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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.

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.

A lump of coal to the authors

The following sentence appeared in a paper in the Proceedings of The National Academy of Sciences USA this year. The names of the authors have been withheld to protect the guilty. The following is an exact quote

These languages were selected because they provide contrasts of transparent vs. opaque orthographies with alphabetic vs. logographic writing systems, which map into monomorphemic and monosyllabic words vs. morphologically complex and multisyllabic words, having concatenated linear morphology vs. nonconcatenated nonlinear morphology, with visually simple vs. complex print, which map into tonal vs. nontonal spoken forms.

A post which may actually be of some use to Safari users

This post may actually be of some use (to those of you using Safari on a Mac anyway). Yesterday, I had the awful experience of a pop-up that I couldn’t get rid of. It said that I had to call a number right away to protect my identity etc. etc. I’d heard about malware that got on your computer encrypting everything so you couldn’t use it, except to pay them a ransom.

So I tried quitting Safari and restarting. No luck. There it was along with sites I always go to on Safari (PNAS, Nature, Science, Cell and Neuron).

So I tried to shut down (which wasn’t possible because I got a note that Safari was busy).

Then I used Force Quit to shut down Safari and was then able to shut down.

Rebooting was of no help whatsoever, as the pop-up appeared along with all 5 sites I usually have open whenever I opened Safari. This happened several times, yours truly being bull headed enough to try it again and again against all hope.

Time to call Applecare — they fixed it immediately. Apparently Safari has a some sore of cache which reopens everything you’ve opened on your last visit. This is what brought up my favored sites and the annoying popup.

The trick is to Open Safari from the Dock (and you must do it this way, not from recently used items) with the shift key held down — this flushed the cache (and the pop-up along with it).

Applecare said this pop-up wasn’t malware, just a scam which charged money to get rid of it (which you can now do free of charge).

Taking a break

No posts for a while. Off to Maine for some R & R after an intense two months of our daughter in law’s pregnancy complicated by pre-eclampsia followed by an emergency delivery at 34 weeks gestation of a 3.5 pound infant who had to spend 3 weeks in the neonatal ICU. Mother and daughter doing well presently. Sometimes you can really know too much. As a neurologist I saw everything which could go wrong in this situation (and plenty did).

There is a lot of very interesting material to post about which I’ve not had time for
l. A thermodynamic (rather than a chemical) explanation of temperature sensitivity of ion channels
2. The importance of a long terminal repeat of an endogenous retrovirus in our genome for the production of induced pluripotent stem cells (IPSCs)
3. A serious attack on the validity of some work which I posted on earlier https://luysii.wordpress.com/2014/02/23/are-memories-stored-outside-of-neurons/

Perhaps when we get back

Physics to the rescue

It’s enough to drive a medicinal chemist nuts. General anesthetics are an extremely wide ranging class of chemicals, ranging from Xenon (which has essentially no chemistry) to the steroid alfaxalone which has 56 carbons. How can they possibly have a similar mechanism of action? It’s long been noted that anesthetic potency is proportional to lipid solubility, so that’s at least something to hang your hat on.

Other work has noted that enantiomers of some anesthetics vary in potency implying that they are interacting with something optically active (like proteins). However, you should note sphingosine which is part of many cell membrane lipids (gangliosides, sulfatides etc. etc.) contains two optically active carbons.

A great paper [ Proc. Natl. Acad. Sci. vol. 111 pp. E3524 – E3533 ’14 ] notes that although Xenon has no chemistry it does have physics. It facilitates electron transfer between conductors (clearly a physical effect). The present work does some quantum mechanical calculations purporting to show that Xenon can extend the highest occupied molecular orbital (HOMO) of an alpha helix so as to bridge the gap to another helix.

This paper shows that Xe, SF6, NO and chloroform cause rapid increases in the electron spin content of Drosophila (probably another physical effect). The changes are reversible. Anesthetic resistant mutant strains (in what protein) show a different pattern of spin responses to anesthetic.

So they think general anesthetics might work by perturbing the electronic structure of proteins. It’s certainly a fresh idea.

What is carrying the anesthetic induced increase in spin? Speculations are bruited about. They don’t think the spin changes are due to free radicals. They favor changes in the redox state of metals. Could it be due to electrons in melanin (the prevalent stable free radical in flies). Could it be changes in spin polarization? Electrons traversing chiral materials can become spin polarized.

Why this should affect neurons isn’t known, and further speculations are given (1) electron currents in mitochondria, (2) redox reactions where electrons are used to break a disulfide bond.

Fascinating paper, and Mark Twain said it the best “There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.”

A Touching Mother’s Day Story

Yes, a touching mother’s day story for you all. It was 47 years ago, and I was an intern at a big city hospital on rotation in their emergency room. The ER entrance was half a block from an intersection with a bar on each corner. On a Saturday night, we knew better than to try to get some sleep before 2AM or until we’d put in 2 chest tubes (to drain blood from the lungs, which had been shot or stabbed). The bartenders were an intelligent lot — they had to be quick thinking to defuse situations, and we came to know them by name. So it was 3AM 47 years ago and Tyrone was trudging past on his way home, and I was just outside the ER getting some cool night air, things having quieted down.

“Happy Mother’s day, Tyrone” sayeth I

“Thanks Doc, but every day is Mother’s day with me”

“Why, Tyrone?”

“Because every day I get called a mother— “

The weirdness of gravity

We experience gravity every waking moment, so it’s hard to recognize just how strange the gravitational ‘force’ actually is. Push a toy sailboat, a rowboat, and a yacht with the same amount of force (effort). What happens?

The smaller the boat, the faster it moves. Physicists would say the acceleration (change in velocity over time e.g. from the boat not moving at all to moving somewhat) is inversely proportional to the mass of the boat. This is Newton’s famous second law force = mass * acceleration. This isn’t actually what he said which you’ll find at the end.

So in every force except gravity, the bigger the force the more the acceleration. In Galileo’s famous experiment (which Wikipedia says might actually not have occurred), he dropped 2 objects of different masses from the leaning tower of Pisa and found that they hit the ground at the same time, so the acceleration of both due to the ‘force’ of gravity is the for all objects regardless of their different masses.

This implies that gravity is a force that adjusts itself to the mass of the object it is pushing on to produce the same acceleration. Weird, but true.

General relativity says, that the motion must be considered not just in space and time, but in 4 dimensional space-time where space can become our conventional time and vice versa. Here all paths are as straight as possible — because the 4 dimensional space-time we inhabit has an intrinsic curvature, produced by the masses found within it.

What Newton said: “The change of motion is proportional to the motive force impressed and is made in the direction of the straight line in which that force is impressed” By motion Newton means what we call momentum — mass * velocity.

The change in momentum is of course a change in velocity — which is what acceleration actually is. Note that mass is assumed constant regardless of how fast the object is moving. This isn’t even true in special relativity (which doesn’t include gravity — that’s what general relativity is all about).

While reading the research literature is a joy, sometimes it isn’t

“In this sense, enhanced connectivity of an essential node [e.g., in this study, as suggested by the previous analysis by Wühle et al. (17), the secondary somatosensory cortex, S2; for the issue of whether S1 is an essential node, see ref. 22] to brain structures, which render information consciously accessible, constitute predefined or privileged pathways along which neural information can propagate when confronted with an appropriate stimulus.”

I won’t tell you where this is from, but it’s but one horrible sentence among many. Even worse, the paper, is about something quite interesting — how much of the brain (and which parts) have to be activated before a barely perceptible stimulus is reported (e.g. when and where does consciousness begin).

Old and New Year’s Resolutions

I haven’t posted in a while because I was preparing for and recovering from some ‘minor’ surgery. As a practicing clinical neurologist, I was called in multiple times after people didn’t wake up, or stroked out from what was thought by all to be trouble free surgery. I came to the conclusion that there is no such thing as minor surgery. Although mine has gone well, I knew all the things which could go wrong, having seen nearly all of them. This sort of thing has a way of concentrating the mind, leaving room for little else.

So the old year’s resolutions are to get a few of the posts I’ve been sitting on out before the end of the year (probably not in this exact order)

Post #1 — further death of the synonymous codon

Post #2 — Heraclitus was right (about the nervous system) — you can’t step into the same brain twice

Post #3 — Book Review of Duncan Watts book

Post #5 — Unhappy 50th birthday for the War on Poverty

Post #6 — Gloating about the minimal hurricane season despite dire predictions about it

Post #7 — What sleep does and why babies sleep so much

Post #8 — The mating dance of ligand and receptor

The new year resolution — to go through the text on relativity by a classmate I hadn’t met until my 50th reunion. I’ve been through most of the math behind it (I hope). It’s the only time (I think) I’ve used the old school tie gambit to get something I wanted. He’s incredibly busy, still writing papers with Hawking etc. etc. but will answer at least a few questions when I get stuck (as I’m certain to do) purely because we were classmates. I doubt that he’d do this for any other 75 year old retired non physicist.

As my kids say, knowing someone can get you in the door, but you have to perform once you’re inside.

The old Ivy League school tie ain’t what it used to be. A cousin’s kid couldn’t get into a grad school in a subtype of English Lit despite a recent degree from one. Back in the day, it did mean a lot. If you were a premed at my institution and the premed advisor put his hand on your shoulder to say you were okay, you got into Columbia Med School. He was already famous and an operation named for him is still in use. A classmate, a smart guy, majored in Near East studies just because he was interested in it. That was enough for Chase which hired him as a banker. He never went near the mideast in his career.