Trump’s health

Here is a link to an article containing the full text of the letter by Trump’s personal physician Harold Bornstein M. D. -=-https://www.washingtonpost.com/apps/g/page/politics/letter-from-donald-trumps-doctor-on-his-latest-physical-exam/2091/?tid=a_inl

Trump’s lipids could be better (total 232) and he is currently taking a lipid lowering agent (a statin). Aside from this, his labs are good (perfect in fact). He does take care of himself, and has annual physicals.

It isn’t clear why he had a transthoracic echocardiogram 2 years ago. Otherwise aside from that every test performed is pretty standard for a man his age.

Despite being overweight his blood pressure is excellent (particularly for man his size).

The indications for low dose aspirin aren’t stated, but yours truly has taken much more for decades based on a reading of the literature while in practice showing that doses of two adult aspirin a day reduced the recurrence rate of stroke by 33%.

So his main health problem is weight and mildly elevated lipids (even on medication).

His BMI (Body Mass Index) is stated to be 29.5. So it’s time for you to calculate your own — don’t worry that BMI is usually based on weight in kilograms and height in meters — the following site lets you put in your weight in pounds, and your height in inches — To get started, calculate your own BMI– http://bmicalculator.cc/?gclid=CM66rIG2tc0CFYQ2gQodOdINEg. A 6 footer would have to weigh 222 pounds to be obese (BMI over 30).

So is Trump’s BMI of 29.5 bad? Overweight is defined as a BMI over 25. So is a BMI over 25 bad? Not if you’re interested in mortality (death) as opposed to morbidity (things like heart attack and stroke). It turns out that the BMI with the lowest mortality at 70 is over 25 — e.g. 26. e.g. in the overweight range as currently defined. I don’t think there are good statistics on overall morbidity vs. BMI (there probably is for heart attack and stroke separately).

Now it gets interesting. That statistic cited above is based on the following data on 3 million people in 97 different studies [ J. Am. Med. Assoc. vol. 309 pp. 71 – 82 ’13 ].

At 6 feet 1+ (which I used to be) a weight of 190 puts me at 24.69. To be obese (BMI over 30) I’d need to weigh 228 (which I almost did 54 years ago).

When you plot BMI vs. probability of death you get a U shaped cure, with the very thin and the very fat showing increased risk of dying (mortality). The paper is interesting as it shows 6 curves for people at ages 20, 30, 40, 50, 60, 70. As one might expect, the curves for each age lie below the next oldest. All of them rise with BMIs under 20 and over 30, so there’s no argument about whether obesity (BMI over 30) is bad for longevity.

Well, if the curve is U shaped, it has a minimum. The excitement comes in because the healthiest weight (the minimum) is a BMI of just over 25 for those in their 60s and around 26 for those in their 70s. Also in ALL 6 age groups the curve is pretty flat between 25 and 30, rising on either side of the range.

Naturally people who’ve invested their research careers in telling everyone to diet and that weight is bad, don’t like this, and a symposium involving 200 unhappy people convened 20 February at the Harvard School of Public Health is described, along with a lot of the back and forth between the authoress of the study (Flegel) and Willett of Harvard who didn’t like it one bit. The best comment IMHO is from Robert Eckel “We’re scientists. We pay attention to data, we don’t try to unexplain them.” Read the article, it’s well written and there’s a lot more.

One final point, which might explain why the minima of the curves shift to higher BMIs at older age — which the article didn’t contain. People lose height as they age, yet the BMI is quite sensitive to it (remember the denominator has height squared). The great thing about BMI is that it’s easily measured, and doesn’t rely on what people remember about their weight or their height. Well as a high school basketball player my height was 6′ 1”+, now (at age 78) it’s 6’0″. So even with constant weight my BMI goes up.

Well it’s 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 ! ! ! This might even be an original observation, and it would explain a lot.

Well, that’s the take of this neurologist on Trump’s health — e.g.it’s pretty good. I’m going to pass this post on to the very smart internist (whose comments about Hillary you can read in — https://luysii.wordpress.com/2016/09/13/hillarys-fainting-spell/) for his take, as there really isn’t anything in the history suggest a neurologic problem. Unlike Hillary, he hasn’t fainted twice in the past 4 years, and hasn’t had a neurologic deficit persisting for a month.

The impeccable timing of the New York Times — take II

Reality keeps intruding. I’d much rather be posting about a marvelous paper (see the end), but the Sunday New York Times of 18 September 2016 had 3 articles telling us all how deplorable, irrational and islamaphobic we are, the day after 3 separate attacks on the citizenry (the Chelsea and Seaside Park bombs and the knife attack in Minnesota).

Two were on the opinion page — one comparing the Jews of the 30s trying to escape the Nazi’s with the mideast refugees, another concerned “England’s Forgotten Muslin History”. Well, we all know what a bunch of terrorists the Jews of the 30s were.

On p. 13 “Level of Hate Crimes Against U. S> Muslims Highest Since After 9/11” “Some Tie Attacks to Trump’s Statements” It couldn’t possibly be anything they’ve done.

For your enjoyment, here’s the post of just 3 months ago (13 June)

The impeccable timing of the New York Times

After putting ex-Weatherman Bill Ayers on page 1 saying he wished he’d ‘bombed more’ the day of the attack on the World Trade Center in 2001, the New York Times kept its unenviable timing record intact by posting “Dreams of my Muslim Son” about Islamophobia on the editorial page the day of the Orlando massacre. Usually they run their invariable innocent Muslims fearing hate crimes by American rednecks story a day or so after the latest atrocity.

Unfortunately Orlando can’t be camouflaged as workplace violence or the response to some video or other a la Benghazi. The perp was far too explicit. Nor can it be blamed on the failure of ‘the MidEast Peace Process’ or Israel, although undoubtedly some will try.

If I were the Muslim leadership in this country, I’d try to put together a Million Muslim March on Washington to protest the Orlando, San Bernadino, Boston etc. etc. massacres, as blots on the name of Islam. ISIS would probably try to kill a few, but it’s time for them to stand up, assuming there are large numbers of US Muslims that actually think this way.

—-

You could not have a better example of how totally out of touch elite opinion is and the placement and timing of these articles is exactly an expression of elite opinion.

I had thought that the terrorists would be lying low until after the election, as terrorist acts work in Trump’s favor. But as a friend said about another Muslim group — they never miss an opportunity to miss an opportunity.

The paper I’d planned to write about is Nature vol. 537 pp. 107 ’16 (1 September 2016 Issue).

Now on to Trump’s health information.

Thank God for the internet, warts and all

Here’s the New York Times Monday reporting on Hillary’s fainting spell the previous day — “Clinton Treated for Dehydration and Pneumonia”, “Falling Ill at 9/11 Event”. Then it states that she ‘had to be helped into a van by Secret Service Agents”.

Still on the first page, “about 90 minutes after arriving there (Chelsea’s apartment) Mrs.Clinton wearing sunglasses emerged from the apartment” She is then quoted as “I’m feeling great” “It’s a beautiful day in New York” On the front page there’s a picture of her at the 9/11 service before anything happened. Inside there’s a picture of her leaving the apartment looking just wonderful and smiling.

The Times does mention the video, and noted that it captured ‘what appeared to be her legs buckling’.

Back in the day when the NYT controlled the news, you’d think nothing much happened. However, anyone looking at the video can see her passing out and nearly hitting the pavement, until she was caught by her handlers.

As I predicted in an EMail to some friends, the Times in its letters to the editor today had a letter praising Hillary as a typical plucky lady who carried on no matter what. For a paper that routinely headlines articles dumping on the church (the front page of 14 Sep has an article concerning how Putin is using the Russian Orthodox Church to extend Russian power abroad) they certainly love one of its institutions (the amen corner — aka letters to the editor).

The paper of record in Northampton described the event has Mrs. Clinton becoming “Unwell”, With Hillary in seclusion and unable to campaign, the lead story on Yahoo yesterday, concerned an attack ad of Hillary’s on Trump, not anything he said or did.

The internet and the blogosphere is often scatological, misleading, irritating and biased. But there’s such massive coverage on the internet that it has broken the monopoly of the mainstream press. Thank God for them warts and all.

Now, hopefully back to the science.

Hillary’s fainting spell

And I thought I’d retired as a neurologist. What is there to say about the video that shows Hillary Clinton being held up by a woman on her left, later by others, and then collapsing sufficiently that her head is at most 3 feet from the pavement in one frame. You don’t have to go to medical school to call this a fainting spell.

As to what caused the episode, we can only speculate. I see no reason to trust what the campaign is putting out, that she had ‘pneumonia’ for the previous two days. Since I’ve already gone on record that she had a stroke in December 2012 ( https://luysii.wordpress.com/2016/08/24/hillary-clintons-stroke-in-2012/ ), not due to head trauma sustained in what was said to another fainting spell, people have asked me what the event could be neurologically.

But I’m a neurologist not an internist, so I talked to a very smart one for his take.

“Somewhat oddly, her campaign now reports that pneumonia had been “diagnosed” as of two days before her collapse. However, she was not acting as if she is infectious, going out into crowds and getting close to small children. The Clintons are known for lawyerly parsing of phrases carefully, so it may matter what the meaning of pneumonia “is.” Therein may lie a clue which puts the chronic non-productive cough of many months duration, along with apparent decreased stamina and a carefully tuned and truncated schedule over a similar period into perspective.

Chronic lung disease, particularly a mildly progressive idiopathic pulmonary fibrosis/interstitial pneumonia could fit that picture. It would also be technically true as a diagnosis. Whatever pulmonary condition she has does not appear to be acute.”

He also had an interesting observation on the way the faint was handled. “There must be some chronic known condition, as she has two attendants with her now at all times–large black male and heavyset white woman. Her collapse was handled as if it were familiar territory. Hustling a woman of her age into a van and driving to her daughter’s apartment is a highly unusual way to handle such a loss of consciousness in a 68-year old woman, particularly when there had to be a number of emergency vehicles loaded with EMT’s on the scene and well as several hospitals at least as close as her daughter’s apartment.” To which a friend noted that the secret service is trained to react immediately to situations like this, going through dry runs of all sorts of eventualities etc. etc.

Taking her to her daughter’s apartment is quite strange, given the way the secret service was acting 40 or so years ago. Back then, a neurosurgeon in Billings Montana told me that the secret service had called him up and asked him to be available in the coming weekend as the president would be visiting Yellowstone, a mere 140 miles away by the nearest road. It seems likely that some hospital close by was on alert that Hillary was in the neighborhood.

The internist has been watching her a lot more closely than I have and noted the following “There were shots a month or so ago of her needing help to get up outdoor stairs and also needing a small step-stool to get up into a Secret Service Suburban. My wife and I hop in and out of a Yukon and do not need any step device (they are of comparable age). After a photo of her doing that was published, she started getting in and out of vehicles on the side away from cameras and was also switched to a taller van with a step mounted on the vehicle. In February, press was forbidden by her staff from filming her climbing the stairs to board her private jet.” He wondered if she could have something like limb girdle dystrophy — watching her walk and stand during the upcoming debates will be helpful for determining that.

Finally he noted — “There are also a number of cardiovascular causes (transient arrhythmia for starters) as well as pulmonary microemboli which can cause collapse like that.”

Now for the neurologic possibilities.

There are peculiar videos purporting to show Hillary having a ‘seizure’ during a press conference. They look doctored to me. She appears to be compulsively laughing. Such seizures are called gelastic epilepsy. They are rare but I’ve seen them. They arise from the hypothalamus and the temporal lobes. Nothing in the current video is suggestive of a seizure. Loss of consciousness at this age rarely is due to a seizure. Cardiovascular causes are far more likely.

Another possible cause is a brainstem transient ischemic attack (TIA), since we have been told that the clot of 2012 was in a draining sinus of the posterior fossa (we have no pictures of any sort from that episode). Recovery in 90 minutes is consistent with either syncope or TIA.

The final possibility is that the event is a warning of an impending second stroke. If you look again at the post about the events of 2012, you’ll see that I speculated that the ‘faint’ occuring in the week of 9 December could have been a transient warning of the cerebral venous thrombosis she suffered that month. I don’t think this likely, but when I examined for the Neurology boards, fellow examiners always wanted to see how many possibilities for diagnoses the candidates can muster.

So what do I think it was? A fainting spell (syncope if you want to be impressive). Her blood pressure dropped for some reason or other, the brainstem which maintains alertness didn’t get enough fresh blood and she passed out nearly. The people with her did NOT help by keeping her erect, which kept the brainstem from getting the blood (and the oxygen it delivers) it needed. In fact holding someone up who has fainted is the perfect crime, as the brain deprived of oxygen long enough begins to die, and no marks will be found on the body.

Why out of the thousands there, on a warm but not excessively hot day, she was the only one to pass out can only be the subject of speculation until more details are forthcoming. The health of a possible future president is simply too important not to speculate about.

What neuropharmacology can’t tell us about opiates and addiction

A friend’s wife had some painful surgery and is trying to get by with as little opiates as possible, being very worried about becoming an addict, something quite reasonable if all she had to go on was the popular press with lurid stories of hapless innocents being turned into addicts by evil physicians overprescribing opiates (it’s the current day Reefer Madness story). Fortunately her surgeon wisely told her that her chances of this happening were quite low, since she’d made it past 50 with no dependency problems whatsoever. Here’s why he’s right and why neuropharmacology can’t tell us everything we want to know about opiates and addiction.

Back in the day, disc surgery required general anesthesia, dissection of the back muscles down to the spine, sometimes chipping away at the bones of the spine to remove a bone spur (osteophyte) and/or removal of the offending herniated intervertebral disc. This meant a hospital stay (unlike my ophthalmologist who had a microdiscectomy as an outpatient a few years ago). This was the era of the discovery of the protein receptor for morphine and other opiates, and we were all hopeful that this would lead to the development of a nonAddicting opiate (narcotic). Spoiler alert — it hasn’t happened and likely won’t.

Often, I was the neurologist who diagnosed the disc and told the surgeon where it was likely to be found (this was in the preCT and later the preMRI era). I’d developed a relationship with most of those I’d referred for surgery (since it was never recommended, without a trial of rest — unless there were compelling reasons not to — trouble controlling bowels and bladder, progressive weakness etc. etc.). I was their doc while they tried to heal on their own.

So post-operatively I’d always stop by to see how the surgery had worked for them. All were on a narcotic (usually Demerol back then) as even if the source of their preoperative pain had been relieved, just getting to the problem had to cause significant pain (see above).

If the original pain was much improved (as it usually was), I’d ask them how they liked the way the demerol made them feel. There were two types of responses.

#1 I hate feeling like this. I don’t care about anything. I’m just floating, and feel rather dopey. I’m used to being in control.

#2 I love it ! ! ! ! I don’t have a care in the world. All my troubles are a million miles away as I just float along.

Love it or hate it, both groups are describing the same feeling. Neuropharmacology can help to tell us why opiates produce this feeling, but it can’t tell us why some like it (about 5%) and the majority (95%) do not. This clearly is the province of psychology and psychiatry. It’s the Cartesian dualism between flesh (opiate receptor) and spirit (whether you like what it does). It also shows the limitation of purely physical reductionism of the way we react to physical events.

The phenomenon of a small percentage of people becoming addicted to a mind altering substance is general and is not confined to one class of drug. We were told never to prescribe chronic benzodiazepines (valium, etc. etc.) to a recovered alcoholic. People who get hooked on one thing are very likely to get hooked on another.

I realize that some of this could be criticized as blaming the victim, but so be it. Medical facts are just that, like what they say or not.

Addendum 11 Sep ’16 — I’m not saying that you won’t become physically dependent on opiates if you get them long enough and at high enough doses. We all would. Even if this happened to you. When you no longer needed them for pain and went through medically supervised withdrawal, you wouldn’t crave them, and do crazy things to get them (e.g. you were physically dependent but never addicted to them — it is important to make the distinction).

Example — when I was in the service ’68 – ’70, we had half a million men in Vietnam. Everyone I’ve talked to who was over there says that heroin use among the troops was 25 – 50% (high grade stuff from Thailand was readily available). As soon as they got back to the states, the vast majority gave them up (and with minimal withdrawal requiring my attention – I think I saw one convulsion due to withdrawal).

Vacation — no posts for a while

Off to Maine (and perhaps Prince Edward Island) and perhaps to see a dying friend (that’s what happens when you reach my age — 78 ). I’ve found that the best way to get back in the swing of things on return is just start with the latest journals, skipping what you missed. Trying to double up on your reading when you get back is unpleasant and makes you wish you never went away. If you missed something important, eventually you will hear about it.

So I stopped reading 26 August, and next evening bumped into a friend who wanted to discuss something in that day’s Science magazine.

Leave a comment on this post, if there’s anything you’d like to hear about.

Baudelaire comes to Chemistry

Could an evil molecule be beautiful? In Les Fleurs du Mal, a collection of poems, Baudelaire argued that there was a certain beauty in evil. Well, if there ever was an evil molecule, it’s the Abeta42 peptide, the main component of the senile plaque of Alzheimer’s disease, a molecule whose effects I spent my entire professional career as a neurologist ineffectually fighting. And yet, in a recent paper on the way it forms the fibrils constituting the plaque I found the structure compellingly beautiful.

The papers are Proc. Natl. Acad. Sci. vol. 113 pp. 9398 – 9400, E4976 – E4984 ’16. People have been working on the structure of the amyloid fibril of Alzheimer’s for decades, consistently stymied by its insolubility. The authors solved it not by Xray crystallography, not by cryoEM, but by solid state NMR. They basically looked at the distance constraints between pairs of isotopically labeled atoms, and built their model that way. Actually they built a bouquet of models using computer aided energy minimization of the peptide backbone. Another independent study produced nearly the same set.

The root mean square deviation of backbone atoms of the 10 lowest energy models of the bouquets in the two studies was small (.89 and .71 Angstroms). Even better the model bouquets of the two papers resemble each other.

There are two chains of Abeta42, EACH shaped like a double horseshoe (similar to the letter S). The two S’s meet around a twofold axis. The interface between the two S’s is form by two noncontiguous areas on each monomer (#15 – #17) and (#34 – #37).

The hydrophilic amino terminal residues (#1 – #14) are poorly ordered, but amino acids #15 – #42 are arranged into 4 short beta strands (I only see 3 obvious ones) that stack up and down the fibril into parallel in register beta-sheets. Each stack of double horseshoes forms a thread and the two threads twist around each other to form a two stranded protofilament.

Glycines allow sharp turns at the corners of the horseshoes. Hydrogen bonds between amides link the two layers of the fibrils. Asparagine side chains form ladders of hydrogen bonds up and down the fibrils. Water isn’t present between the layers because the beta sheets are so close together (counterintuitively this decreases the entropy, because water molecules don’t have to align themselves just so to solvate the side chains).

Each of the horseshoes is stabilized by hydrophobic interactions among the hydrophobic side chains buried in the core. Charged residues are solvent exposed. The interface between the two horsehoes is a hydrophobic interface.

Many of the famlial mutations are on the outer edges of double S structure — they are K16N, A21G, D23N, E22A, E22K, E22G, E22Q.

The surface hydrophobic patch formed by V40 and A42 may explain the greater rate of secondary nucleation by Abeta42 vs. Abeta40.

The cryoEM structures we have of Abeta42 are different showing the phenomenon of amyloid polymorphism.

The PNAS paper used reombinant Abeta and prepared homogenous fibrils by repeated seeding of dissolved Abeta42 with preformed fibrils. The other study used chemically synthesized Abeta and got fibrils without seeding. Details of pH, peptide concentration, salt concentration differed, and yet the results are the same, making both structures more secure.

The new structure doesn’t immediately suggest the toxic mechanism of Abeta.

To indulge in a bit of teleology — the structure is so beautiful and so intricately designed, that the aBeta42 peptide has probably been evolutionarily optimized to perform an (as yet unknown) function in our bodies. Animals lacking Abeta42’s parent (the amyloid precursor protein) don’t form neuromuscular synapses correctly, but they are viable.

Hillary Clinton’s stroke in 2012

Now that Hillary Clinton is the Democratic Party nominee and the campaign has less than 3 months to go, it is time to republish the post of April 2016 so that people can think it over. I am a retired board certified neurologist and former examiner for the American Board of Psychiatry and Neurology.

First: a timeline.

At some point in the week of 9 December 2012 Mrs. Clinton is said to have fainted suffering a concussion. The New York Times reported on this 13 December.

She remained at home until 30 December at which point she was admitted to New York-Presbyterian Hospital when a blood clot was found in a vein draining her brain.

Subsequently she had double vision due to her eye muscles not working together for a month or so and had to wear special glasses (Fresnel lenses) to correct this.

Second: The following explanation for these events was given by Lisa Bardach M. D, a board certified internist in a letter released by the Clinton campaign 31 July 2015 (as of 24 August 2016 nothing more has been forthcoming).

You may read the entire letter at http://online.wsj.com/public/resources/documents/clintonhealth2015.pdf but the relevant paragraph is directly quoted below.

“In December of 2012, Mrs. Clinton suffered a stomach virus after traveling, became dehydrated, fainted and sustained a concussion. During follow up evaluations, Mrs. Clinton was found to have a transverse sinus venous thrombosis and began anticoagulation therapy to dissolve the clot. As a result of the concussion, Mrs. Clinton also experienced double vision for a period of time and benefited from wearing glasses with a Fresnel Prism. Her concussion including the double vision, resolved within two months and she discontinued the use of the prism. She had followup testing in 2013, which revealed complete resolution of the effects of the concussion as well as total dissolution of the thrombosis. Mrs. Clinton also tested negative for all clotting disorders. As a precaution, however, it was decided to continue her on daily anticoagulation.”

In my opinion this letter essentially proves that Mrs. Clinton had a stroke.

Third: Why should you believe what yours truly, a neurologist and not a neurosurgeon says about the minimal likelihood of this clot being due to the head trauma she sustained when she fainted? Neurologists rarely deal with acute head trauma although when the smoke clears we see plenty of its long term side effects (post-traumatic epilepsy, cognitive and coordination problems etc. etc.). I saw plenty of it in soldiers when I was in the service ’68 – ’70, but this was after they’d been stabilized and shipped stateside. However, I had an intense 42 month experience managing acute head injuries.

To get my kids through college, I took a job working for two busy neurosurgeons. When I got there, I was informed that I’d be on call every other night and weekend, taking first call with one of the neurosurgeons backing me up. Fortunately, my neurosurgical backup was excellent, and I learned and now know far more about acute head trauma than any neurologist should. We admitted some of the head trauma cases to our service, but most cases had trauma to other parts of the body, so a general surgeon would run the show with our group as consultants. I was the initial consultant in half the cases. When I saw them initially, I followed the patients until discharge. On weekends I covered all our patients and all our consults, usually well over 20 people.

We are told that Hillary had a clot in one of the large draining veins in the back of her head (the transverse dural venous sinus). I’d guess that I saw over 300 cases of head trauma,but I never saw a clot develop in a dural sinus due to the trauma. I’ve spoken to two neuroradiologists still in practice, and they can’t recall seeing such a clot without a skull fracture over the sinus. Such a fracture has never been mentioned at any time about Hillary.

Fourth: Why does the letter essentially prove Hillary had a stroke back then ?

I find it impossible to believe that the double vision occurred when she fainted. No MD in their right mind would not immediately hospitalize for observation in a case of head trauma with a neurologic deficit such as double vision. This is just as true for the most indigent patient as for the Secretary of State. I suppose it’s possible that the double vision came up right away, and Dr. Bardach was talked into following her at home. Docs can be bent to the whims of the rich and powerful. Witness Michael Jackson talking his doc to giving him Diprivan at home, something that should never be given outside the OR or the ICU due to the need for minute to minute monitoring.

My guess was that the double vision came up later — probably after Christmas. Who gets admitted to the hospital the day before New Year’s Eve? Only those with symptoms requiring immediate attention.

Dr. Bardack’s letter states, “As a precaution,however, it was decided to continue her on daily anticoagulation.” I couldn’t agree more. However, this is essentially an admission that she is at significant risk to have more blood clots. While anticoagulation is not without its own risks, it’s a lot safer now than it used to be. Chronic anticoagulation is no walk in the park for the patient (or for the doctor). The most difficult cases of head trauma we had to treat were those on anticoagulants. They always bled more.

Dr. Bardack’s letter is quite clever. She never comes out and actually says that the head trauma caused the clot, but by the juxtaposition of the first two sentences, the reader is led to that conclusion. Suppose, Dr. Bardack was convinced that the trauma did cause the clot. Then there would be no reason for her to subject Mrs. Clinton to the risks of anticoagulation, given that the causative agent was no longer present. In all the cases of head trauma we saw, we never prescribed anticoagulants on discharge (unless we had to for non-neurosurgical reasons).

This is not a criticism of Dr. Bardach’s use of anticoagulation, spontaneous clots tend to recur and anticoagulation is standard treatment. I highly doubt that the trauma had anything at all to do with the blood clot in the transverse sinus. It is even possible that the clot was there all the time and caused the faint in early December.

Fifth: Isn’t this really speculation? Yes, of course it is and this is absolutely typical of medical practice where docs do the best they can with the information they have while always wishing for more. The Clinton campaign has chosen to release precious little.

So what information that we don’t currently have would be useful? First Dr. Bardach’s office notes. I’m sure Mrs. Clinton was seen the day she fainted, and subsequently. The notes would tell us when the double vision arose. Second the admission history and physical and discharge summary from NY Pres. Her radiologic studies (not just the reports) — plain skull film, CT (if done), MRI (if done) should be available.

Sixth: why is this important? Fortunately, Mrs. Clinton has recovered. However, statistically a person who has had one stroke is far more likely to have another than a person who has never had one. This is particularly true when we don’t know what caused the first (as in this case.

We’ve had two presidents neurologically impaired by stroke in the past century (Woodrow Wilson after World War I and Franklin Delano Roosevelt at Yalta). The decisions they made in that state were not happy for the USA or the world.

Seventh (new): I’ve seen the videos of the ‘seizure’ during a press conference. I find them unconvincing and possibly doctored. The idea that Mrs. Clinton suffers from post-traumatic syndrome seems far fetched to me. She wouldn’t be on anticoagulants if all she did was fall and hit her head. Stay tuned. Mrs. Clinton has not had a press conference in 300 days.
Actually, 264 days. Washington Post keeps a counter on this, which is running as you view the following https://www.washingtonpost.com/news/the-fix/wp/2016/07/07/heres-how-long-it-has-been-since-hillary-clinton-held-a-press-conference/
The debates should be watched closely As Joe Louis (almost) said in another context “[s]he can run but [s]he can’t hide”.

Addendum 11 Sep ’16 — Lest you think that my concern about Mrs. Clinton’s health is something new, or politically driven, have a look at the following post written the last day of 2012. https://luysii.wordpress.com/2012/12/31/medical-tribulations-of-politicians-degrees-of-transparency/. She was but one of 3 politicians I blogged about that day.The initial story about Hillary’s medical problems made no sense to me back then, nor does it now.

The plural of anecdote is NOT data (in medicine at least)

The previous post (https://luysii.wordpress.com/2016/08/22/the-plural-of-anecdote-is-data/) showed that collecting a bunch of small studies (anecdotes) was extremely helpful in seeing the larger picture.

In medicine exactly the opposite occurs. The only way to find out if something works is to do a controlled study. [ Science vol. 297 p 325 ’02 ] There were over 50 observational studies showing benefits for hormone replacement in menopausal women.. Observational studies are basically anecdotes. During the planning study for the Women’s Health Initiative (WHI), some argued that it was unethical to deny some women hormones and give them a placebo. The reason HERS (Heart and Estrogen/Progesterone Replacement Study) was even done was that Wyeth couldn’t get the FDA to approve hormone replacement therapy as a treatment to prevent cardiovascular disease, so they funded HERS to prove their case. Most readers of this have probably read all sorts of bitching about the slowness of the FDA in approving drugs but in this case they did the female populace a huge favor.

As you probably know, the results of hormone replacement in both studies were a disaster (the HERS trial was stopped at 5.2 years after because of increased breast cancer in the treated group). There was also an increased risk of coronary heart disease by 30%, stroke by 41%. At least hip fracture was reduced. Fortunately, even though these were bad outcomes, they were infrequent,(but more frequent in the treated group).

These weren’t lab animals, but someone’s wife and/or mother.

How could they have been so far off? Before all this started, estrogen users were different from nonUsers in several respects — first they were doing something about their health, and clearly had more medical supervision. In addition they were better educated, smoked less and of a higher social class, all of which tend to diminish morbidity and mortality.

Something very similar happened in my field of neurology (not that vascular disease doesn’t severely impact the nervous system). There was a very logical operation to improve cerebral circulation — the pulse just in front of your ear is the superficial temporal artery, a branch of the common carotid after it splits in the internal carotid which goes into the skull and supplies blood to the brain, and the external carotid. If the internal carotid is blocked and the common carotid artery is open, then open the skull and hook (anastomose) the superficial temporal artery to a vessel on the surface of the brain, bypassing the blockage. If you want to know how it is done see — http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1150876/.

There was all sorts of anecdotal evidence of miraculous recovery from stroke. The neurosurgeons and vascular surgeons mounted a wonderful controlled study of the surgery even though many thought it was unnecessary — so 1377 patients were prospectively randomized to have the surgery or medical management. The surgery wasn’t better than medical management N Engl J Med 1985; 313:1191-1200November 7, 1985DOI: 10.1056/NEJM198511073131904, so the procedure was abandoned.

The plural of anecdote IS data

Five years ago I wrote a post on the perils of implicating a gene as the cause of a disease because one or two people with the disease had a mutation there (see the bottom). That is now back in spades with a new report from the Exome Aggregation Consortium (ExAC) [ Nature vol. 536 pp. 249, 277 – 278, 285 – 291 ’16 ].

What they did was to aggregate sequence data from 60,704 people on the parts of their genomes coding for the amino acids making up proteins (the exome — https://en.wikipedia.org/wiki/Exome). The paper has 80+ authors. The data is publicly available and is planed to grow to 120,000 exomes and 20,000 whole genomes in the next year. Both are orders of magnitude larger than any individual exome study so far. So study enough anecdotes (small studies) and pretty soon you have real data

The articles state that over a million people have now had either their exomes or their whole genomes sequenced ! ! !

The amount of variation in the human genome is simply incredible. Some 7,404,909 variants in the exome were described, of which 54% had never been seen before. These account for 1/8 of all the sites in all our exomes, implying that the exome comprises 60 megaBases of the 3200 megaBase human genome (1.8%). Most of the variants were single amino acid changes due changes in a single nucleotide, but there were 317,381 insertions or deletions (95% shorter than 6 nucleotides).

99% of all variants had a frequency of under 1% (e.g. not found in in more than 607 people), with half being found only once in the 60,704. 8% of the sites with variation contain more than one (consistent with what you’d expect of a Poisson distribution).

What is so remarkable is that the average participant has 54 variants previously classified as responsible for a genetic disorder. Not only that 183/192 variants thought to cause a rare hereditary disease were found in many healthy people, implying that they were incidental findings (anecdotes) rather than causal. It shows you what happens when you have adequate data.

They are pretty sure that their work will stand, because the exomes were sequenced many times over (deeply sequenced in the lingo) more than 10x in over 80% of the cohort.

I’d also written earlier about how full of errors our genomes are — see https://luysii.wordpress.com/2012/07/31/how-badly-are-thy-genomes-oh-humanity/

A lot of the variants produced termination codons in the body of the exome, so a full-length protein couldn’t be produced from the gene (these are called truncation variants) — some 179,774 in the 7,404,909. Most occurred just once. Even so this means that most of the cohort had at least one or two. Even this rather negative knowledge was useful — since we have about 20,000 protein coding genes, they found 3,230 in which truncation variants NEVER occurred, implying that the protein is crucial to survival.

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We’ve found the mutation causing your disease — not so fast, says this paper (posted 17 July 2011)

This post takes a while to get to the main points, but hang in there, the results are striking (and disturbing).

First: a bit of history. In the bad old days (any time over about 30 years ago) there was basically only one way to look for a disc in the spinal canal pressing on a nerve producing symptoms (usually pain, followed by numbness and weakness). It was the myelogram, where a spinal tap was done, an oily substance (containing iodine which Xrays don’t penetrate well) was injected into the spinal canal, and Xrays taken. The disc showed up as a defect in the column of dye (not really a dye as any chemist can see). This usually led to surgery if a disc was found, even if it was one or two spinal levels from where clinicians thought it should be based on their examination and other tests such as electromyography (EMG). This was usually put down to anatomic variability. Results were less than perfect.

Myelography was a rather stressful procedure, and I usually brought patients into the hospital the night before, got a cardiogram (to make sure their heart could take it, and that they hadn’t had a silent heart attack). Then the myelography itself, which wasn’t painful as the radiologist put the needle in under fluoroscopy so they could see exactly where to go. However many people got severe post-spinal headaches (invariably doctor’s wives), sometimes requiring a blood patch to plug the hole where the (large) needle used to inject the ‘dye’ went — it had to be large because the ‘dye’ was rather oily (viscous). The bottom line was that you didn’t subject a patient to a myelogram unless they were having a significant problem. Only very symptomatic people had the test, and usually when nonsurgical therapy had been tried and failed.

Fast forward to the MRI (Magnetic Resonance Imaging) era (nuclear magnetic resonance to the chemist, but radiologists were smart enough to get the word nuclear removed so patients would submit to the test). A painless technique, but stressful for some because of the close quarters in the MRI machine. You could look at the whole spinal canal, and see far more anatomic detail, because you actually see the disc (rather than its impression on a column of dye) and the surrounding bones, ligaments etc. etc.

What did we find? There were tons of people with discs where they shouldn’t be (e.g. herniated discs) who were having no problems at all. This led to a lot more careful assessment of patients, with far better correlation of anatomic defect and clinical symptoms.

What in the world does this all have to do with the genetics of disease? Patience; you’re about to find out.

There’s an interesting interview with Eric Lander (of Human Genome Project fame) in the current PNAS (p. 11319). He notes that in 1990 sequencing a single genome cost $3,000,000,000. He thinks that at some time in the next 5 years we’ll be able to do this for $1,000, a 3 million-fold improvement in cost. The genome has around 3,000,000,000 positions to sequence. As things stand now, it’s literally nothing to determine the sequence of a few million positions in DNA.

On to Cell vol. 145 pp. 1036 – 1048 ’11 which sequenced some 9,000,000 positions of DNA. This didn’t make a big splash (but its implications might). Just a single paper, buried in the middle of the 24 June ’11 Cell — it didn’t even rate an editorial. Now, as chemists, if you’re a bit shaky on what follows, all the background you need can be found in the series of articles found here –https://luysii.wordpress.com/category/molecular-biology-survival-guide/

As a neurologist, I treated a lot of patients with epilepsy (recurrent convulsions, recurrent seizures). 2% of children and 1% of adults have it (meaning that half of the kids with it will outgrow it, as did the wife of an old friend I saw this afternoon). Some forms of epilepsy run in families with strict inheritance (like sickle cell anemia or cystic fibrosis). 20 such forms have been tied down to single nucleotide polymorphisms (SNPs) in 20 different genes coding for protein (there are other kinds of genes) — all is explained in the background material above). 17/20 of these SNPs are in a type of protein known as an ion channel. These channels are present in all our cells, but in neurons they are responsible for the maintenance of a membrane potential across the membrane, which has the ability change abruptly causing an nerve cell to fire an impulse. In a very simplistic way, one can regard a convulsion (epileptic seizure) as nerve cells gone wild, firing impulses without cease, until the exhausted neurons shut down and the seizure ends.

However, the known strictly hereditary forms of epilepsy account for at most 1 – 2% of all people with epilepsy. The 9,000,000 determinations of DNA sequence were performed on 237 ion channel genes, but just those parts of the genes actually coding for amino acids (these are the exons). They studied 152 people with nonhereditary epilepsy (also known as idiopathic epilepsy) and, most importantly, they looked at the same channels in 139 healthy normal people with no epilepsy at all.

Looking at the 17/237 ion channels known to cause strictly hereditary epilepsy they found that 96% of cases of nonhereditary (idiopathic) epilepsy had one or more missense mutations (an amino acid at a given position different than the one that should be there). Amazingly, 70% of normal people also had missense mutations in the 17. Looking at the broader picture of all 237 channels, they found 300 different mutations in the 139 normals, of which 23 were in the 17. Overall they found 989 SNPs in all the channels in the whole group, of which 415 were nonsynonumous.

Well what about mutational load? Suppose you have more than one mutation in the 17 genes. 77% the cases with idiopathic epilepsy had 2 or more mutations in the 17, but so did 30% of the people without epilepsy at all.

The relation between myelography and early genetic work on disease should be clear. Back then, a lot was taken as abnormal as only the severely afflicted could be studied, due to time, money and technological constraints. As the authors note “causality cannot be assigned to any particular variant”. Many potentially pathogenic genetic variants in known dominant channel genes are present in normals.

What was not clear to me from reading the paper is whether any of the previously described mutations in the 17 are thought to be causative of strictly hereditary epilepsy were present in the 139 normals.

A very interesting point is how genetically diverse the human population actually is (and they only studied Caucasians and Hispanics — apparently no Blacks). No individual was free of SNPs. No two individuals (in the 139 + 152) had the same set of SNPs. Since they found 989 SNPs in the combined group, even in this small sample of proteins (17 of 20,000) this averages out to more than 3 per individual. Well, are there ‘good’ SNPs in the asymptomatic group, and ‘bad’ SNPs in the patients with idiopathic epilepsy? Not really, the majority of the SNPs were present in both groups.

I leave it to your imagination what this means for ‘personalized medicine’. We’re literally just beginning to find out what’s out there. This is the genetic analog of the asymptomatic disc. We may not know all we thought we knew about genetics and disease. Heisenberg must be smiling, wherever he is.