick wall 7/2008
• A peculiar finding of a 2010 RSV infection and transient autoimmune diabetes leads to … nothing. 2/2016

Aspirin, NSAIDs, cell death and the treatment of arthritis and interstitial cystitis

While doing some research on interstitial cystitis Google uncovered an extraordinary claim by the Cleveland Clinic’s Raymond Rackley:

Microsoft Word - Transcript for IC Video.doc

… exposure to TNF−α produces a dysfunctional activation pattern in IC urothelial cells that leads to cellular apoptosis…

Aberrant NF−κB signaling activation may be responsible for the imbalance of apoptotic and survival mechanism of the bladder epithelium that gives rise to the pathogenesis of IC … asking all IC patients to avoid aspirin or aspirins like products such as NSAIDs that block normal NF- B signaling …

I can’t tell when this transcript was created, there’s no date information on the PDF. As of Feb 2016 Rackley has 71 publications, but the only one that might lead in this direction was from 2011. I don’t think there have been any publications out of this particular video presentation.

The claim is extraordinary for two reasons. The first is that interstitial cystitis is a common cause of significant suffering, we have no good treatments (see also), and patients often use NSAIDs or even aspirin (which acidifies urine, for some that might help). If this claim were true those people should all switch to acetaminophen.

The other reason, of course, is that the transcript notes that aspirin and NSAIDS (ibuprofen, etc) have a significant effect on the mechanisms that influence cell death (apoptosis). This is mentioned as though it were common knowledge, but it was a surprise to me. Perhaps it shouldn’t have been, I know here has been a suspicion for at least 10 years that NSAIDs slow tendon injury healing. I’m also aware of epidemiology studies of an inverse association between colon cancer and aspirin use, and recently the USPSTF added colorectal cancer prevention to its draft aspirin use guidelines.

I suppose, in retrospect, if aspirin reduces the risk of colorectal cancer it may well do so by empowering our cellular level anti-cancer controls (vs. say, altering the microbiome). One way to empower those controls is to bias our cellular monitoring systems towards more aggressive cellicide (apoptosis) — and away from healing.

This has occurred to researchers. A search on apoptosis and aspirin returns 181 results starting in 1995 and accelerating in 2008 (NSAIDs) with a flurry of publications in the past few years. So among researchers, the idea that aspirin and NSAIDs shift our cellular systems away from healing and towards apoptosis (for better or worse) is probably not so surprising.

For clinicians however, this is potentially significant. We use aspirin for heart disease of course, but only in modest doses. More importantly, we use NSAIDs extensively for arthritic conditions where we may want more rather than less healing. (Not to mention interstitial cystitis).

It would be good to know how real this effect is. As Emily reminds me it is perilous to extrapolate from basic research to clinical practice. Even so, I would suggest people suffering from interstitial cystitis may want to consider acetominophen, assuming their liver is in good health.

Rebooting medical research - the world needs Canada.

My mother had a bottle of thalidomide on the shelf.

It was her first pregnancy and she was sick. Thalidomide was the hot new treatment for morning sickness. It wasn’t approved in the US, but Canada was ahead of the curve and a keen young obstetrician gave her the meds. 

Being a nurse she was suspicious of physicians, so she never took them and my arms and legs developed normally. I don’t know why thalidomide helped with morning sickness, but it was quite toxic to the developing fetus. 

Thalidomide had a second life though. Over the past 50 years it’s come to be used for a complication of Leprosy, for early multiple myeloma and for a few other conditions. Research has led to development of several related drugs.

It all took a long time though. There’s not much money to be made from off-patent medications, so there’s no funding from drug companies. There’s not a lot of support from traditional government sources either — there’s nothing exciting or sexy about this kind of costly, slow, research. Individual clinicians might do small trials on their own initiative, but unless the results are extremely positive nothing more will come of them. Worse, those small trials are increasingly hard to do in an era of humane and ethical research. Perhaps these are some of the reasons medical process has slowed since the early 1980s.

There are lots of odd drugs out there that have accumulated small research results but languish for lack of further investigation. Cimetidine was popular in the 1980s for ulcer disease, but in it’s off-patent life it’s been used for interstitial cystitis, persistent calcific tendinitis, animal studies of the innate immune system, eosinophilic fasciitis, warts, herpes simplex cold sores and doubtless other unpublished experiments. It probably doesn’t work for warts, but does it work for any of these conditions? We don’t know. There’s no money for the boring and expensive animal model development and clinical trials.

There are many drugs like cimetidine. They show up as “possible treatments” in the extensive literature around diseases we can’t fix. They are shots in the dark often based on biological plausibility, chance observations, and unreplicated animal experiments.

We can do better than this.

And by “we” I mean the world, not the United States. Our peculiar strain of anti-government and anti-science politics makes it hard for the US to play a leadership role in rebooting practical medical research. Other nations are in a better place to lead. Canada, the UK, Germany and the Nordics come to mind, but perhaps also Brazil, Israel, and India.

Canada, the world needs you.

Inflammatory osteoarthritis treatments: is there anything to watch for?

See also: Arthritis - the feeds and queries (reference post).

There’s something problematic about human tendons and cartilage. A wide range of infectious, auto-immune and idiopathic disorders land on them. I think dogs are no better, I can’t speak for other mammals.

We’ve tried to put boundaries around these disorders, to name them and attach treatments to the names. Some of our boundaries are better than others. Rheumatoid arthritis isn’t a bad tag. Osteoarthritis though, that label kind of sucks. It includes a wide range of clinical presentations at varied ages with diverse and poorly understood contributions of genetics, auto-immune activity, injury and healing, tendon and cartilage, inflammation and age. The one thing all of the diverse forms of osteoarthritis have in common is that there’s no useful treatment. We might as well call them the idiopathic untreatable arthritides (IUA).

Over the past 20 years or so IUA, or osteoarthritis, has had a few partitions. The biggest one so far was to carve out psoriatic arthritis; a history article claims it spun off in the 1960s (I thought 1980s, but maybe it took a while to make it into textbooks.) There have been efforts to split out “inflammatory osteoarthritis” (sometimes also called erosive osteoarthritis), but since there are no treatments (NSAIDs don’t count) IOA hasn’t quite launched.

I have something between psoriatic arthritis and inflammatory osteoarthritis, so I did a recent search of the UK’s Clinical Trials database for osteoarthritis + inflammatory, trials in UK, US, Canada and Germany and a similar search on the NIH ClinicalTrails.gov. The UK database draws on data from the WHO’s International Clinical Trails Registry Platform, but most of the trials were in the US. Of the two the UK database had the more interesting results.

These are the investigations for slowing disease progression that looked slightly interesting

• Hydroxychloroquine: This is an old antimalarial often used for Rheumatoid Arthritis and Psoriatic Arthritis. It’s something one could probably induce an adventurous rheumatologist to try. The most interesting possible mechanism of action is through inhibition of toll-like receptor (TLR) 9 family receptors, these are a part of the “innate immune system”. The role of the innate immune system in inflammatory osteoarthritis is interesting.
• ABT-981: Inhibitor of interleukin-1 (IL-1) alpha and IL-1 beta cytokines. More here.
• GSK3196165: HuCAL antibody, Granulocyte macrophage colony stimulating factor (GM-CSF) receptor agonist
• ABT-652: Histamine H3 receptor modulator. Targeting the H3 receptor is interesting because of a possible roll in Toll-like receptor activity and the innate immune system.
• Gevokizumab: monoclonal antibody inhibitor of interleukin-1 beta (IL-1 beta), a cytokine. 

The innate immune system connection is new to me, but a search in Google had an auto-complete….

Spooky AI world indeed. Here’s the PubMed abstract for the article The Goog is suggesting, emphases mine:

Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound?
Curr Opin Rheumatol. 2008 Sep;20(5):565-72. Scanzello CR1, Plaas A, Crow MK.

PURPOSE OF REVIEW:
Synovial inflammation is increasingly recognized as an important pathophysiologic process in osteoarthritis, but the stimuli and downstream pathways activated are not well defined. Innate immune system activation, best documented in responses to pathogens, likely plays a role in induction of inflammatory mediators and the specific cellular infiltrate seen in osteoarthritis. Thus, the Toll-like receptors (TLRs) and their signaling pathways are of particular interest. These innate pattern-recognition receptors are activated not only by pathogens but by endogenous 'danger signals'. In this report, we review evidence that certain extracellular matrix components of joint tissues (hyaluronan and fibronectin) may act as TLR stimuli, and summarize recent literature implicating TLR activation in osteoarthritis.
RECENT FINDINGS:
Convincing evidence exists that hyaluronan/TLR interactions drive responses to tissue injury. Evidence of a similar role for fibronectin is growing. TLRs are expressed and functional in the joint, and many proteases and cytokines that promote cartilage catabolism are dependent on nuclear factor-kappaB, a TLR-activated transcription factor.
SUMMARY:
Activation of TLR pathways seems likely in osteoarthritis and may play a central role in disease development and progression. A model of osteoarthritis as a chronic wound, in which the innate immune response is triggered by molecular signals of tissue damage, is presented as a framework for future study of inflammation in this prevalent joint disease.

Well, well, well. That feels like me. I particularly liked this followup article from 2 years later, note the reference to dividing “osteoarthritis" into subsets:

The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive
J Rheumatol. 2015 Mar;42(3):363-71. doi: 10.3899/jrheum.140382. Epub 2015 Jan 15.

Although osteoarthritis (OA) has existed since the dawn of humanity, its pathogenesis remains poorly understood. OA is no longer considered a "wear and tear" condition but rather one driven by proteases where chronic low-grade inflammation may play a role in perpetuating proteolytic activity. While multiple factors are likely active in this process, recent evidence has implicated the innate immune system, the older or more primitive part of the body's immune defense mechanisms. The roles of some of the components of the innate immune system have been tested in OA models in vivo including the roles of synovial macrophages and the complement system. This review is a selective overview of a large and evolving field. Insights into these mechanisms might inform our ability to identify patient subsets and give hope for the advent of novel OA therapies.

So now I need to research currently FDA approved medications that are thought to be TLR antagonists, like H3 receptor antagonists. Ciproxifan could be ordered from suspicious Chinese suppliers. Ok, Am I feeling lucky?

Probably not.

Exploring the “similar articles” and “citing articles” streams for the 2008 Scanzello et al article is quite interesting. Maybe we’ll make some progress. I’ve added some of those articles to my Pinboard arthritis stream, quite a few have free full text and are PubReader viewable. (yay NLM — the only good thing GWB ever did). I have some reading to do.

PS. As of Jan 2016 there are no interesting hits on “Heberden’s Nodes” and “Innate Immunity”. 

Update 1/21/2016

While discussing this with post with Emily something she said led us to a discussion of the curious history of the “H2 blockers”, particularly cimetidine (Tagamet). We remember when those drugs were introduced for gastric mucosa injury, as was common in OA patients taking NSAIDs.

The H2 blockers have an odd history with immune disorders. I recall eosiniphilic fasciitis had a curious response to cimetidine. Cimetidine is a physician-folk remedy for recurrent “cold sores” (usually ascribed to herpes simplex infection), which are now considered to be an innate immune response disorder. Cimetidine and ranitidine are also sometimes used to treat warts. As long ago as 1989 it was considered an immune response modifier, but researchers lost interest in the 00s. I did find a 2003 Japanese publication on cimetidine activity in suppressing rat adjuvant-induced experimental arthritis and a 2011 article suggesting sedating first-generation antihistamines and H2 blockers (cimetidine) impair innate immune responses to bacterial infection in mice.

On the other hand, there are some studies suggesting Cimetidine increases NK cell activity. I could easily see how shifting H2/3 balances would worsen osteoarthritis. I’m not quite ready to start taking a nightly cocktail of over-the-counter cimetidine and chlorpheniramine.

Update 1/21/2016

If you Google on Cimetidine and Osteoarthritis you’ll find a factmed page titled “Is Osteoarthritis a side-effect of cimetidine?” It says “Between January 2004 and October 2012, 78 individuals taking CIMETIDINE reported OSTEOARTHRITIS to the FDA…. of 2258 CIMETIDINE drug adverse event reaction reports”

I think what this group does is to dump the FDA FAERS files into Microsoft Access, then they generate web pages for each Drug - Condition pair and they sell ads off the pages. It’s a not-quite-criminal but not-quite-wonderful enterprise.

I doubt this is a meaningful finding, but if cimetidine truly does act on histamine receptors associated with NK activity and/or innate immunity it would not be surprising if it made some diseases worse as well as some better!

Update 1/23/2016

My intuition is not misplaced…

Antihistamines as treatments for autoimmune disease?
http://www.nature.com/nrrheum/journal/v9/n12/pdf/nrrheum.2013.169.pdf?WT.ec_id=NRRHEUM-201312
Jenny Buckland
Nature Reviews Rheumatology 9, 696 (2013) doi:10.1038/nrrheum.2013.169
Published online 29 October 2013

I’ve found articles on immune modulation activity of H1 and H2 antagonists, like chlorpheniramine, cimetidine and ranitidine dating back to the 1980s, including speculation on H1 and H2 receptor activity on human chondrocytes. Many starts and stops, but now we have innate immune system and the H3 and H4 receptors…

Update 1/24/2016

The Buckland article merely recapitulated an H4 blocker review — not worth paying Nature $8.

Meanwhile, I’ve started my own quixotic trial - Cimetidine 400mg/daily. A true shot in the dark, but it’s not like there are any alternatives. I’ll report out an ’n of 1’ observational result in 4-6 weeks one way or another. I reserve the right to terminate the trial if things go abruptly downhill but I’ll report out regardless.

Update 1/26/2016

Prion Disease and the Innate Immune System - mast cells in the brain play a role - of some kind. So what does cimetidine do there?

Upregulation of H2 receptors after cimetidine use - a risk of rebound with this experiment.

Update 2/1/2016

Cimetidine for chronic calcifying tendinitis of the shoulder, 2003.

Cimetidine decreases calcium levels and improves symptoms in patients with hyperparathyroidism… Cimetidine, 200 mg twice daily, was given orally for 3 months in 16 patients who did not respond to more than 6 months of conservative treatment… Calcium deposits disappeared in 9 patients (56%), decreased in 4 patients (25%), and did not change in 3 patients (19%) . Our results indicate that cimetidine is effective in treating chronic calcifying tendinitis of the shoulder; however, the mechanism by which cimetidine improves the symptoms is unknown.

Weird. I do have a long history of intermittent calcific tendinitis of the shoulders, though I’ve always managed it conservatively. There is only one article citing this study…The H2 blocker famotidine suppresses progression of ossification of the posterior longitudinal ligament in a mouse model. - PubMed - NCBI

Update 2/13/2016

This is peculiar …

Cimetidine in painful bladder syndrome: a histopathological study. - PubMed - NCBI

… Cimetidine is a useful medical treatment for bladder pain but the presence or absence of gastrin or histamine-like immunoreactivity does not explain its therapeutic benefit….

Arthritis - the feeds and queries (reference post)

I feel like I’m tied to a railroad track, and see the light of the train approaching. And I don’t know if it’s one mile away, or 500. 
Anonymous, a patient three years into leukemia remission.

Cancer will give many of us that oncoming train feeling, but of course the light is always there. We’re just good at denial. When we’re young and healthy the train is probably far away. When we’re 93 it’s pretty close. In between we try not to look.

There’s only one “train”, but there are lots of smaller hits along the way. Bicycles and cars maybe. One of them ran into me recently, so I’ve renewed an old interest in the so-called “rheumatic disorders” (misleadingly named after bodily fluid flow).

It really is an old interest. Before I figured out how to do medical school [1], I closely read the 1982 version of the Arthritis Foundation’s “Primer on the Rheumatic Diseases”. Within the broad bounds of unreliable memory I recall that osteoarthritis was a “wear and tear” disorder of aging, rheumatoid arthritis and a handful of other disorders were “auto-immune” diseases, gout and non-gout crystal deposition were relatively well understood, and many viral and non-viral diseases (Gonorrhea and, a bit later, Lyme) caused arthritis. Steroids (not the androgen variety!) worked very well on the auto-immune disorders, but the long term side-effects were horrible and inevitable. We had reasonable drugs for Gout, gold for Rheumatoid arthritis (some value [7]), and nothing for osteoarthritis. Okay, so we had NSAIDs like ibuprofen, but we already suspected they were a mixed blessing. We’ve kind of given up on them.

Things aren’t that much different 33 years later. Relatively recently we’ve realized that “osteoarthritis” covers a multitude of evils, some or all of which, like “psoriatic” arthritis, are more than “wear and tear”. We still don’t have any great treatments for Systemic Lupus Erythematosis, though we now do less harm with the treatments we have. Rheumatoid arthritis has seen the most care improvements, but, amazingly, we can’t actually cure it or any other auto-immune arthritis [3]. We still wonder about the role of infectious agents in creating or sustaining auto-immune disorders but we have few leads [2][6]. The most recent (2005) edition of the Primer on Rheumatic disease says of Osteoarthritis “It is clear that this … includes a variety of different conditions, but we have made less progress …”.

More recent publications have even undone old certainties; we’re no longer confident that the various flavors of psoriatic and osteoarthritis are primarily “arthritic” (greek: Arthron, joint). Disorders along the osteoarthritis - psoriatic arthritis spectrum may begin as diseases of the tendons. Some of them may be lifelong disorders of tissue healing; small injuries accumulate due to a healing defect, perhaps with later onset of an auto-immune component reacting to disordered tissues.

My medical school interest became personal as I watched my mother go through the arthritis experience for about 35 years, ending as “rheumatoid arthritis” (our classifications are imprecise). It wasn’t pretty.

Which is all by way of introducing this “reference post”; a blog post that I’m going to be revising and extending. It’s a post supporting my surveillance of our historically limited knowledge base. I’ll revise it periodically over the next year or two. Sometimes I’ll post/tweet about updates to this reference post, but most of the interesting results will appear in a pinboard RSS stream tagged “arthritis” [4].  

My surveillance relies on PubMed [5] (National Library of Medicine) RSS feeds. Anyone can create these, but I’ve never seen anyone but me write about them. I’ll list them by topic below, but first I’ll describe what I’m not monitoring.

I’m not monitoring care guidelines or the cutting edge of rheumatologic practice. I see a rheumatologist for that; that’s his job. If I want an update on current practices I’ll take a look at FP Notebook’s Rheumatology Book. I’m not interested in alternative or complementary therapies — that way lies madness. I’m only mildly curious about lifestyle factors; mostly because we know so little and very little research is going to get funded.

I am curious about tolerance induction — the Holy Grail of the rheumatic disorder treatment. We’ve been hammering on this decades, but we have new tools now. This is what we really want - a cure for at least some of these diseases. I’m looking for articles on disordered healing and secondary arthritic conditions, but I’ve yet to figure out a good search for that one. Likewise I’m looking for articles that relate loss of self-tolerance to a dysfunctional pseudo-neoplastic component of the immune system (yeah, this is definitely fuzzy). More concretely anything about the role of infections organisms in precipitating or maintaining arthritis.

Here are the RSS feeds and “similar articles” queries I’m revising and using for each of these topics. I wish there were RSS feeds for the “similar to” queries, as I learn the topics i’ll put create RSS feeds with similar results.

tolerance induction

• tolerance induction in arthritis (feed)
• peptide based immunotherapy (not limited arthritis, feed)
• T cell immunoglobulin-3 (Tim-3) therapy (query)
• tolerogenic dendritic cells

tendon injury (enthesitis) and arthritis

• enthesitis in psoriatic arthritis (query)

microbiome and role of infection in creating and maintaining arthritis

• microbial dysbiosis in rheumatoid arthritis (query)

Immune system and neural networks (because I figure the immune system is a form of neural network)

• Google scholar related article query

other

• psoriatic arthritis - natural history (not a query because this seems to be only article!)
• cimetidine and innate immunity (feed - because of this post)

- fn -  

[1] The way to do the didactic portion medical school is to maintain a relentless focus on examinations. If you’re doing well you may then indulge your passion and curiosity. 
[2] As a still distractible student I read the first speculative article written on an association between bugs living in the high acid stomach and gastric ulcer disease. Before then we thought the stomach was sterile; nothing could live in such a disagreeable environment. That probably contributed to my extremophiles and auto-immune disease post.
[3] Juvenile Rheumatoid Arthritis does resolve about half the time. Which is curious.
[4] Like all things Pinboard it has an RSS Feed: http://feeds.pinboard.in/rss/secret:c6ea18730310000211dc/u:jgordon/t:arthritis/. Sadly there are no RSS feeds for “similar article” queries and “My NCBI” doesn’t show feeds.
[5] My medical informatics career began in Family Medicine residence as a beta tester of the “Grateful Med” software. I believe the product manager, Rose Marie Woodsmall, was a dead head. I was among the last generation of medical students to use the paper Index Medicus to do journal research.
[6] I’d wondered years ago why we weren’t mining synovial fluid for foreign DNA. Turns out this was done in 2001 with interesting results, but the follow-up was limited until “microbiome” became a funding source.
[7] Gold was used to treat Rheumatoid arthritis from at least 1945 through the early 1990s. I seem to remember it was sometimes associated with extended remissions. I can find almost nothing on it written after 1965 or so, and nothing at all on how it worked. There’s very little on long term outcomes. Which is, you know, profoundly weird.

Update 12/18/2015

I have a hunch that whatever is afflicting me now is the end-stage of a congenital defect with soft tissue/tendon formation. I’ve always been prone to calcium deposits along tendons and to overuse tendonopathies. It would not be surprising that as I’ve aged my body’s ability to manage this problem, and heal from injury, has declined. That in turn could lead to some secondary auto-immune issues (prolonged inflammatory/antigen spill issues). I haven’t come up with a search criteria yet to explore this idea; it would probably show up in whole genome analyses. I would need to look for discovery of a gene associated with auto-immune arthritis/osteoarthritis that was important for tendon formation.

Extremophiles and auto-immune disease

The extremophiles are at home in near boiling water and the deep crust of the earth. Every ecological niche is colonized by life; and life forms everywhere work to change their ecology to suit themselves.

It is the inevitable logic of natural selection in action.

So then, why should the hot tissues of auto-immune disease be any different? How could there not be life forms evolved to that extreme environment? Life forms that might facilitate it, to defeat their enemies and extend their preferred environment. An ecology that, once created, will host competitors, some liking it hotter, some coder. An ecology with successor species, like any forest.

It seems inevitable.

Gene-environment interactions and the modesty of 2014 personalized medicine: Obesity, Reefer madness

Between 2007 and 2008 my work life got unusually exciting. Most of the time I work on software development in well understood aspects of medicine, but back then we were, once again, super-excited about genomics and “personalized medicine”. I made a couple of funded trips to meet with Stanford research teams maintaining genomic ontologies. I had a blast using exciting tools for navigating poorly maintained and unreliable massive web UI databases of gene-phenotype relationships.

At last we were going to realize the NIH predictions of 1994 — 10 years late, but better late then never.

Then the hammer fell. My 2008 post on schizophrenia [1] doesn’t talk about the work I was doing then, but it explains why we gave up. The disorders we cared about, schizophrenia, diabetes, lipid disorders, depression and so on, didn’t have a handful of generic recipes. Turns out there are hundreds, or thousands, or “recipes” for schizophrenia made up of environment (especially intra-uterine) and lots and lots of interacting genes. Even worse — lots of seemingly “normal” minds run on brains built with buggy genomics. Turned out “family” (genetic relative) history was a much more useful guide to predicting disease and treatment than genomic analysis — and that didn’t justify big investments.

Everything stopped, and then health care IT turned from the excitement of personalized medicine to the painful tedium of “meaningful use” and the more scientifically tractable domain of population health.

I still follow the field of course, and there has been slow but interesting progress …

Gene Linked to Obesity Hasn’t Always Been a Problem, Study Finds

… In 2007, researchers discovered that people with a common variant of FTO tend to be heavier than those without it. … Two copies of the gene bring 7 extra pounds — and increase a person’s risk of becoming obese by 50 percent.

… A new study shows that FTO became a risk only in people born after World War II.

… A variant of a gene called AKT1, for example, can raise the risk of psychosis — but only if the carrier smokes a lot of marijuana….

Small progress admittedly, but scientifically interesting. Exercise is good for most things — but we know that for most people moderate exercise [2] doesn’t add much to dietary control of weight. For people with the FTO gene though, exercise might indeed control weight. People with AKT1 are susceptible to persistent Reefer Madness — they really shouldn’t use marijuana [3]. In a related vein, there’s some evidence that the dementia protection of exercise is much stronger in the 14% of Americans with the APOE4 gene variant [4] than in APOE4 negative populations.

Progress — but darned slow. At this rate it will take decades to build what we expected before the year 2000.

- fn -

[1] Quite a good post, if I say so myself. I’d forgotten autism was once considered a variant of pediatric schizophrenia. We’re again merging both of those diagnostic categories.

[2] Extreme exercise is another matter, but one that’s rather hard to study. Though there is this recent NYT article on super-short higher intensity workouts that are to CrossFit as a snack is to a smorgasbord.

[3] Incidentally, marijuana legalization will be a boon to addiction medicine. Investors now include rehab clinics in the category of cannabis business opportunities.

[4] Why is a nasty gene so prevalent? The Wikipedia article mentions APOE4 helps with Vitamin D update — a particular problem in northern europeans. We presume it does have some survival advantage in some settings.

The relativistic version of the linear motion equation: velocity = acceleration*time.

My son is starting to do … physics.

It is fair to say I am more excited about this than he is. There is a reason I have a copy of the 1973 Edition of Misner, Thorne and Wheeler’s Gravitation ($35!) on my bookcase. I’m saving it for retirement, by which time Desmos.com will breeze through all the visualizations. It is true I was a failure (non-physicist) at Caltech, but there’s still time…

Ahem. So when #w was given an assignment to create a poster about linear motion, with equations on time, velocity, constant acceleration and the like, I thought it would be fun to show that the equations of linear motion are merely a low velocity approximation to the relativistic equations of linear motion. I was sure a quick Google search would turn up a simple simulation that would look like:

v=a*t (starting at rest velocity after time t is acceleration times t)

Riiiight. I’m sure that simulation exists, but I was never able to find it. With a bit of thought about the problem I realized I might be better off dropping the tricksy concept of acceleration and looking for a relativistic version of:

v= (F/m)*t (since change in velocity is Force*Time/Mass. Push a trike, push a truck, which moves faster?)

That found an “off-topic” [1] stack overflow article which was just a few parentheses short of the good-enough equation [2]: v = c * tanh(asinh((F*t)/(m*c))).

This is the first time I’ve personally run into hyperbolic trig functions, so I thought that was pretty cool, especially since I’d just read Jon Butterworth’s lovely description of how one hops from simple physics to quantum physics simply by tossing the square root of -1 (i) into a classical wave equation (uses Euler’s Formula, so extra points). That article used the familiar sin/cos functions, so I was getting an extra dose of trig. 

Plugging v = c * tanh(asinh((F*t)/(m*c))) into Wolfram Alpha gave me this cool output (yes, the AIs wll be our death, but for now they’re fun):

Now that is what I was looking for! It clearly reduces to v = (F/m)*t when the squared stuff is relatively small. [5]

We can now compare my son’s high school textbook linear motion equation (v=F/m*t) to the relativistic equation, using the sneaky physics trick of geometrized units so c=1. Just to make things even nicer I’ll arbitrarily set the applied force to “1” (some unit) and the mass to “1” (some unit). This is what Desmos shows:

 

The last shows how simple this is in geometrized units (v is change in velocity over time t in our funky units):

and here’s the magic graph that shows what happens as velocity (y axis) approaches “1” (speed of light) in the original linear motion equation and the relativistic version:

Yeah, hits the speed limit. [5]

—

[1] The iron law of StackOverflow is that any article of interest will sooner or later by marked off-topic.

[2] I discovered the problem when I plugged it into Wolfram alpha, I had to do some web searches and play around the parens to get the correct expression.

[3] Incidentally, if you’d told me in 1995 that we would still lack easy entry of mathematical notation into web pages in 2014 I’d have assumed some kind of worldwide civilizational collapse.

[4] Once I had this expression, which was provided by the Wolfram AI, I found a discussion thread (scroll down) telling me it can be derived by “substituting F/m for a in the Baez equations(where m is the proper mass) and dividing by c where the tanh/sinh stuff is related to “proper and coordinate time”.

[5] I’ve done great violence here to the principles of general relativity — the meaning of time and distance are entirely dependent on frames of reference and I’ve glossed over all of that — largely because, you know, I’m not a physicist. It is kind of neat, however, what one can kludge together with a handful of web tools. In the general vein of non-physicist at play, it’s fun to compare this to Butterworth’s masterly representation of quantum physics using high school math. I again am left with feeling that physics will be easier to understand once we figure out what “distance” and “time” emerge from.

Coming to terms with the multiverse

Like most people, my neurons were rebooted a few times between birth and adulthood. So I don’t remember that much about childhood, but I do remember sitting in a schoolyard, perhaps in grade one or two, trying to get my head around the end of the universe.

I’m not at all sure, but I believe at that time, around 1970, I thought of the universe as infinite. Later it became finite, a theoretically countable number of galaxies somewhere between 10-20 billion light years “across” with an estimated age that didn’t quite add up. Then came inflation and the height of a human defined the mid-point between Neutrino and the Universe. That was six or seven years ago.

Those were the good old days. Now we have the Multiverse, and Tegmark’s taxonomy of multiversi …

Level I: Beyond our cosmological horizon[edit]

… A generic prediction of chaotic inflation is an infinite ergodic universe, which, being infinite, must contain Hubble volumes realizing all initial conditions.

Accordingly, an infinite universe will contain an infinite number of Hubble volumes, all having the same physical laws and physical constants…. 

Level II: Universes with different physical constants…

… In the chaotic inflation theory, a variant of the cosmic inflation theory, the multiverse as a whole is stretching and will continue doing so forever, but some regions of space stop stretching and form distinct bubbles, like gas pockets in a loaf of rising bread….Different bubbles may experience different spontaneous symmetry breaking resulting in different properties such as different physical constants…

Level III: Many-worlds interpretation of quantum mechanics … 

Level IV: Ultimate ensemble …

I’m slowly reading Tegmark’s popular book of which some criticism might be made. That review, however, offers little solace to universe nostalgics (emphases mine)…

Level I [is] just lots of unobservable extensions of what we see, with the same physics, an uncontroversial notion. Level III is the “many-worlds” interpretation of quantum mechanics, which again sticks to our known laws of physics. Level II is where conventional notions of science get left behind, with different physics in other unobservable parts of the universe. This is what has become quite popular the past dozen years …

So an infinite number of universes like the one we observe is “uncontroversial” and the idea that our infinite multiverse is only one extreme instance of vastly larger number (mostly unsuitable for particles, much less life) is “quite popular”.  There are necessarily an infinite number of John Gordon’s typing versions of this post…

Yes, infinity is like that.

I prefer to think that nothing ever happened, and that we are merely granite dreaming, but I try to creep up on the multiverse by way of metaphor. One person standing on a barren planet is inexplicable; 8 billion people on a planet infested with life is relatively easy to understand.

Perhaps so it is with universes.

Reconstructing our medical evidence base by algorithmic trust assignment across the medical literature

Over the past two decades it has become apparent that the knowledge base for clinical medicine has been corrupted by publication bias, positive result bias, the increasingly strained competition for funding and tenure, and a non-trivial amount of outright fraud.

Perhaps as a result of these problems we see a very high level of research result contradiction and retraction. Sometimes it seems everything we believed in 1999 was reversed by 2014. Retrospective studies of the sustainability of medical research has taught us that the wise physician is better to read textbooks and ignore anything that doesn't get to the front page of the New York Times.

For those of us who grew up on evidence-based medicine in the 1980s, and who proselytized the value of literature currency in the 80s and 90s, these have been humbling times. Humbling times that I wish the creators of the AHA's new statin guideline remembered. (More on that later, perhaps).

We can't change the past, but what do we do with the medical literature we've inherited? It is vast, but we know the quality is mediocre. Can we salvage the best of it?

Maybe we can borrow from the metadata techniques of the NSA and the NLP methods used by banks looking for suspicious language in financial reports. We have quite a bit of metadata to work with: authors, institutions, funding sources, time of publication, and more. We have full text access to most abstracts. We know the history of authors and institutions. We have citation links. We know particularly problematic research domains. We know that mice studies with male researchers may suffer from pheromone induced mouse trauma.

If we were to mine the literature with modern metadata and language processing tools, could we algorithmically assign trust ranks to the entire research literature? We'd then know what we don't know...

Human domestication, the evolution of beauty, and your wisdom tooth extraction

My 16yo is having his wisdom teeth removed tomorrow. Blame it on human domestication.

The Economist explains the process. Domestication, whether it occurs in humans, foxes, or wolves, involves changes to "estradiol and neurotransmitters such as serotonin" (for example). These changes make humans less violent and better care givers and partners -- major survival advantages for a social animal. They also have unexpected side-effects, like shortened muzzles and flattened faces for wolves, foxes, (cows?) and humans.

Since domesticated humans out-compete undomesticated humans, the physiologic markers of domestication become selected for. They being to appear beautiful. Sex selection reinforces the domestication process.

It seems to be ongoing ...

 The evolution of beauty: Face the facts | The Economist:

... People also seem to be more beautiful now than they were in the past—precisely as would be expected if beauty is still evolving...

Which may be why we are becoming less violent.

Of course a shortened muzzle and smaller mandible have side-effects. Teeth in rapidly domesticating animals don't have room to move. Which is good news for orthodontists, and bad news for wisdom teeth.

See also:

• A link between autism and the domestication of humans and dog: "MET gene selection appears to be related to human and canine domestication, including sociability. Variants of it are associated with autism-like behavior."
• The canid domestication of homo sapiens brutalis