Good to see Charlie’s still at it

Good to see Charlie Perrin is still pumping out papers, and interesting ones to boot.  I knew him in grad school.  He’s got to be over 80.

This one —J. Am. Chem. Soc. 141, 4103 (2019) –is about something that any undergraduate organic chemist can understand (if not the techniques he used) — keto/enol tautomerism, in which the hydrogen bounces between two oxygens, so that, given N molecules in solution, N/2  have the hydrogen bound to one oxygen and N/2 have it bound to the other.

No so in what Charlie found — a compound where the hydrogen is smack dab in the middle.  Some fancy NMR techniques were used to show this.

Hydrogen bonds are extremely subtle (which is why we don’t understand water as well as we might).  Due to the small mass of the proton it isn’t appropriate to treat the proton in hydrogen bonded systems as a classical particle.  When quantum mechanics enters, aspects such as zero point motion, quantum delocalization and tunneling come into play.  These are called quantum nuclear effects (aka Ubbelohde effects).

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Why Organic Chemistry should always be taken (and passed) by pre-meds — take II

An old friend’s mother died of a ruptured intracranial aneurysm and he asked me what his risk was.  So I looked up my old notes on the medical literature that I took when I was in practice (copied below).  They show once again why someone who can’t pass organic chemistry doesn’t belong in medicine.  They are far too out of date to be of clinical use, and hopefully more work has been done since I retired in 2000.

But look at the notes.  All are in reputable journals and have been refereed.  But they conflict.  You have to evaluate this data to give decent advice, just as you have to weigh conflicting steric effects, electronegativity, bond strength, electrostatic effects in solving an organic chemistry problem.  Memorization of the various effects is necessary, but you have to keep them in your head and weigh them.   A perfect memory alone just won’t do.

Here are my notes, followed by the first post on this point (which was almost 10 years ago). You don’t have to go to medical school to see how conflicting they are.

      [ New England J. Med. vol. 341 pp. 1344 – 1350 ’99 ] 626 first degree relatives of 160 patients with subarachnoid hemorrhage were screened for aneurysm by MRI angiography.  Aneurysms were found in 25/626 (not much higher than the literature would imply in any of us — they use the figure of 2.3%) — total number of aneurysms were 33.  18/25 had surgery and 11/18 had a decrease in function (disabling in 1).    They estimate the increase in life expectancy due to the surgery at 2.5 years.   They don’t think the morbidity of surgery is worth it.  The study is from the Netherlands.
      These results can’t be extrapolated to cases were there is more than one member affected by aneurysm (they may have a higher yield of aneurysms, and the risk of rupture may be different).   The screening led to 5 angiographies in patients who didn’t turn out to have an aneurysm — thus exposing a normal person to risk.
      [ Brit. Med. J. vol. 320 pp. 141 – 145 ’00 ] A study of 6175 patients with aneurysmal subarachnoid hemorrhage and 14781 first degree relatives (of whom 11640 were children followed for 108933 patient years showed 19 subarachnoid hemorrhages during followup.   This is an increased risk 3 times that of the general population — however, this translates to an absolute risk of under 1/500 per year.
      [ J. Neurosurg. vol. 66 pp 522 – 528 ’87 ]  A review of the literature on familial aneurysms shows that familial aneurysms tend to rupture at a smaller size and when the patient is younger.   There is a similar incidence of multiple aneurysms and predominance of females over males with multiple aneurysms in the familial cases.  Anterior communicating artery aneurysms are slightly less frequent.  In sibling pairs, the aneurysms occur at the same or at mirror sites and rupture within the same decade twice as frequently as randomly selected nonfamilial aneurysm patient pairs.
      [ Stroke vol. 27 pp. 630 – 632 ’96 ] Familial subarachnoid hemorrhage is said to account for 6 – 9% of all such cases.  The outcome is said to be worse in familial than sporadic subarachnoid hemorrhage.
      [ Stroke vol. 25 pp. 2028 – 2037 ’94 ]  Since the initial report in ’54, there have been 238 families with 560 affected members reported in the literature through ’93. Only 3% of these families had 5 or more affected.   Siblings of an affected male proband are more likely to be affected than siblings of an affected female.  After review of 73 families, the authors conclude that no single pattern of inheritance can account for all families (unsurprise ! ).
        [ Neurosurg. vol. 12 pp. 214 – 216 ’83 ] A family with 4 members with intracranial aneurysms is reported.  Two of these were in an unusual location, the distal anterior cerebral artery.
        The 5th case report of identical twins with multiple aneurysms is given [ Acta. Neurochir. vol. 95 pp 121 – 125 ’88 ]
        [ Neurosurg. vol. 20 pp 226 – 239 ’87 ]  A prospective study of 579 consecutive patients with subarachnoid hemorrhage was done.  1/250 siblings had an aneurysm, but an aneurysm occurred in another family member in 1/14.
      [ Stroke vol. 22 pp. 1426 – 1430 ’91 ]  3 families (among 175 patients with spontaneous dissections of the cervical arteries seen at the Mayo Clinic between 1970 and 1989) were found with intracranial aneurysms.  No patient had both conditions.  Both Ehlers Danlos type IV (ED – IV ) and Marfan’s syndrome can have aneurysm and cervical artery dissection as components.
       [ Stroke vol. 25 pp. 2028 – 2037 ’94 ]  Intracranial aneurysms have been associated with the following hereditary disorders.  However, only polycystic kidney disease, Ehlers Danlos, Marfan’s neurofibromatosis and pseudoxanthoma elasticum are at increased risk of aneurysm.  The others may be fortuitous.  Among the others a alpha-glucosidase deficiency, alpha-antitrypsin deficiency, alkaptonuria, Fabry’s disease, hereditary hemorrhagic telangiectasia, Noonan’s syndrome, tuberous sclerosis, and multiple endocrine neoplasia type I syndrome.
      [ Brit. Med. J. vol. 311 pp. 288 – 289 ’95 ] A study of the first degree (1290) and second degree (3038) relatives of 163 patients with subarachnoid hemorrhage from the Netherlands showed that 10/1290 first degree and 4/3038 second degree relatives had had a subarachnoid hemorrhage.  This is a 6 fold higher risk for first degree relatives than the population at large (however, fewer than 1% of first degree relatives had had a subarachnoid hemorrhage).   3 other studies (which the authors criticize) hadn’t found this.  [ Stroke vol. 27 pp. 7 – 9 ’96 ] A further study of this group showed that hypertension was 2.3 times as common in first degree relatives, stroke was 1.8 times as common and coronary heart disease was 1.9 times as common in first degree relatives (as compared to second degree relatives).  Thus the increased risk of subarachnoid hemorrhage in first degree relatives may reflect an increase in known risk factors for subarachnoid hemorrhage rather than a ‘new’ defect in the arterial walls.
       [ Arch. Neurol. vol. 52 pp. 202 – 204 ’95 ] A much higher incidence of subarachnoid hemorrhage in first degree relatives of the 149 cases of subarachnoid hemorrhage in Seattle over 2 years is reported.  An astounding 11.4% of cases had a first degree relative with a history of subarachnoid hemorrhage (vs. 6.4% of controls through random digit dialing).    When I take family histories (which I do for every patient I see), I don’t get anything nearly this high (I think, but I’ll have to look).   Another study estimated that the percentage of first degree relatives should be 5.5% [ Stroke vol. 23 pp. 1024 – 1030 ’92 ].
     [ Neurol. vol. 53 pp. 982 – 988 ’99 ] Another study on aneurysm risk of first degree relatives of patients who suffered a subarachnoid hemorrhage from an intracranial aneurysm.  There were 193 index patients and 626 first degree relatives studied 78% of those eligible).    Aneurysms were found in 25/626 — a 4% incidence.  The group with aneurysm didn’t have a high number of atherosclerotic risk factors.    This only twice the 2.3% prevalence of unruptured aneurysms in the general population.    The rate of subarachnoid hemorrhage in first degree of aneurysmal bleeders is 3- 7 fold that of the general population.   Given the only twofold increased prevalence of aneurysm found in this study, this may mean that there may be two types of aneurysms which run in families — the bleeding kind and the nonbleeding kind.
     [ Stroke vol. 27 pp. 1050 – 1054 ’96 ] In a study of 30 patients with ruptured aneurysm from 14 families in which another member had an aneurysm 24/30 were women.
        [ Lancet vol. 349 pp. 380 – 384 ’97 ] A study from Finland screened first degree relatives over the age of 30 of index cases of subarachnoid hemorrhage with magnetic resonance angiography (MRA)  There were 698 available of whome 438 were screened with magnetic resonance angiography.  38/438 had aneurysms (families with polycystic kidney disease, Marfan’s, Ehlers Danlos IV were excluded).
        [ Can. J. Neurol. Sci. vol. 24 pp. 326 – 331 ’97 ] The Saguenay Lac Saint Jean area of Quebec contains  ~ 300,000 people (all inbred).  The incidence of familial aneurysm is very high (related to the total aneurysm burden) and 144/502 individuals with ruptured intracranial aneurysm had another affected family member (first to third degree relative).   However, they think this is due to accidental aggregation as the families are large (average number of siblings is 7 ! ).
        [ Neurol. vol. 51 pp. 1125 – 1130 ’98 ] A study of 125 relatives of patients in 23 families in which 2  more individuals had aneurysmal subarachnoid hemorrhage.  116 had no history of aneurysm themselves and 7/116 had an asymptomatic ruptured aneurysm.  9 had a history of aneurysm and 3/9 had new asymptomatic intracranial aneurysms.   MRA was used to study the 116 and CT angiography was used to study the 9.
Here is the first post on the subject, written almost 10 years ago

Why Organic Chemistry should always be taken (and passed) by pre-meds

Back when I was posting on “The Skeptical Chymist”, the editor (Stuart Cantrill), told me that noises were being made about dropping organic chemistry from the pre-med curriculum and asked me to comment. I didn’t because the idea seemed so ridiculous. There is no possibility of really understanding anything about cellular biology, drug action, molecular biology etc. etc. without a firm grounding in organic chemistry. You simply must have some idea what vitamins, proteins, DNA and RNA and the drugs you’ll be using look like and how they chemically interact — which is what organic chemistry gives you the background for. Not that you can stop there — but all medical schools teach biochemistry — which starts at organic chemistry and takes off from there. Organic certainly helped me follow molecular biology as it exploded starting in the 60s.

Cynics might say that docs don’t synthesize things or crystallize the drugs they use. Knowing what’s going on under the hood is just esthetic filigree. Just tell them what ‘best practice’ is, and let them follow it like robots. Who cares if they know the underlying science. People drive cars without really understanding what a carburator or a manifold does (myself included).

It wasn’t until I got about 400 pages into the magnificent textbook of Organic Chemistry by Clayden, Greeves, Warren and Wothers (only 1100 action packed pages to go !) that the real answer became apparent. The stuff is impossible to memorize. Only assimilating principles and applying them to novel situations will get you through — exactly like the practice of medicine.

Let us suppose you have an eidetic memory, and know the best treatment for every condition. You wouldn’t have to know any science at all, would you?

What’s wrong with this picture? First of all, there isn’t a best treatment known for every condition. Second, every doc will see conditions and problems that simply aren’t in the books. When I first started out, I was amazed at how much of this there was. I asked an excellent internist who’d been in practice for 30 years if he’d seen it all. He thought he saw something completely new each week. Third, conditions occur in combinations, and many patients (and nearly all the elderly) have many more than one problem. The conditions and treatments interact in a highly nonlinear fashion. The treatment for one problem might make another much worse (see below).

Here is a concrete example using a familiar person (Sonia Sotomayor) and a disorder which should be known to all (the new Swine Flu which swept America and the world this spring). Let’s say that you’re that lucky soul with the perfect memory who knows all the best treatments (well those that exist anyway) and as such you’ve been given the responsibility of taking care of her.

It is public knowledge (e.g. Wikipedia) that Justice Sotomayor has had diabetes since age 8, requiring insulin since that time. Pictures show, that like many diabetics, she is overweight — depending on how tall she is I’d guess by 25 – 45 pounds. Influenza is usually a disease of the fall and winter, and the new Swine Flu is now down in South America, but it’s likely to sweep back up here this fall. We know it’s extremely infectious, but so far fortunately rather benign. There is no guarantee that it will stay that way. Suppose that while down in S. A. it mutated and has become more virulent (a possibility that the CDC takes extremely seriously).

What if she gets the new Swine flu next month? At this point there is no ‘best treatment’ known. Diabetics don’t do well with infections — they get more of them, and have more complications when they do. Her diabetes is certainly going to get worse. What if some think the ‘best treatment’ is corticosteroids (which is often used for severe lung infections) — which will really raise hell with her diabetes? Should you give it? Recall that corticosteroid use during the Asian SARS epidemic (another serious lung infection) seemed to hurt rather than help (Journal of Infection, Volume 51, Issue 2, Pages 98-102). There is no data to help you here and you and your patient don’t have the luxury of waiting for it. Don’t forget that her father died at 42 of heart disease. That could be relevant to what you do. Suppose, like many overweight diabetics she has high blood pressure and elevated lipids as well. How will that affect her management?

Your perfect eidetic memory of medicine will not be enough to help you with her management — you are going to have to think, and think hard and apply every principle of medicine you know to a new and unfamiliar situation with very little data to help you.

Sounds like Organic Chemistry doesn’t it? Anyone without the particular type of mind that is able absorb and apply multiple and (often) conflicting principles doesn’t belong in medicine. A hardnosed mathematician I audited a course from a few years ago, said that people would come up to him saying that if they couldn’t pass Calculus, they wouldn’t get into medical school. He felt that if they couldn’t, he didn’t want them in medical school (I’m not sure he told them this — probably he did). The same thing holds in spades for Organic Chemistry.

Stock tip — update

The FDA approved esketamine (Spravato) last week (see copy of original post at the end).  I had recommended buying Johnson and Johnson if the FDA approved it.  I think it’s a good long term buy, but there is no rush for the following reason — Esketamine is not a drug you can get a prescription for and take on you own. Because of the psychiatric side effects it must be administered in a SPRAVATO REMS.

Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO™ is available only through a restricted program called the SPRAVATO™ REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.

Important requirements of the SPRAVATO™ REMS include the following:

  • Healthcare settings must be certified in the program and ensure that SPRAVATO™ is:
    • Only dispensed in healthcare settings and administered to patients who are enrolled in the program.
    • Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO™.
  • Pharmacies must be certified in the REMS and must only dispense SPRAVATO™ to healthcare settings that are certified in the program.

So you can’t go to some shady practitioner who’ll say you have treatment resistant depression and get some (e.g. the pill pushers for opiates, ‘medical’ marihuana  etc. etc.)

So there aren’t going to be hordes of users right away, although the stuff I’ve read implies that there will be eventually.

If you have a subscription to Cell have a look at vol. 101 pp. 774 – 778 ’19 by the guys at Yale who did some of the original work.  If not content yourself with this.

They are refreshingly honest.

Was the Discovery of Ketamine’s Antidepressant Serendipitous?Of course. However, its discovery emerged from the testing of a novel mechanistic hypothesis related to the pathophysiology of depression.”

Basically the authors rejected the regnant theory of depression, namely that the cause was to be found in monoamine neurotransmission (e.g. by dopamine, norepinephrine, serotonin).  There was some evidence that the cerebral cortex was involved in depression (not just the monamine nuclei of the brainstem), so they looked at the two major neurotransmitters in brain (glutamic acid, and GABA), and chose to see what would happen if they blocked one of the many receptors for glutamic acid, the NMDA receptor.  They chose ketamine to do this.
Here’s what they found,  A single dose of ketamine produced antidepressant effects that began within hours peaked in 24 – 72 hours and dissipated within 2 weeks (if ketamine wasn’t repeated).  This was in 50 – 75% people with treatment resistant depression.  Remarkable 1/3 of treated patients went into remission.    There simply has never been anything like this, which is why I thought the drug would be a blockbuster.
There is a lot of speculation about just which effect of esketamine is crucial (increase in glutamic acid release with AMPAR stimulation, brain derived neurotrophic factor (BDNF) release, TrkB receptor stimulation, mTORC1 activation, local protein synthesis, restoration of functional connectivity in functional MRI.   In animals one sees a rapid proliferation of dendritic spines.
As promised – here’s a copy of the first post

Stock tip

The past performance of stock recommendations is no guarantee that it will continue — which is fortunate as my first tip (ONTX) was a disaster.  I knew it was a 10 to one shot but with a 100 to 1 payoff.  People play the lottery with worse odds.  Anyway ONTX had a rationale — for the gory details see — https://luysii.wordpress.com/2016/06/01/in-a-gambling-mood/

For those brave souls who followed this recommendation (including yours truly) here’s another.

On 4 March 2019 if the FDA approves esketamine for depression, buy Johnson and Johnson.  Why?  Some people think that no drug for depression works that well, as big Pharma in the past only was reporting positive studies.  The following is from Nature 21 February 2019.

Depression drug A form of the hallucinogenic party drug ketamine has cleared one of the final hurdles towards clinical use as an antidepressant. During a 12 February meeting at the US Food and Drug Administration (FDA) in Silver Spring, Maryland,an independent advisory panel voted 14 to 2 in favour of recommending a compound known as esketamine for use in treating depression.

What’s so hot about esketamine?  First its mechanism of action is completely different than the SSRIs, Monoamine oxidase inhibitors, or tricyclic antidepressants.

As you likely know, antidepressants usually take a few weeks to work at least in endogenous depression.  My clinical experience as a neurologist is slightly different, as I only used it for patients with disease I couldn’t help (end stage MS etc. etc.) where the only normal response to the situation was depression.  They often helped patients within a week.

I was staggered when I read the following paper back in the day.  But there was no followup essentially.

archives of general psychiatry volume 63 pp. 856 – 864 2006
The paper is not from St. Fraudulosa Hospital in Plok Tic, but from the Mood Disorders Research Unit at the National Institute of Mental Health.
Here are the basics from the paper

Patients  Eighteen subjects with DSM-IV major depression (treatment resistant).

Interventions  After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.

Main Outcome Measure  Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.

Results  Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

Read this again: showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week.

This is absolutely unheard of.  Yet the paper essentially disappeared.

What is esketamine?  It’s related to ketamine (a veterinary anesthetic and drug of abuse) in exactly the same way that a glove for your left hand is related to a right handed glove.  The two drugs are optical isomers of each other.

What’s so important about the mirror image?  It means that esketamine may well act rather differently than ketamine (the fact that ketamine worked is against this).  The classic example is thalidomide, one optical isomer of which causes horrible malformations (phocomelia) while the other is a sedative used in the treatment of multiple myeloma and leprosy.

If toxic side effects can be avoided, the market is enormous.  It is estimated that 25% of women and 10% of men will have a major depression at some point in their lives.

Initially, Esketamine ( SPRAVATOTM)  will likely be limited to treatment resistant depression.  But depressed people will find a way to get it and  their docs will find a way to give it.  Who wants to wait three weeks.  Just think of the extremely sketchy ‘medical indications’ for marihuana.

If you are over 50 it’s healthier to be overweight than not

Seriously folks, the lowest mortality rates over 50 occur in people currently defined as overweight. This is not theory, but data based on millions of people (see later).

So how does medicine define who is overweight?  By the Body Mass Index (BMI) being over 25 and under 30.  Obesity is defined as a BMI over 30.

Saying that someone over 50 with a BMI between 25 and 30 is overweight is true by medical definition, but that doesn’t make being overweight unhealthy (which is of course the implication of the term).

Well medically, you can define words any way you want, but Abraham Lincoln had it right

” How many legs does a dog have if you call his tail a leg?

Four.

Saying that a tail is a leg doesn’t make it a leg.”

 

If you’re itching to find out what your BMI is, the following site works for meters and kilograms or pounds, feet and inches — https://bmicalculator.mes.fm/?gclid=CM66rIG2tc0CFYQ2gQodOdINEg.

Here is where you can read the paper summarizing data on nearly 3 million people– https://jamanetwork.com/journals/jama/fullarticle/1555137?__rtqa=f4c5e818aba04f769cfc65207b2199b9

It’s better to read the following article in Nature.  It actually includes  the mortality curves at different ages which you can inspect at your leisure —

http://www.nature.com/news/the-big-fat-truth-1.13039

The only thing I don’t like about the BMI vs. mortality diagram, is that it is rather compressed, with data from BMI’s ranging from 15 to 45.  So the overweight range (25 – 30) doesn’t take up much space.  But look carefully at the overweight range — the curve is pretty flat here regardless of age showing that it really doesn’t matter how overweight you are (as long as you’re not obese, or superskinny).

Naturally this did not sit well people who’d staked their research careers on telling people to lose weight. One study by a Harvard guy removed 900,000 people from the JAMA study.    Robert Eckel, an endocrinologist at University of Colorado in Denver made the great comment that  “It’s hard to argue with data. We’re scientists. We pay attention to data, we don’t try to un-explain them.”

Now here is an explanation which I’ve not seen elsewhere so it might be original.

The BMI is far from perfect, but to calculate it all you need are two simple measurements that anyone can make — height and weight. It doesn’t rely on what people remember (how much they usually eat, what they weighed in the past.   However the calculation of BMI is not a simple ratio of weight divided by height but weight divided by height squared.

People lose height as they age, so the BMI is quite sensitive to it (remember the denominator has height squared). As a high school basketball player my height was 6′ 1”+, (at age 75) it was 6’0″ (God knows what it is now). So even with constant weight my BMI goes up.

It is now time to do the calculation to see what a fairly common shrinkage from 73.5 inches to 72 would to to the BMI (at a constant weight). Surprisingly it is not trivial — (72/73.5) * (72/73.5) = .9596. So the divisor is 4% less meaning the BMI is 4% more, which is almost exactly what the low point on the curve does with each passing decade after 50 ! ! !

I mistrust models

This is not a new post, but I think it’s worth republishing some old ones given the serious proposals out there to radically alter our society and economy based on what models have predicted about our climate.

Here are three, the second with a few apocalyptic predictions from the past, the third about why the US was smart to withdraw from the Paris accord

I mistrust models.

I have no special mistrust of climate models, I mistrust all models of complex systems.  Here are six reasons why.

Reason #1:  My cousin runs an advisory service for institutional investors (hedge funds, retirement funds, stock market funds etc. etc.)  Here is the beginning of his latest post 16 June ’17

There were 3 great reads yesterday.

First was Neil Irwin’s article in the NY Times “Janet Yellen, the Fed and the Case of the Missing Inflation.”  He points out that Yellen is a labor market scholar who anticipated the sharp decline in the unemployment rate. However the models on which the Fed has relied anticipate higher levels of inflation. Yet every inflation measure that the Fed uses has fallen well short of the Fed’s 2% stability rate. If they continue raising short-term rates in the face of low inflation, then “real” rates could restrain future economic growth.

Second was Greg Ip’s article “Lousy Raise? It Might Not Get Better.” Greg makes the point that tight labor markets are a global phenomenon in many industrialized countries, yet wage inflation remains muted. Writes Greg “If a labor market this tight can’t generate better pay, quite possibly it never will in Germany & Japan.”

Third was an article by Glenn Hubbard (Dean of Columbia Business School & former chairman of the Council of Economic Advisors under George W. Bush). His Wall Street Journal op-ed was titled “How to Keep the Fed from Following its Models off a Cliff.”  Hubbard suggests that Fed officials should interact more with market participants and business people. And Fed governors should be selected because of their varied life experiences, and they should encourage a healthy skepticism of prevailing economic models.

Serious money was spent developing these models.  Do you think that climate is in some way simpler than the US economy, so that they are more likely to be accurate?  I do not.

Addendum 5 March 2019: In numbers just in today, US GDP grew by  3.1 percent between fourth quarter 2017 and fourth quarter 2018. The Federal Reserve’s December 2017 median projection of  growth for 2018 was 2.5%.  They were off by nearly 25%.  My wife’s college roommate is a very bright woman who worked for the Fed as a mathematical economist for years.  The problem is not her intelligence nor those of her colleagues, but the models they are using. 

Reason #2: Americans are getting fatter yet living longer, contradicting the model that being mildly overweight is bad for you.  It is far too long to go into so here’s the link — https://luysii.wordpress.com/2013/05/30/something-is-wrong-with-the-model-take-2/.

The first part is particularly fascinating, in that data showed that overweight (not obese) people tended to live longer.  The article describes how people who had spent their research careers telling the public that being overweight was bad, tried to discount the data. The best quote in the article is the following ““We’re scientists. We pay attention to data, we don’t try to un-explain them.”,

Reason #3: The economic predictions of the Congressional Budget Office on just about anything –inflation, gross national product, economic growth, the deficit — are consistently wrong — http://www.ncpa.org/sub/dpd/?Article_ID=21516.

Addendum 28 June “White house economists overestimated annual economic growth by about 80 percent on average for a six year stretch during Barack Obama’s presidency, according to Freedom Works economic consultant Stephen Moore.

Economists predicted growth between 3.2 to 4.6 percent for the years 2010 through 2015. Actual economic growth never hit above 2.6 percent.”

Reason #4:  Animal models of stroke:  There were at least 60, in which some therapy or other was of benefit.  None of them worked in people. It got so bad I stopped reading the literature about it.  We still have no useful treatment for garden variety strokes

Reason #5:  The Club of Rome,  — dire prediction based on a computer model which got a lot of play in the 70s.  For details see — https://luysii.wordpress.com/2017/06/01/a-bit-of-history/.  The post also has a lot about “The Population Bomb” and its failed predictions and also a review of a book about “The Bet” between Paul Ehrlich and Simon

Reason #6: Live by the model, die by the model. A fascinating book “Shattered” about the Hillary Clinton campaign, explains why the campaign did no polling in the final 3 weeks of the campaign. The man running the ‘data analytics’ (translation: model) Robby Mook, thought the analytics were better and more accurate (p. 367).

A bit of history

I’ve been reading Nature since I’ve been able to afford a subscription, e.g. since about 1972. To put their undoubted coming hysteria about Trump’s withdrawal from the Paris agreement into perspective, consider the fact that they bought the arguments of the Club of Rome, hook line and sinker. The Wikipedia article is quite sanitized, but here’s a direct quote from the jacket flap of the club’s book “The Limits to Growth” which came out in 1972.

“Will this be the world that your grandchildren with thank you for? A world where industrial production has sunk to zero. Where population has suffered a catastrophic decline. Where the air, sea and land are polluted beyond redemption. Where civilization is a distant memory. This is the world that the computer forecasts. What is even more alarming, the collapse will not come gradually, but with awsome suddenness, with no way of stopping it”

Well, it’s 45 years later and their grandchildren have seen no such thing. Nature’s online available archives go back to 1975, but I’ve been unable to find a link to one of their articles. If anyone out there has found one, post a comment.

When we were down in New Haven, I picked up a book by a Yale Prof, Paul Sabin called “The Bet” concerning the intellectual conflict between Paul Ehrlich — he of the population bomb and Julian Simon. Ehrlich said we’d run out of just about everything shortly (presumably because of too many people), so economist Simon bet him that we wouldn’t. The intellectual war began in earnest in the 80’s and dragged on for a decade or so.

I recommend the book. In it you will find John Holdren, Obama’s ‘science’ advisor, also a devout malthusian, although with a degree in physics.

Perhaps Nature has it right this time, and that the models of warming which failed to predict the climate stasis of 17 years duration (the term pause gives away the game implying that temperature will continue to increase) are a reliable guide to the future.

Even if Nature is right, the Paris Agreement was terrible, no verification, no penalties for missing targets etc. etc. A massive expansion of governmental control and clamps on economic expansion, for minimal benefit.

So relax. Protest if you wish, it’s a cheap display of virtue which costs you nothing, even though you’re quite willing to fight global warming down to the last coal miner.

A climate treaty based on a failed model, a victory for the political class

Scientific theories stand or fall based on the accuracy of their predictions. Exactly 100 years ago Einstein’s theory of  gravity was welcomed because it corrected an inacurate prediction of Newton’s theory.

It’s worth staying the course to follow what I’m about to describe. The orbits of all our planets are nearly circular — but not exactly so. A circle has a single center; an ellipse has two ‘centers’ (focal points). Planetary orbits have the sun at one focal point of the ellipse (this was known even before Newton). This means that every orbit has a point at which the planet is farthest from the sun (called the aphelion) and a point at which it is closest (the perihelion).

The perihelion doesn’t stay in the same place with each succesive orbit. Rather it moves — this is called the precession of the perihelion. Newton’s formulation of gravity predicted a certain rate at which the perihelion of the planet Mercury moved between sucessive planetary orbits — which was not corroborated by actual measurement.

Physicists a century ago were seriously exercised by this inaccuracy. So how large was it? Quite small. Recall that a circle contains 360 degrees. A degree is far too large for astronomical work. So each degree contains 60 minutes and each minute contains 60 seconds. So a second is 1/3600 of a degree. The discrepancy was a mere 43 seconds per CENTURY.

Contrast this with the inaccuracy of the models of global warming, NONE of which predicted the current stability of global atmospheric temperature as measured by satellite for the past 18+ years. It’s not that CO2 isn’t a greenhouse gas the accumulation of which (other things being equal) should reflect radiation back to earth and warm the planet. No one disputes that. It is the magnitude of the CO2 effect and the importance of other factors determining global temperature which is crucial. Clearly global temperature should have continued to rise in the past 19 years as CO2 rose. This is what the models on which the Paris agreement is predicated predicted But there has been  no rise.

It’s also fairly sleazy that all the ‘adjustments’ being made to temperatures as measured on the surface of the earth mostly adjust past temperatures downward to preserve the rise. Note that satellite temperatures are the most accurate we have and there is no way to adjust them. Unfortunately they just don’t go back that far.

It is far more accurate to say that global warming has stopped for the past 18+ years. Saying that it has paused implies that it will continue.  Some 50 post-hoc explanations of ‘the pause’ have been published.

Bottom line: the concern over global warming is based on models which have failed in their predictions of the present. There is little reason to regard them as more accurate for their predictions of the future.

 

Does gamma-secretase have sex with its substrates?

This is a family blog (for the most part), so discretion is advised in reading further.   Billions have been spent trying to inhibit gamma-secretase.  Over 150 different mutations have been associated with familial Alzheimer’s disease.  The more we know about the way it works, the better.

A recent very impressive paper from China did just that [ Science vol. 363 pp. 690- 691, 701 eaaw0930 pp. 1 –> 8 ’19 ].

Gamma secretase is actually a combination of 4 proteins (presenilin1, nicastrin, APH1 (anterior pharynx defect) and PEN-2 (presenilin enhancer 2). It is embedded in membranes and has at least 19 transmembrane segments.  It cleaves a variety of proteins spanning membranes (e.g it hydrolyzes a peptide bond — which is just an amide).  The big deal is that cleavage occurs in the hydrophobic interior of the membrane rather than in the cytoplasm where there is plenty of water around.

Gamma secretase cleaves at least 20 different proteins this way, not just the amyloid precursor protein, one of whose cleavage products is the Abeta peptide making up a large component of the senile plaque of Alzheimer’s disease.

To get near gamma secretase, another enzyme must first cleave APP in another place so one extramembrane fragment is short.  Why so the rest of the protein can fit under a loop between two transmembrane helices of nicastrin.  This is elegance itself, so the gamma secretase doesn’t go around chopping up the myriad of extracellular proteins we have.

The 19 or so transmembrane helices of the 4 gamma secretase proteins form a horseshoe, into which migrates the transmembrane segment of the protein to be cleaved (once it can fit under the nicastrin loop).

So why is discretion advised before reading further?  Because the actual mechanism of cleavage involves intimate coupling of the proteins.    One of the transmembrane helices of presenilin1 unfolds to form two beta strands, and the transmembrane helix of the target protein unfolds to form one beta strand, the two strands pair up forming a beta sheet, and then the aspartic acid at the active site of gamma secretase cleaves the target (deflowers it if you will).  Is this sexual or what?

All in all another tribute to ingenuity (and possibly the prurience) of the blind watchmaker. What an elegant mechanism.

Have a look at the pictures in the Science article, but I think it is under a paywall.

Stock tip

The past performance of stock recommendations is no guarantee that it will continue — which is fortunate as my first tip (ONTX) was a disaster.  I knew it was a 10 to one shot but with a 100 to 1 payoff.  People play the lottery with worse odds.  Anyway ONTX had a rationale — for the gory details see — https://luysii.wordpress.com/2016/06/01/in-a-gambling-mood/

For those brave souls who followed this recommendation (including yours truly) here’s another.

On 4 March 2019 if the FDA approves esketamine for depression, buy Johnson and Johnson.  Why?  Some people think that no drug for depression works that well, as big Pharma in the past only was reporting positive studies.  The following is from Nature 21 February 2019.

Depression drug A form of the hallucinogenic party drug ketamine has cleared one of the final hurdles towards clinical use as an antidepressant. During a 12 February meeting at the US Food and Drug Administration (FDA) in Silver Spring, Maryland,an independent advisory panel voted 14 to 2 in favour of recommending a compound known as esketamine for use in treating depression.

What’s so hot about esketamine?  First its mechanism of action is completely different than the SSRIs, Monoamine oxidase inhibitors, or tricyclic antidepressants.

As you likely know, antidepressants usually take a few weeks to work at least in endogenous depression.  My clinical experience as a neurologist is slightly different, as I only used it for patients with disease I couldn’t help (end stage MS etc. etc.) where the only normal response to the situation was depression.  They often helped patients within a week.

I was staggered when I read the following paper back in the day.  But there was no followup essentially.

archives of general psychiatry volume 63 pp. 856 – 864 2006
The paper is not from St. Fraudulosa Hospital in Plok Tic, but from the Mood Disorders Research Unit at the National Institute of Mental Health.
Here are the basics from the paper

Patients  Eighteen subjects with DSM-IV major depression (treatment resistant).

Interventions  After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.

Main Outcome Measure  Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.

Results  Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

Read this again: showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week.

This is absolutely unheard of.  Yet the paper essentially disappeared.

What is esketamine?  It’s related to ketamine (a veterinary anesthetic and drug of abuse) in exactly the same way that a glove for your left hand is related to a right handed glove.  The two drugs are optical isomers of each other.

What’s so important about the mirror image?  It means that esketamine may well act rather differently than ketamine (the fact that ketamine worked is against this).  The classic example is thalidomide, one optical isomer of which causes horrible malformations (phocomelia) while the other is a sedative used in the treatment of multiple myeloma and leprosy.

If toxic side effects can be avoided, the market is enormous.  It is estimated that 25% of women and 10% of men will have a major depression at some point in their lives.

Initially, Esketamine ( SPRAVATOTM)  will likely be limited to treatment resistant depression.  But depressed people will find a way to get it and  their docs will find a way to give it.  Who wants to wait three weeks.  Just think of the extremely sketchy ‘medical indications’ for marihuana.

 

Goodbye to the blind watchmaker — take I

The Michelson and Morley experiment destroyed the ether paradigm in 1887, but its replacement didn’t occur until Einstein’s special relativity in 1905.  One can disagree with a paradigm without being required to come up with something to replace it. Unfortunately, we tend to think in dichotomies, so disagreeing with the blind watchmaker hypothesis for life itself tends to place you in the life was created by some sort of conscious entity.  “Hypotheses non fingo”  (Latin for “I feign no hypotheses”) which is what  Newton famously said  when discussing action at a distance which his theory of gravity entailed (which he thought was pretty crazy).

Here are  summaries of four previous posts (with links) showing why I have problems accepting the blind watchmaker hypothesis.  These are not arguments from faith which nowhere appears, but deduction from experimental facts about the structures and processes which make life possible. Be warned.  This is hard core chemistry, biochemistry and molecular biology.

First the 20,000 or so proteins which make us up, a nearly vanishing fraction of the possible proteins.  For how vanishing see — https://luysii.wordpress.com/2009/12/20/how-many-proteins-can-be-made-using-the-entire-earth-mass-to-do-so/.  Just start with 20 amino acids, 400 dipeptides, 8000 tripeptides.  Make one molecule of each and see how long a protein you wind up with making all possibilities along the way.  The answer will surprise you.

Next the improbability of a protein having a single shape (or a few shapes) for some chemical arguments about this — see https://luysii.wordpress.com/2010/08/04/why-should-a-protein-have-just-one-shape-or-any-shape-for-that-matter/

After that — have a look at https://luysii.wordpress.com/2010/10/24/the-essential-strangeness-of-the-proteins-that-make-us-up/.

The following quote is from an old book on LISP programming (Let’s Talk LISP) by Laurent Siklossy.“Remember, if you don’t understand it right away, don’t worry. You never learn anything, you only get used to it.”   Basically I think biochemists got used to thinking of proteins have ‘a’ shape or a few shapes because that’s what they found when they studied them.

If you think of amino acids as letters, then proteins are paragraphs of them, but to have biochemical utility they must have ‘meaning’ e.g. a constant shape.

Obviously the ones making us do have shapes, but how common is this in the large universe of possible proteins.  Here is an experiment which might show us (or not)– https://luysii.wordpress.com/2010/08/08/a-chemical-gedanken-experiment/.

From a philosophical point of view, the experiment is quite specific.  From a practical point of view quite possible to start, but impossible to carry to completion.

Well this is a lot of reading to do (assuming anyone does it) and I’ll stop now (although there is more to come).

Why do this at all?  Because I’ve been around long enough to see authoritative statements (by very authoritative figures) crash and burn.  Most of them I didn’t believe at the time — here are a few

l. The club of Rome’s predictions

2. The population bomb of Ehrlich

3. Junk DNA

4. We are 98% Chimpanzee because our proteins are that similar.

5. Gunther Stent, very distinguished molecular biologist, writing that we were close to the end of our understanding of genetic biology.  This in 1969.

The links elaborate several reasons why I find the Blind Watchmaker hypothesis difficult to accept.  There is more to come.

“Hypotheses non fingo”

You might as well watch the Kardashians

You might as well watch the Kardashians.  Reading Shakespeare will not protect you against cognitive decline.  Although you can spindle and mutilate the intellectual cards you were dealt, you can’t play them.  That’s the rather depressing result of from  large (over 1,000 subjects) just in [ Proc. Natl. Acad. Sci. vol. 116 pp. 1832 – 1833, 2021 – 2026 ‘ 19 ].  You have doubtless heard that people who have higher educational attainment, who have had intellectually demanding occupations, who stay mentally and physically active have a lower incidence of Alzheimer’s disease.  This is true, but it’s because they were smarter to begin with.

Before describing the paper please do note that high intellectual attainment (due to high intellectual ability) is not absolutely  protective against Alzheimer’s.  Claude Shannon died of it (https://en.wikipedia.org/wiki/Claude_Shannon), as did a Fields medalist who entered college when I did, as did a classmate who wrote 43 papers testing new drugs.   It does lower the odds though.

There were intimations of this years ago [ J. Am. Med. Assoc. vol. 275 pp. 538 – 532 ’96 ] Catholic nuns ages 75 – 95 were studied. All had written an autobiographical essay at age 22 explaining why they wanted to enter the order.  14 died and some had Alzheimer’s.  The essays were read blind and scored for idea density, grammatical complexity etc. etc. Those with the lowest idea density etc. had Alzheimer’s, while those with the most intellectual complexity were free of Alzheimer neuropathology.  Of the 79 living nuns, the smart ones at age 22 remained smart for the most part at 75+ while the less gifted stayed the same.  This was a select and far from average group — all were college educated and were parochial school teachers for most of their lives.  So the group was controlled for education and occupation.

The PNAS study concerned military recruits (average age 20) entering the service between 1965 and 1975.  The people going in at age 20 were not Ivy League types, who had concocted all sorts of reasons they couldn’t serve.  The Ivy league types going in were JAG officers or Docs like myself, but we were educated and long past 20.  89% were white, 80% did not have combat exposure.

The group was part of the Vietnam Era Twin Study of Aging.  Subjects took the Armed Forces Qualification Test (AFQT) which measures cognitive ability.  Then some 1,237 were  retested at ages 51 – 59 and 1,009 were retested at an average age of 62.

Subjects filled out questionnaires concerning education, job complexity, physical and mental activity etc. etc.

So what was the best predictor of General Cognitive Ability (GCA) at 62?  It was not subsequent education, job complexity, intellectual engagement.  Each of them predicted under 1% of the variance of GCA at age 62.  The best predictor (and not that great) was GCA at 20, which accounted for over 10% of the variance.

Pretty depressing.  You can’t even play the hand you were dealt.

Somehow Princeton undergraduates have found this out and p. 15 of the 6 Feb ’19 issue of the Princeton Alumni Weekly describes the” Kardashian Lifestyle Klub, a registered student organization with about 150 members, meetings and University support“.

Proline rides again !

Proline is a kinky amino acid.  Kinky in the sense that it is only one of the twenty with a fixed configuration of its alpha carbon because of the ring (which may be why there is more of it in organisms living at high temperature) and kinky in the sense that when present in alpha helices it produces a kink.  The previous post shows how it is used to schlep the body weight’s worth of ATP we make each day out of our mitochondria — https://luysii.wordpress.com/2019/01/30/3939/.

Well here it is in one of the marijuana receptors (CB1).  Binding of delta9 THC in the 7 transmembrane alpha helix bundles of the G Protein Coupled Receptor (GPCR) causes an alteration in the kink allowing transmembrane helix 6 (TM6) to move outward toward the cytoplasm, creating a cavity on the intracellular side, where the G protein trimer can bind.

You can read much more about this in an exquisite paper [ Cell vol. 176 pp. 448 – 458 `19 ] describing the CB1 receptor bound to a synthetic ligand 20 times more potent that delta-9 tetrahydrocannabinol (delta9 THC).  It is a cryoEM study which used 177,000 projections to come up with a 3 Angstrom resolution structure of CB1 bound to MBDB-FUBINACA in complex with its G protein trimer.  They had to use a single chain variable fragment (scFv6) along with a positive allosteric modulator (PAM) called ZCZ-011 to stabilize the complex.

MBDB-FUBINACA is a story in itself.  It is presently the fentanyl of synthetic cannabinoids, which “has been linked to thousands of hospitalizations and numerous fatalities”  [ New England Journal of Medicine vol. 376 pp. 235 – 242 ’17 ].  I’m surprised I’ve never heard of it — have you? But then I’ve been retired from clinical practice for some time. Perhaps the mainstream press, pushing marihuana legalization as it has been, kept it quiet, or more likely there have been no further episodes of mass intoxication from the AMB-FUBINACA (aka the zombie drug) since 2017.

I’ve never knowingly used marihuana.  Frankly it scares me — for why please see — https://luysii.wordpress.com/2014/05/13/why-marihuana-scares-me/.

There are 4 molecular switches buried in GPCRs [ Current Med. Chem. vol. 19 pp. 1090 – 1109 ’12 ]

1. The ionic lock switch between the D/E R Y sequence at the cytoplasmic end of TM3 and E286 at the cytoplasmic end of TM6 (single letter amino acid code used) –http://130.88.97.239/bioactivity/aacodefrm.html

2. TM3 – TM7 lock switch.  In rhodopsin it is between the protonated Schiff base of lysine and a glutamic acid and it broken on light activation,.=

3. Toggle switch linked with the n P x x Y motif in TM7 (x stands for any amino acid) — much more about this later in the post.

4. Transmission switch — produced by agonist binding, the outward movement of TM6 to to ligand binding creating a hole fo the G protein to bind to the receptor on the cytoplasmic side.

So why did I call the Cell paper exquisite?  Because of the molecular detail it provides about just how MDMB FUBINACA activates CB1.  Here’s the structure of AB-FUBINACA — https://en.wikipedia.org/wiki/AB-FUBINACA.   Both look like drugs designed by a committee.  They both have a para-iodophenyl group, an amide, and a fused indole ring with an extra nitrogen (imidazole ring — I never could keep heterocyclic nomenclature straight).    MDMB has a methyl ester (in place of the amide) and a tertiary butyl group (in place of the isoPropyl group).

I don’t have time to look up how Pfizer came up with it.  The FUBINACAs do not resemble delta9 THC at all — https://en.wikipedia.org/wiki/Tetrahydrocannabinol.

The pictures in the paper show how the hydrophobic aromatic side chains of FIVE phenylalanines and 2 tryptophans create a nice oily space for delta9 THC and MBDB-FUBINACA to bind.

F200 (phenylAlanine 200) and W356 are the toggle twin switch which stabilize the inactive conformation of CB1.  The rotation of F200 to interact with the imidazole of FUBINACA, allows W356 to rotate outward, changing the kink produced the the proline #358  in TM6 allowing the helix to straighten and rotate outward toward the cytoplasm, creating a cavity for the G protein to bind to.

Definitely a tour de force for the blind watchman.