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  They are far too out of date to be of clinical use, and hopefully more work has been done since I retired in 2000.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.

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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.

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/668195

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 ( SPRAVATO^TM)  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 ! ! !

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.

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/668195

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 ( SPRAVATO^TM)  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.

 

Another way to study Alzheimer’s

Until I read the paper PLOS Genet. 14, e1007791 (2018)., I thought that this was a sure way to win Nobel prize.  It’s still pretty interesting.  The abstract in Science was misleading, implying that there was an APOE4 variant which was actually protective against Alzheimer’s disease. That would have been fantastic, as it would provide a clue as to just what the APOE4 allele was doing to increase the risk of Alzheimer’s disease.

A huge amount of work has been done on APOE4.   Googling produced 433,000 results (0.46 seconds).  Theories abound but we still don’t know.

The authors studied Blacks and Puerto Ricans and found that if you inherited the APOE4 allele from an African source (rather than a European source), your chance of developing Alzheimer’s disease was significantly less.  A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study.

The numbers: ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background).

Note that the ORs are still up for Alzheimer’s if you have APOE4, but the differences are significant and certainly real given the size of the study.

The authors think it’s the area around the APOE  gene, rather than the total genetic background (African vs. European etc. etc.)

It still might be worth doing the following.  Take skin fibroblasts from all four types of people (Puerto Ricans with APOE4 on African background, Puerto Ricans with APOE4 on European background, Blacks with APOE4 on African background, APOE4 on a European background).

Make induced pluripotent stem cells (iPSCs) from them (the technology to do so is quite advanced). Differentiate these iPSCs into neurons  and others into glia (technology quite available).  Study protein and mRNA expression, epigenetic modifications in neurons and glia from all 4 groups.  This might tell you just what APOE4 was doing in high and lower risk people, and possibly might give a clue as to how it was increasing Alzheimer’s risk.

My hopes were really up, because the abstract in Science implied that APOE4 in Blacks and Puerto Ricans was actually absolutely rather than relatively protective, which would have given us some serious clues to Alzheimer pathogenesis, when APOE4 protective cells were contrasted with APOE4 increased risk cells.

Oh well.

What else are we not being told?

All the best to justice Ginsburg and her recent surgery for two tumors on her lung. What else are we NOT being told?  Recall that today’s release noted that the tumors were discovered 6 weeks ago when she fell and broke some ribs.  Not a word about them until today.  Typical obfuscation about the health of a major figure — see some old posts on this point with other people.

https://luysii.wordpress.com/2012/12/31/medical-tribulations-of-politicians-degrees-of-transparency/

https://luysii.wordpress.com/2012/02/26/diagnosis-by-media-release-the-continuing-saga-of-hugo-chavez/

It may well be that Ginsburg (who has total control over her medical information as all patients should have) didn’t want this released.

 

This sort of thing  happens over and over.  Arafat was doing wonderfully after being airlifted to  France (until he didn’t).  Subsequently it was found that the family (not his physicians)  was releasing this information.  Essentially he was a corpse the whole time there.  The soi-disant ‘investigative press’ was nowhere to be found.  They could have noted the source of this information (e.g. the family not the docs taking care of him)  before he died, but they didn’t.

Is a little infection good for you? If so what about radiation?

Could a little infection be good for you?  Well how about the immune stimulation it produces?  We’re talking about trained immunity here, and evidence for it started nearly 100 years ago in northern Sweden.  TB was a much bigger problem back then (Hell, my grandmother died of undiagnosed tuberculosis in a university hospital in 1967).  Bacille Calmette Guerin (BCG) is an attenuated form of mycobacterium tuberculosis (TB to you). Immunizing with BCG was thought to be protective against TB.  100 years later people are still arguing about it.

What no one is arguing about is the fact the unvaccinated infants had a 10% mortality in the first year of life (the good old days weren’t that good), while the vaccinated ones had a 3% one year mortality.  The 10% that did die, didn’t die of TB either.

It’s pretty technical, but basically BCG vaccination jazzes up the immune system, making it more responsive to the zillions of critters infesting us. [ Proc. Natl. Acad. Sci. vol. 109 pp. 17537 – 17542 ’12 ] has the details  — inferferon gamma, monocyte derived cytokines, the NOD2 receptor, histone 3 lysine 4 trimethylation etc. etc.

These are rather nonspecific features of innate immunity, and not specifically directed at anything in particular (which is why it is called trained immunity).

Well infection jazzes up the immune system too.  Cell vol, 175 pp. 1634 – 1650 ’18 showed that white cells of mice found in the lungs (alveolar macrophages) developed it after a viral infection, making them more resistant to a subsequent bacterial infection.  Could this be general?

Which brings us to a much larger fish to fry –hormesis.

Toxicology basically had two models of how we deal with toxic agents

l. Threshold model — below a certain dose, no harm results.  Arguably true — can one molecule of anything kill you?  Used by the EPA for nonCarcinogens

2. Linear no-threshold model — now matter how lot the dose, damage is seen. This is obviously crazy (see #1 above) but apparently is used by the EPA for carcinogens.

Enter model #3 — Hormesis

The best example is the famous J curve for alcohol in which small amounts are beneficial  at low doses for the heart and huge amounts are horrible (although a recent meta-analysis has challenged this  [ Lancet vol. 392 pp. 1015 – 1035 ’18 ], but I don’t trust them — for why see http://science.sciencemag.org/content/sci/361/6408/1184.full.pdf.

Hormesis says that other toxic agents (radiation, cadmium, dioxin, saccharin, polychlorinated biphenyls) all have J curves like alcohol.   Articles explaining hormesis can be found in — Nature vol. 421 pp. 691 -692 2003, Scientific American 9/2003.  The reaction to it — Science vol,. 302 pp. 376 – 379, 2003.

So the moral might be don’t be an immunological or a toxicological snowflake — that which doesn’t kill you makes you stronger.

Cell biological porn

Could there actually be cell biological porn?  Yes indeedy, and hopefully the following is not behind a paywall.  https://www.cell.com/cell/fulltext/S0092-8674(18)31308-4 — [ Cell vol. 175 pp. 1430 – 1442 ’18 ]

For why I find the pictures (and videos) in the article sexy, we have to go back the bad old days of 1962 when I entered medical school and saw my first electron micrograph.  Possessed of an immense ego and a newly minted masters of chemistry, I thought I could look at the pictures and figure out what what going on chemically to produce what was seen, namely Robertson’s unit membrane.  We know what’s going on in cell membranes now, but here’s what I had to deal with back then.

Membranes fixed with osmium tetroxide revealed a characteristic tri-laminar appearance con­sisting of two parallel outer dark (osmiophilic) layers and a central light (osmiophobic) layer.

The osmiophilic layers typically measured 20-25 Å (2.0-2.5nm) in thickness and the osmiophobic layers measured 25-35 Å (2.5-3.5 nm), yielding a total thickness of 65-85 Å (6.5-8.5 nm). This value com­pared favorably with the thickness predicted on the basis of chemical studies.

According to Robertson, the unit membrane consisted of a bimolecular lipid leaflet sandwiched between outer and inner layers of protein organized in the pleated sheet con­figuration. Such an arrangement was presumed to be basically the same in all cell membranes.

Well that was the state of the art back then.  I figured I could do better, particularly since I’d used osmium tetroxide as a chemist to convert olefins to vic-diols.  Little did I know that the osmium was being used because of its high atomic weight (76 protons and over 100 neutrons) making it relatively impenetrable to the electrons of the electron microscope.

But then I looked at what was done to prepare tissue for electron microscopy — fix with glutaraldehyde, then osmium.  Dehydrate the (dead) dissue, and embed it in a monomeric resin which polymerizes to form a solid block of plastic, then cut the block, into a very thin section, place it on a copper grid covered with carbon, pump the air out so the electrons could get through, and take a picture (prayer optional).

As soon as I read this, any hope of chemical analysis disappeared.  It also taught me that it was a very large leap to assume the electron micrographs reflected what was going on in living tissue.

Which is why the above paper is so spectacular.  It uses two types of living cells (COS-7 a fibroblast like cell line from kidney and U2OS, an osteosarcoma cell line). The technique (Grazing Incidence Structured Illumination Microscopy — GI-SIM) is incredibly complicated (but well described in the paper).  It allows you to image events near the part of the cell resting on the microscope stage at 970 Angstrom resolution at rates of ‘up to’ 266 frames/second over thousands of time points.  Recall that the lowest wavelength of visible light is 3,800 Angstroms.

Various dyes are used to differentially stain microtubules, the membranes of the endoplasmic reticulumn (ER), late endosomes (LEs), mitochondria and lysosomes.  To my amazements the pictures look the electron micrographs of yore.

You can watch mitochondria touching the ER and then splitting, ER tubules growing and shrinking and being pulled along LEs riding on microtubules etc. etc. The pictures show the same cell over a period of 4 minutes.

Then to make a neurologist’s day complete, they watch dendritic spines form and unform in cultured hippocampal neurons.

So look at the paper if you can.  You don’t even have to read it th,e pictures are explanatory.

An extraordinarily impressive work, considering where we’ve been.

Lactose intolerance and the proteins of the synaptic cleft

What does lactose intolerance have to do with the zillions of proteins happily infesting the synaptic cleft?  Only someone whose mind was warped into very abstract thinking by rooming with philosophy majors in college would see a connection.

The synaptic cleft is of immense theoretical interest to neuroscientists, drug chemists and pharmacologists, and of great practical interest to people affected by neurologic and psychiatric disease either in themselves or someone they know (e.g. just about everyone).

Almost exactly a year ago I wrote a post about a great paper on the proteins of the synaptic cleft by Thomas Sudhof.  You may read the post after the *****

Well Dr. Sudhof is back with another huge review of just how synapses are formed [ Neuron vol. 100 pp. 276 – 293 ’18 ], which covers very similar ground.

It is clear that he’s depressed by the state of the field.  Here are a few quotes

“I believe that we may need to pay more attention to technical details than customary because the pressures on investigators have increased the tendency to publish preliminary results, especially results obtained with new methods whose limitations are not yet clear.”

Translation: a lot of the stuff coming out is junk.

“Given the abundance of papers reporting non-validated protein interactions that cannot possibly be all correct, it seems that confidence in a possible protein-protein interaction requires either isolation of a stable complex or biophysical measurements of interactions using recombinant purified proteins.”

Translation:  Oy vey !

“Pre- or postsynaptic specializations are surprisingly easy to induce by diverse signals. This was first shown in pioneering studies demonstrating that polylysine beads induce formation of presynaptic nerve terminals in cultured neurons and in brain in vivo.” Obviously this means that you have to be very careful when you claim that a given protein or two causes a synapse to form, which researchers have not been.”

Translation not needed.

Then on to the meat of the review.  “An impressive number of candidate synaptic Cell Adhesion Molecules (CAMs) has been described (9 classes are given each with multiple members). For some of these CAMs, compelling data demonstrate their presence in synapses and suggest a functional role in synapses. Others, however, are less well documented. If one looks at the results in total, the overall impression is puzzlement: how do so many CAMs contribute to shaping a synapse?”

Then from 281 – 286 he goes into the various CAMs, showing the extent and variety of proteins found in the synaptic cleft.  Which ones are necessary and what are they doing?  Can they all be important.  There must be some redundancy as knockout of some doesn’t do much.

Here is where lactose tolerance/intolerance comes in to offer succor to the harried investigator.

Bluntly, they must be doing something, and something important,  or they wouldn’t be there.

People with lactose intolerance have nothing wrong with the gene which breaks down lactose.  Babies have no problem with breast milk.  The enzyme (lactase)  produced from the gene is quite normal in all of us.  However 10,000 years ago and earlier, cattle were not domesticated, so there was no dietary reason for a human weaned from the breast to make the enzyme.  Something turned off lactase production — from my reading, it’s not clear what.   The control region (lactase enhancer) for the lactase gene is 14,000 nucleotides upstream from the gene itself.  After domestication of cattle, so that people could digest milk their entire lives a mutation arose changing cytosine to thymine in the enhancer.  The farthest back the mutation has been found is 6.500 years. 3 other mutations are known, which keep the lactase gene expressed past weaning.  They arose independently.  All 4 spread in the population, because back then our ancestors were in a semi-starved state most of the time, and carriers had better nutrition.

How does this offer succor to Dr. Sudhof?  Simply this, here is a mechanism to turn off production of an enzyme our ancestors didn’t need past weaning.  Don’t you think this would be the case for all the proteins found in and around the synapse.  They must be doing something or they wouldn’t be there.  I realize that this is teleology writ large, but evolutionary adaptations make you think this way.

*****

The bouillabaisse of the synaptic cleft

The synaptic cleft is so small ( under 400 Angstroms — 40 nanoMeters ) that it can’t be seen with the light microscope ( the smallest wavelength of visible light 3,900 Angstroms — 390 nanoMeters).  This led to a bruising battle between Cajal and Golgi a just over a century ago over whether the brain was actually made of cells.  Even though Golgi’s work led to the delineation of single neurons he thought the brain was a continuous network.  They both won the Nobel in 1906.

Semifast forward to the mid 60s when I was in medical school.  We finally had the electron microscope, so we could see synapses. They showed up as a small CLEAR spaces (e.g. electrons passed through it easily leaving it white) between neurons.  Neurotransmitters were being discovered at the same time and the synapse was to be the analogy to vacuum tubes, which could pass electricity in just one direction (yes, the transistor although invented hadn’t been used to make anything resembling a computer — the Intel 4004 wasn’t until the 70s).  Of course now we know that information flows back and forth across the synapse, with endocannabinoids (e. g. natural marihuana) being the major retrograde neurotransmitter.

Since there didn’t seem to be anything in the synaptic cleft, neurotransmitters were thought to freely diffuse across it to being to receptors on the other (postsynaptic) side e.g. a free fly zone.

Fast forward to the present to a marvelous (and grueling to read because of the complexity of the subject not the way it’s written) review of just what is in the synaptic cleft [ Cell vol. 171 pp. 745 – 769 ’17 ] http://www.cell.com/cell/fulltext/S0092-8674(17)31246-1 (It is likely behind a paywall).  There are over 120 references, and rather than being just a catalogue, the single author Thomas Sudhof extensively discusseswhich experimental work is to be believed (not that Sudhof  is saying the work is fraudulent, but that it can’t be used to extrapolate to the living human brain).  The review is a staggering piece of work for one individual.

The stuff in the synaptic cleft is so diverse, and so intimately involved with itself and the membranes on either side what what is needed for comprehension is not a chemist but a sociologist.  Probably most of the molecules to be discussed are present in such small numbers that the law of mass action doesn’t apply, nor do binding constants which rely on large numbers of ligands and receptors. Not only that, but the binding constants haven’t been been determined for many of the players.

Now for some anatomic detail and numbers.  It is remarkably hard to find just how far laterally the synaptic cleft extends.  Molecular Biology of the Cell ed. 5 p. 1149 has a fairly typical picture with a size marker and it looks to be about 2 microns (20,000 Angstroms, 2,000 nanoMeters) — that’s 314,159,265 square Angstroms (3.14 square microns).  So let’s assume each protein takes up a square 50 Angstroms on a side (2,500 square Angstroms).  That’s room for 125,600 proteins on each side assuming extremely dense packing.  However the density of acetyl choline receptors at the neuromuscular junction is 8,700/square micron, a packing also thought to be extremely dense which would give only 26,100 such proteins in a similarly distributed CNS synapse. So the numbers are at least in the right ball park (meaning they’re within an order of magnitude e.g. within a power of 10) of being correct.

What’s the point?

When you see how many different proteins and different varieties of the same protein reside in the cleft, the numbers for  each individual element is likely to be small, meaning that you can’t use statistical mechanics but must use sociology instead.

The review focuses on the neurExins (I capitalize the E  to help me remember that they are prEsynaptic).  Why?  Because they are the best studied of all the players.  What a piece of work they are.  Humans have 3 genes for them. One of the 3 contains 1,477 amino acids, spread over 1,112,187 basepairs (1.1 megaBases) along with 74 exons.  This means that just over 1/10 of a percent of the gene is actually coding for for the amino acids making it up.  I think it takes energy for RNA polymerase II to stitch the ribonucleotides into the 1.1 megabase pre-mRNA, but I couldn’t (quickly) find out how much per ribonucleotide.  It seems quite wasteful of energy, unless there is some other function to the process which we haven’t figured out yet.

Most of the molecule resides in the synaptic cleft.  There are 6 LNS domains with 3 interspersed EGFlike repeats, a cysteine loop domain, a transmembrane region and a cytoplasmic sequence of 55 amino acids. There are 6 sites for alternative splicing, and because there are two promoters for each of the 3 genes, there is a shorter form (beta neurexin) with less extracellular stuff than the long form (alpha-neurexin).  When all is said and done there are over 1,000 possible variants of the 3 genes.

Unlike olfactory neurons which only express one or two of the nearly 1,000 olfactory receptors, neurons express mutiple isoforms of each, increasing the complexity.

The LNS regions of the neurexins are like immunoglobulins and fill at 60 x 60 x 60 Angstrom box.  Since the synaptic cleft is at most 400 Angstroms long, the alpha -neurexins (if extended) reach all the way across.

Here the neurexins bind to the neuroligins which are always postsynaptic — sorry no mnemonic.  They are simpler in structure, but they are the product of 4 genes, and only about 40 isoforms (due to alternative splicing) are possible. Neuroligns 1, 3 and 4 are found at excitatory synapses, neuroligin 2 is found at inhibitory synapses.  The intracleft part of the neuroligins resembles an important enzyme (acetylcholinesterase) but which is catalytically inactive.  This is where the neurexins.

This is complex enough, but Sudhof notes that the neurexins are hubs interacting with multiple classes of post-synaptic molecules, in addition to the neuroligins — dystroglycan, GABA[A] receptors, calsystenins, latrophilins (of which there are 4).   There are at least 50 post-synaptic cell adhesion molecules — “Few are well understood, although many are described.”

The neurexins have 3 major sites where other things bind, and all sites may be occupied at once.  Just to give you a taste of he complexity involved (before I go on to  larger issues).

The second LNS domain (LNS2)is found only in the alpha-neurexins, and binds to neuroexophilin (of which there are 4) and dystroglycan .

The 6th LNS domain (LNS6) binds to neuroligins, LRRTMs, GABA[A] receptors, cerebellins and latrophilins (of which there are 4)_

The juxtamembrane sequence of the neurexins binds to CA10, CA11 and C1ql.

The cerebellins (of which there are 4) bind to all the neurexins (of a particular splice variety) and interestingly to some postsynaptic glutamic acid receptors.  So there is a direct chain across the synapse from neurexin to cerebellin to ion channel (GLuD1, GLuD2).

There is far more to the review. But here is something I didn’t see there.  People have talked about proton wires — sites on proteins that allow protons to jump from one site to another, and move much faster than they would if they had to bump into everything in solution.  Remember that molecules are moving quite rapidly — water is moving at 590 meters a second at room temperature. Since the synaptic cleft is 40 nanoMeters (40 x 10^-9 meters, it should take only 40 * 10^-9 meters/ 590 meters/second   60 trillionths of a second (60 picoSeconds) to cross, assuming the synapse is a free fly zone — but it isn’t as the review exhaustively shows.

It it possible that the various neurotransmitters at the synapse (glutamic acid, gamma amino butyric acid, etc) bind to the various proteins crossing the cleft to get their target in the postsynaptic membrane (e.g. neurotransmitter wires).  I didn’t see any mention of neurotransmitter binding to  the various proteins in the review.  This may actually be an original idea.

I’d like to put more numbers on many of these things, but they are devilishly hard to find.  Both the neuroligins and neurexins are said to have stalks pushing them out from the membrane, but I can’t find how many amino acids they contain.  It can’t find how much energy it takes to copy the 1.1 megabase neurexin gene in to mRNA (or even how much energy it takes to add one ribonucleotide to an existing mRNA chain).

Another point– proteins have a finite lifetime.  How are they replenished?  We know that there is some synaptic protein synthesis — does the cell body send packages of mRNAs to the synapse to be translated there.  There are at least 50 different proteins mentioned in the review, and don’t forget the thousands of possible isoforms, each of which requires a separate mRNA.

Old Chinese saying — the mountains are high and the emperor is far away. Protein synthesis at the synaptic cleft is probably local.  How what gets made and when is an entirely different problem.

A large part of the review concerns mutations in all these proteins associated with neurologic disease (particularly autism).  This whole area has a long and checkered history.  A high degree of cynicism is needed before believing that any of these mutations are causative.  As a neurologist dealing with epilepsy I saw the whole idea of ion channel mutations causing epilepsy crash and burn — here’s a link — https://luysii.wordpress.com/2011/07/17/we’ve-found-the-mutation-causing-your-disease-not-so-fast-says-this-paper/

Once again, hats off to Dr. Sudhof for what must have been a tremendous amount of work

Who doesn’t want to be smarter?

I’ve never met anyone (even future Nobel laureates) who didn’t wish they were smarter.  So cognitive training should do the trick.  Right?  Not so fast.  In a very well written (and even funny in parts) article in PNAS vol 115 pp. 9897 – 9904 ’18 titled “How to play 20 questions with nature and lose: Reflections on 100 years of brain training research” all the pitfalls of setting up a study to prove or disprove the benefits of cognitive training are laid out.  The paper is worth reading for anyone considered any sort of manipulation to change human behavior it (including medication which is why drug chemists should be interested in it).  You can read it for free at

http://www.pnas.org/content/early/2018/09/26/161702114.full

This didn’t work for someone —

Try this one — http://www.pnas.org/content/115/40/9897

An enormous number of pitfalls of the work already done on the efficacy of cognitive training are laid out, far too numerous to summarize here.

I’ve written about one such pitfall (expectancy effects) earlier — here it is

Science proves cognitive training will raise your IQ 5 – 10 points

Who among you doesn’t want to be smarter? A placebo controlled study with 25 people in each group showed that cognitive training raised IQ 5 – 10 points [ Proc. Natl. Acad. Sci. vol. 113 pp. 7470 – 7474 ’16 ].

You know that there has to be a catch and there is. The catch points to a problem with every placebo controlled trial ever done, particularly those with drugs, so drug chemists pay attention.

What was the placebo? It was the way subjects are recruited for these studies. Of 19 previous studies in the literature, 17 recruited patients using terms like ‘cognition’ or ‘brain training’, so the authors put out two ads for subjects.

Here are the two ads they used

Ad #1

Brain Training and Cognitive Enhancement
Numerous studies of ahown that working memory training can increase fluid intelligences (several references cited)
Participate in a study today !
EMail for more information GMUBrainTraining@Gmail.com

Ad #2

EMail Today and Participate in a study
Need SONA credits? (I have no idea what they are)
Sign up for a study today and earn up to 5 credits
Participate in a study today !
cforough@masonlive.gmu.edu

I might mention that the two ads were identical in total size, font sizes, coloration used etc. etc.

” Two individual difference metrics regarding beliefs about cognition and intelligence were also collected as potential moderators. The researchers who interacted with participants were blind to the goal of the experiment and to the experimental condition”  Not bad. Not bad at all.

The results: those recruited with ad #1 showed the increase in IQ, those recruited with ad #2 showed no improvement.

It was an expectancy effect. Those who thought intelligence could be raised by training, showed the greatest IQ improvement.   Every sick patient wants to get better, and any drug trial simply must mention what it is for, the risks and rewards, so this effect is impossible to avoid. It probably explains the high placebo response rate for migraine and depression (over 30% usually).

What is really impressive (to me at least) is that the improvement was not in a subjective rating scale (such as is used for depression), but in something as objective as it gets. IQ questions have a right and wrong answers. You can argue about whether they ‘really’ measure intelligence, but they measure what they measure and fluid intelligence is one of them.

Medicine is full of fads and fashions, sugar is poison, fat is bad (no it’s good) etc. etc. and this is true in spades for treatments, particularly those touted in the press. Next time you’re in a supermarket, look at the various nostrums mentioned in the magazines at the checkout stand.

When I first started out in practice, one particular headache remedy was getting great results. The rationale behind it seemed bizarre, so I asked a very smart  old GP about it — his advice — “use it while it works”. Rest in peace, Herb