Back from the 50th Med School Reunion

Mostly some social notes from my 50th Med School reunion (Penn), but first some serious science.

I did two years of graduate work in chemistry between college and med school, and one of the guys I taught organic to is an academic research neurologist. He told me that they had some encouraging results using antisense oligonucleotides to remove the excessive repeat CTGs from myotonin, the gene defective in myotonic dystrophy. They were able to get it into cells, and even showed some clinical benefit in animal models. So he’s still using chemistry.

Myotonic dystrophy is one of the few triplet expansion diseases that makes sense to me, because unlike most of them, it affects a wide variety of tissues, not just the nervous system.

Just about everyone had a great time at the reunion. On entering med school I was told, that I’d know my classmates better than my spouse. Well, I certainly spent more time with them in the clinical years.

It was a happy time and yet sad as well, as we all knew that this was probably the last time we’d all see each other.

The previous post https://luysii.wordpress.com/2016/05/11/off-to-the-50th/ had a lot about (the lack of) minority representation back then.

Things have improved, as there is now an office of diversity (so Penn is now doing more than paying hypocritical lip service to it — vide Elizabeth Warren).

Our Nigerian classmate came back. He’d spent 17 years back home in Africa but left because he was unable to fight the corruption there, even as a native son. He hassled a black medical student from Africa, finding that she was of the Yoruba tribe, telling her to go back and serve her country (at least for a while).
So things have improved, but not enough. An an affair Friday night, all 5 or so of the blacks present were sitting at the same table. I barged in saying I was bringing some diversity to their table, and initially got some strange looks. But then I told them a few of the events of the previous post and they warmed up. At least the country is  now getting the benefit of their brains.

We’ll know things have really improved, when black physicians feel comfortable enough to mingle with the crowd.

About 65 of the 125 of us were back. Only 18 people were listed as having died, which seems like a very small number for a group of 125 26 year olds 50 years later. I do know of one unreported death of a classmate from AIDS.

This is actually nothing new — and here are my notes on a study done nearly 30 years ago. My speculation is that, docs get a lot of reinforcement, seeing the effects of negative health choices. I doubt that all of it is due to social or economic class, although some must be.

****

[ J. Am. Med. Assoc. vol. 259 p. 3158 ’88 ] This is an overview of the Physicians’ Health study in which 22,000 American physicians took either aspirin or placebo in a double blind study. They were only taking 5 grains of aspirin every other day. Cardiovascular mortality was cut, but overall mortality was not. However the group experienced just 88 deaths when 733 would have been expected. . This may be due to a beneficial life style, or social class. Thus the EIGHTFOLD lower mortality throughout makes the study harder to interpret. Amazingly, the authors of the study don’t really focus on why the study group (even those on placebo) did so well, but whether the aspirin added anything extra. What we need is to reduce mortality in our patients eightfold and then worry about giving aspirin.

****

Here is a tale of the bad old days for the feminists among you. There were under 10 women in our class of 125. One very bright woman wanted to be a surgeon. She asked Dr. Everett Koop about it. This was when Koop was basically inventing the specialty of pediatric surgery at Children’s Hospital of Philadelphia (CHOP), and long before he became Surgeon General.

He gave her some very hard and very honest advice (this was Koop after all). He told her that the first rate surgery residencies simply were not accepting women. To rise to the true level of her ability, she’d need to choose something else. She didn’t like this one bit, but did follow his advice, went into another field and became department chair at another Ivy League med school.

Lastly two stories about the All American basketball player in our Class (Jerry Gardner Kansas ’62). He’s about 6′ 2″ now, and using a cane as he’d had hip surgery a few months ago. He did note that back then Freshman weren’t allowed to play, so he still has a year of eligibility left. Jerry went to NIH after graduation and established a lab studying GI hormones.

Further proving that time does not heal all wounds, Jerry reminisced about the two foul shots he missed at the tail end of a game in the NCAA final (or semifinal) which might have won them the game. For further examples of the phenomenon see — https://luysii.wordpress.com/2010/10/25/time-does-not-heal-all-wounds/

Off to the 50th

No posts for a while as I’ll be going to my 50th Med School Reunion (Penn ’66) tomorrow. If there is a creator, he has a fairly sardonic sense of humor

Here’s why.

I arrived in the fall of ’62 having spent 2 years as a grad student in the Harvard Chemistry department (Woodward the last year or so), quite full of myself. The biochemistry (and chemistry) being taught at Penn was quite primitive compared to what I’d been exposed to, and I was a fairly obnoxious prick about it.

How could I have known that classmate (Mike Brown) would win a Nobel for his work on the LDL receptor which led to the statins. The work involved some fairly brilliant chemistry (particularly on regulated intramembrane proteolysis). I hope he doesn’t remember me when we meet, but he probably will.

In defense, although none of us knew it at the time, the Harvard Chemistry department back then was probably one of the greatest in world history. Here’s why. There were 7 future Nobel laureates in the department when I was there from ’60 to ’62 — Woodward, Corey, Lipscomb, Bloch, Herschbach, Gilbert and Karplus. Even better, these guys weren’t sitting on their laurels having already won, but were engaged in doing the work which won them the  Nobels.

But there are far more issues to address at Penn than just this. Here’s a copy of an old post —

Two American (social) tragedies

When the team members entered the clinic, they were appalled, describing it to the Grand Jury as ‘filthy,’ ‘deplorable,’ ‘disgusting,’ ‘very unsanitary, very outdated, horrendous,’ and ‘by far, the worst’ that these experienced investigators had ever encountered. There was blood on the floor. A stench of urine filled the air. A flea-infested cat was wandering through the facility, and there were cat feces on the stairs. Semi-conscious women scheduled for abortions were moaning in the waiting room or the recovery room, where they sat on dirty recliners covered with blood-stained blankets. All the women had been sedated by unlicensed staff – long before Gosnell arrived at the clinic – and staff members could not accurately state what medications or dosages they had administered to the waiting patients. Many of the medications in inventory were past their expiration dates… surgical procedure rooms were filthy and unsanitary… resembling ‘a bad gas station restroom.’ Instruments were not sterile. Equipment was rusty and outdated. Oxygen equipment was covered with dust, and had not been inspected. The same corroded suction tubing used for abortions was the only tubing available for oral airways if assistance for breathing was needed…”[29]
[F]etal remains [were] haphazardly stored throughout the clinic– in bags, milk jugs, orange juice cartons, and even in cat-food containers… Gosnell admitted to Detective Wood that at least 10 to 20 percent… were probably older than 24 weeks [the legal limit]… In some instances, surgical incisions had been made at the base of the fetal skulls. The investigators found a row of jars containing just the severed feet of fetuses. In the basement, they discovered medical waste piled high. The intact 19-week fetus delivered by Mrs. Mongar three months earlier was in a freezer. In all, the remains of 45 fetuses were recovered … at least two of them, and probably three, had been viable.”

A classic back alley abortion mill, except that it was all quite legal.

This wasn’t supposed to happen after Roe vs. Wade. It is so uncanny that the doc (Kermit Gosnell) convicted yesterday of these 3 infanticides graduated from a med school in Philly (Jefferson) the same year (1966) that I graduated from another (Penn). At the time Philly had 3 more (Hahnemahn, Women’s and Temple).

What is so socially tragic about Gosnell, is that he was one of very few blacks in medical school back then. Our class of 125 at Penn had one, but he was a Nigerian Prince. Whether Gosnell liked it or not he was a standard bearer for what we hoped (at the time) was the wave of the future (it was). For just how very few Blacks were being educated at elite institutions back then please see

https://luysii.wordpress.com/2012/05/22/warren-harvard-and-penn-sanctimony-hypocrisy-and-fraud/ — copy to be found below

The second tragedy is a black woman M. D twenty or so years younger (Harvard undergrad, Penn Med followed by an MBA from Wharton) who lost her license to practice in NY State after she went off the deep end and became a holistic practioner (or whatever). She treated a new onset juvenile diabetic with diet and juice after which he came to the ER in diabetic ketoacidosis with a sugar over 300.

My father was an attorney as was my uncle, later a judge. They took it very personally when an attorney was disbarred for some malfeasance or another. I feel the same way when this happens to an M. D. Imagine how the black docs must feel about Gosnell, or the idiot, Conrad Murray, who basically killed Michael Jackson with Diprivan.

If you didn’t follow the link, I’ll close with a more uplifting ending from it.

My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist, having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references her cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents and grandparents of today’s black MDs, Attorneys, teachers etc. etc. were likely just as intelligent as their offspring of today. This country certainly pissed away an awful lot of brains of their generations.

*****

Warren, Harvard and Penn — Sanctimony, Hypocrisy and Fraud

I find the behavior of Elizabeth Warren, Harvard and Penn incredibly disturbing and sad. It’s the perfect storm of sanctimony, hypocrisy and fraud. I imagine that I’m a lot older than the readership, so let’s revisit the bad old days of the 50’s and 60s to see how things were back then and why the behavior of all three besmirches heroic attempts to set things right.

Fall 1956: Enter Princeton along with 725+ others. The cast of characters included about 5 Asians, 1 Indian Asian, no hispanics and/or latinos as I recall, and all of 2 blacks. I was the first to attend from a small (212 kids in 4 grades) NJ High School. I’d never been west of Philly, and immediately appreciated what passed for diversity back then — a roommate from Florida, and 2 guys next door from Wisconsin and Tennessee, the four of us packed like sardines into two miniscule rooms (each of which is now a single).

Although my High School was above the Mason Dixon line, there was only 1 black student in all 4 classes when I was there. A 2nd cousin who graduated 6 years before I entered, noted that there were NO blacks when she was there and asked why, and was told “we don’t encourage them to attend”. To be fair, there were very few black families in the area.

So, because we were musicians, and in the marching band, I got to know one of the blacks. At away games there were postgame parties (what’s the point of having games after all?). Girls would come up to Harvey and tell him that he must meet Virginia, she’s wonderful. etc. etc. Virginia being the black girl at their school, as Harvey was the black boy at ours. There was no condescension involved, and I never saw anyone at Princeton give Harvey a hard time, and we had plenty of southerners. It was the way things were, and we had no idea that things could be different.

Spring 1958: Back at the H. S. The one black girl in the class 2 years behind me was very smart. She graduated as the Salutatorian. However, she should have been the Valedictorian, the powers that be having decided that it wouldn’t do to have a black in that position. That didn’t stop her of course. The high school was so small that it was folded into a regional H. S. the next year. So our little school has reunions every 5 years or so for anyone who ever went there, and I saw her 40 – 50 years later. She’d become a very high powered R. N. with a very responsible position.

Fall 1960: Harvard Chemistry department. Not a black, not a latino, not an Asian to be found in the grad school (there was one Sikh). I don’t recall seeing any as undergraduates. There were a fair number of Japanese, and Asian Indian postdocs however. Fast forward to the present for what it looks like now — https://luysii.wordpress.com/2012/04/19/the-harvard-chemistry-department-reunion-part-i/.

Fall 1962: Entering Penn Med school — 125 students, one black (a Nigerian) no latinos/hispanics, no asians of any sort, under 10 women. They really can’t be blamed for this, the pipeline was empty.

Summer 1963: Visiting my wife to be at her home in Alexandria Virginia. A drive perhaps 10 – 20 miles south toward Richmond finds restaurants with Colored entrances.

2008: My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references the cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents (grandparents) of today’s blacks , are likely just intelligent as their MD, Attorney, teacher etc. etc. offspring today. This country certainly pissed away an awful lot of brains of these generations. So clearly, I’m all for letting the best into our elite institutions whatever they look like.

This is why Warren, and the behavior of Harvard and Penn is such a perversity.

First the sanctimony. Many at Harvard think they are head, neck and groin above you in every sense, intellectual and moral. Do not think for a minute that their previous rejection of a military presence on campus had anything to do with the military’s treatment of gays. It was a cover for their antiwar and antimilitary agenda (present when I was there ’60 -’62 long before Vietnam). They were what my father called “Bible-backed Bastards”, using scripture as cover for what they wanted to do.

Second and Third. That Warren would claim to be Indian and that Penn and Harvard would tout her as evidence of their commitment to diversity, is hypocritical in the extreme and fraudulent as well.

Well, it’s just another scam.like all the rest. Isn’t it? We’ve got State Troopers sitting on their ass in their cars with lights flashing on the Mass. Pike at construction sites. We’ve got politically connected drones handing out tickets on the Pike standing next to machines which do the job when they’re not around. No one seems to mind. It may be one of the reasons unenlightened Florida and Texas grew faster in the last 10 years and acquired one of our representatives (along with 5 more from NY, NJ, Illinois and Pennsylvania).

But it isn’t like the rest. It perverts something the country desperately needed to do and gives arms to those opposing it. Ironic that it wasn’t done by rednecks, but by the very institutions that led the charge.

I hope the powers that be at Penn don’t cluck about diversity at the reunion,  but if they do I plan to find my inner obnoxious prick again.

Spot the flaw

Mathematical talent varies widely. It was a humbling thing a few years ago to sit in an upper level college math class on Abstract Algebra with a 16 year old high school student taking the course, listening with one ear while he did his German homework. He was later a double summa in both math and physics at Yale. So do mathematicians think differently? A fascinating paper implies that they use different parts of their brain doing math than when not doing it. The paper has one methodological flaw — see if you can find it.

[ Proc. Natl. Acad. Sci. vol. 113 pp. 4887 – 4889, 4909 – 4917 ’16 ] 15 expert mathematicians and 15 nonMathematicians with comparable academic qualifications were studied (3 literature, 3 history 1 philosophy 2 linguistics, 1 antiquity, 3 graphic arts and theater 1 communcation, 1 heritage conservation — fortunately no feminist studies). They had to listen to mathematical and nonMathematical statements and decide true false or meaningless. The nonMathematical statements referred to general knowledge of nature and history. All this while they were embedded in a Magnetic Resonance Imager, so that functional MRI (fMRI) could be performed.

In mathematicians there was no overlap of the math responsive network (e.g. the areas of the brain activated by doing math) with the areas activated by sentence comprehension and general semantic knowledge.

The same brain networks were activated by all types of mathematical statement (geometry, analysis, algebra and topology) as opposed to nonMathematical statement. The areas activated were the dorsal parietal, ventrolateral temporal and bilateral frontal. This was only present in the expert mathematicians (and only to mathematical statements) These areas are outside those associated with language (inferior frontal gyrus of the left hemisphere). The activated areas are also involved in visual processing of arabic numbers and simple calculation. The activated areas in mathematicians were NOT those related to language or general knowledge.

So what’s wrong with the conclusion? The editorialist (pp. 4887 – 4889) pointed this out but I thought of it independently.

All you can say is that experts working in their field of expertise use different parts of their brain than they use for general knowledge. The nonMathematicians should have been tested in their field of expertise. Shouldn’t be hard to do.

A Touching Mother’s Day Story

Yes, a touching mother’s day story for you all. It was 49 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 49 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— “

Has the great white whale of oncology finally been harpooned?

The ras oncogene is the great white whale of oncology. Mutations in 20 – 40% of cancer turn its activity on so that nothing can turn it off, resulting in cellular proliferation. People have been trying to turn mutated ras off for years with no success.

A current paper [ Cell vol. 165 pp. 643 – 655 ’16 ] describes a new and different way to attack it. Once  ras is turned on (either naturally or by mutation) many other proteins must bind to it, to produce their effects — they are called RAS effectors, among which are the uneuphoniously named RAF, RalGDS and PI3K. They bind to activated ras by the cleverly named Ras Binding Domain (RBD) which has 78 amino acids.

The paper describes rigosertib, a not that complicated molecule to the chemist, which inhibits the binding (by resembling the site on ras that the RBD binds to). It is a styryl benzyl sulfone and you can see the structure here — https://en.wikipedia.org/wiki/Rigosertib.

What’s good about it? Well it is in phase III trials for a fairly uncommon form of cancer (myelodysplastic syndrome). That means it isn’t horribly toxic or it wouldn’t have made it out of phase I.

Given the mechanism described, it is possible that Rigosertib will be useful in 20 – 40% of all cancer. Can you say blockbuster drug?

Do you have a speculative bent? Buy the company testing the drug and owning the patent — Oncova Therapeutics. It’s quite cheap — trading at $.40 (yes 40 cents !). It once traded as high as $30.00 — symbol ONTX. I don’t own any (yet), but for the price of a movie with a beer and some wings afterwards you could be the proud owner of 100 shares. If Rigosertib works, the stock will certainly increase more than a hundredfold.

Enough kidding around. This is serious business. In what follows you will find some hardcore molecular biology and cellular physiology showing just what we’re up against. Some of the following is quite old, and probably out of date (like yours truly), but it does give you the broad outlines of what is involved.

The pathway from Ras to the nucleus

The components of the pathway had been found in isolation (primarily because mutations in them were associated with malignancy). Ras was discovered as an oncogene in various sarcoma viruses. Mutations in ras found in tumors left it in a ‘turned on’ state, but just how ras (and everything else) fit into the chain of binding of a growth factor (such as platelet derived growth factor, epidermal growth factor, insulin, etc. etc.) to its receptor on the cell surface to alterations in gene expression wasn’t clear. It is certain to become more complicated, because anything as important as cellular proliferation is very likely to have a wide variety of control mechanisms superimposed on it. Although all sorts of protein kinases are involved in the pathway it is important to remember that ras is NOT a protein kinase.

l. The first step is binding of a growth factor to its receptor on the cell surface. The receptor is usually a tyrosine kinase. Binding of the factor to the receptor causes ‘activation’ of the receptor. Activation usually means increasing the enzymatic activity of the receptor in the tyrosine kinase reaction (most growth factor receptors are tyrosine kinases). The increase in activity is usually brought about by dimerization of the receptor (so it phosphorylates itself on tyrosine).

2. Most activated growth factor receptors phosphorylate themselves (as well as other proteins) on tyrosine. A variety of other proteins have domains known as SH2 (for src homology 2) which bind to phosphorylated tyrosine.

3. A protein called grb2 binds via its SH2 domain to a phosphorylated tyrosine on the receptor. Grb2 binds to the polyproline domain of another protein called sos1 via its SH3 domain. At this point, the unintiated must find the proceedings pretty hokey, but the pathway is so general (and fundamental) that proteins from yeast may be substituted into the human pathway and still have it work.

4. At last we get to ras. This protein is ‘active’ when it binds GTP, and inactive when it binds GDP. Ras is a GTPase (it can hydrolyze GTP to GDP). Most mutations which make ras an oncogene decrease the GTPase activity of RAS leaving it in a permanently ‘turned on’ state. It is important for the neurologist to know that the defective gene in type I neurofibromatosis activates the GTPase activity of ras, turning ras off. Deficiencies (in ras inactivation) lead to a variety of unusual tumors familiar to neurologists.

Once RAS has hydrolyzed GTP to GDP, the GDP remains bound to RAS inactivating it. This is the function of sos1. It catalyzes the exchange of GDP for GTP on ras, thus activating ras.

5. What does activated ras do? It activates Raf-1 silly. Raf-1 is another oncogene. How does activated ras activate Raf-1 ?  Ras appears to activate raf by causing raf to bind to the cell membrane (this doesn’t happen in vitro as there is no membrane). Once ras has done its job of localizing raf to the plasma membrane, it is no longer required. How membrane localization activates raf is less than crystal clear. [ Proc. Natl. Acad. Sci. vol. 93 pp. 6924 – 6928 ’96 ] There is increasing evidence that Ras may mediate its actions by stimulating multiple downstream targets of which Raf-1 is only one.

6. Raf-1 is a protein kinase. Protein kinases work by adding phosphate groups to serine, threonine or tyrosine. In general protein kinases fall into two classes those phosphorylating on serine or threonine and those phosphorylating on tyrosine. Biochemistry has a well documented series of examples of enzymes being activated (or inhibited) by phosphorylation. The best worked out is the pathway from the binding of epinephrine to its cell surface receptor to glycogen breakdown. There is a whole sequence of one enzyme phosphorylating another which then phosphorylates a third. Something similar goes on between Raf-1 and a collection of protein kinases called MAPKs (mitogen activated protein kinases). These were discovered as kinases activated when mitogens bound to their extracellular receptors.There may be a kinase lurking about which activates Raf (it isn’t Ras which has no kinase activity). Removal of phosphate from Raf (by phosphatases) inactivates it.

7. Raf-1 activates members of the MAPK family by phosphorylating them. There may be several kinases in a row phosphorylating each other. [ Science vol. 262 pp. 1065 – 1067 ’93 ] There are at least three kinase reactions at present at this point. It isn’t known if some can be sidestepped. Raf-1 activates mitogen activated protein kinase kinase (MAPK-K) by phosphorylation (it is called MEK in the ras pathway). MAPK-K activates mitogen activation protein kinase (MAPK) by phosphorylation. Thus Raf-1 is actually mitogen activated protein kinase kinase kinase (sort of like the character in Catch-22 named Junior Junior Junior). (1/06 — I think that Raf-1 is now called BRAF)

8. The final step in the pathway is activation of transcription factors (which turn genes off or on) by MAP kinases by (what else) phosphorylation. Thus the pathway from cell surface is complete.

A new wrinkle in an old reaction

Just when you thought we knew everything there was to know about the Diels Alder reaction, cometh Nature vol. 532 pp. 484 – 488 ’16 in which triple bonds are used in both the diene and the dienophile. Naturally they are all put in the same molecule so they can’t get away from each other. I can’t draw the structure in this post, but it’s worth a look, particularly since a benzyne intermediate is formed in one, and an even more bizarre (and labile) intermediate (a diradical with the unpaired electrons, each on an atom, separated by two more carbons) is formed in the other. It’s sort of chemical bonsai. Enjoy

Carly ‘s Cancer

Today Senator Cruz said that Carly Fiorina would be his running mate, should he get the republican nomination. It’s worth reposting (with a few modifications) what I wrote last September about her cancer when it looked like she had a chance of getting the nomination. See the end for why the health problems of our leaders are problems for us all.

Carly Florina had breast cancer surgery (bilateral mastectomy) 2 March 2009 at Stanford University Hospital followed by chemotherapy and radiation. She was given an excellent prognosis for full recovery — https://en.wikipedia.org/wiki/Carly_Fiorina.

So far so good and it’s just over 7 years. But it is reasonable to ask just what her prognosis really is, particularly as she may be our next vice-president. I asked an old friend and colleague who has been involved in research on breast cancer and in many of the clinical trials of therapy over the past 35 years.

So I wrote the following — I’m writing you for some idea what the chances of someone with breast cancer being free for 6+ years (Carly’s surgery was 2/09) will be free for the next 5+? I know that there are all sorts of statistics on survival in breast cancer (because the cohort is so large). If anyone would know them, it would be you.

and got this back

Impossible to answer your question. Too many variables and NO DATA or info. Many people, docs and patients alike call ductal carcinoma in situ,” cancer” but cure rate is 99%. If she was one of those then, of course, she’s likely to be cured . Stage 1 ,luminal A tumors (even though real cancers) have excellent prognoses—probably > 90% cured. For other real cancers Lots depend on stage, hormone receptors ad infinitum. On thin ice lumping anyone into a broad statement without lots more info

just what you’d expect from an circumspect intelligent expert

So I dug a bit more and sent him this

I tried to find out just what type of breast cancer Carly had. No luck, but various newspaper articles show that she did receive postop chemo causing her hair to fall out as well as radiation. Would ductal carcinoma in situ (Dcis) be treated this way? Would stage 1 luminal A tumors be treated this way?

He replied

Dcis definitely no. luminal a probably shouldn’t be. Sounds like a significant cancer. Next issue is did she get antihormonal therapy. Estrogen receptor tumors are the ones that tend to relapse after 5 years. ER neg. tumors while more aggressive overall seldom recur >5 yrs after dx. The radiation part doesn’t mean much unless she had a mastectomy since all lumpectomy patients get radiation. – If she had mastectomy and chemo and radiation it was probably a poorer risk tumor. Even chemo might not be so bad—–we give chemo to node neg tumors which could end up with very good long term prognosis.AMONG RELAPSES in ER pos pts. 15% recur before year 5 and 17% recur after year 5. However overall likelihood of relapse depends on whether or not she had positive or negative nodes and was ER + or Neg. Sorry to be so wordy but prognosis has been improving steadily. I would guestimate that we’re curing about 70% of women with newly diagnosed breast cancer—excluding dcis who are virtually all cured.

I realized that I’d neglected to tell him that she’d had a bilateral mastectomy as well and got the following back after I did.

If she indeed had radiation after a mastectomy as well as chemo it speaks for a more aggressive presentation. Rule of thumb—-post mastectomy xrt reserved for patients with > 4 positive nodes or tumors >5 cm in size. Today, many are giving post mastectomy xrt to 1-3 positive nodes although that was very controversial for years . newer data impies benefit. So, just guessing, but she probably had positive nodes—a poorer prognostic sign for long term—but only if she was estrogen receptor pos. as noted in prior email.

So there you have it — she’s fortunately well presently, but the tumor and prognosis doesn’t sound that good. Still unknown are histologic type of the tumor, presence or absence of spread to lymph nodes (and if so how many), estrogen receptor positivity, which would certainly give us a better idea of her ultimate prognosis (and the country’s should she become president).

I take no pleasure in any of these posts. https://luysii.wordpress.com/2016/04/24/why-hillary-clinton-had-a-stroke-in-2012/ Both Carly and Hillary are brilliant women it would be an honor to know and I wish them both the best. FYI Hillary was valedictorian of her class at Wellesley.

So why write about their potential health problems? Look at the sad saga of Hugo Chavez who claimed he was cured in July elected in the fall with death before he could take office in March of the following year — see https://luysii.wordpress.com/2013/03/05/q-e-d/. Also consider the last months in office of Woodrow Wilson and Franklin Roosevelt and the results of the League of Nations and the Yalta conference when they were both impaired.

Why Hillary Clinton had a stroke in 2012

Hillary Clinton decimated Bernie Sanders in the New York primary and is the likely nominee. This makes the nature of her illness in December 2012 even more important. This retired board certified Neurologist and Neurology Board examiner thinks she had a stroke back then. Here’s why.

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.

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 it is and this is 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 would be useful? First Dr. Bardach’s office notes. I’m sure Mrs. Clinton was seen the day she fainted, and subsequently. They would tell us when the double vision came up. 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 decision they made in that state were not happy for the USA or the world.

NonAlgorithmic Intelligence

Penrose was right. Human intelligence is nonAlgorithmic. But that doesn’t mean that our physical brains produce consciousness and intelligence using quantum mechanics (although all matter is what it is because of quantum mechanics). The parts (even small ones like neurotubules) contain so much mass that their associated wavefunction is too small to exhibit quantum mechanical effects. Here Penrose got roped in by Kauffman thinking that neurotubules were the carriers of the quantum mechanical indeterminacy. They aren’t, they are just too big. The dimer of alpha and beta tubulin contains 900 amino acids — a mass of around 90,000 Daltons (or 90,000 hydrogen atoms — which are small enough to show quantum mechanical effects).

So why was Penrose right? Because neural nets which are inherently nonAlgorithmic are showing intelligent behavior. AlphaGo which beat the world champion is the most recent example, but others include facial recognition and image classification [ Nature vol. 529 pp. 484 – 489 ’16 ].

Nets are trained on real world images and told whether they are right or wrong. I suppose this is programming of a sort, but it is certainly nonAlgorithmic. As the net learns from experience it adjusts the strength of the connections between its neurons (synapses if you will).

So it should be a simple matter to find out just how AlphaGo did it — just get a list of the neurons it contains, and the number and strengths of the synapses between them. I can’t find out just how many neurons and connections there are, but I do know that thousands of CPUs and graphics processors were used. I doubt that there were 80 billion neurons or a trillion connections between them (which is what our brains are currently thought to have).

Just print out the above list (assuming you have enough paper) and look at it. Will you understand how AlphaGo won? I seriously doubt it. You will understand it less well than looking at a list of the positions and momenta of 80 billion gas molecules will tell you its pressure and temperature. Why? Because in statistical mechanics you assume that the particles making up an ideal gas are featureless, identical and do not interact with each other. This isn’t true for neural nets.

It also isn’t true for the brain. Efforts are underway to find a wiring diagram of a small area of the cerebral cortex. The following will get you started — https://www.quantamagazine.org/20160406-brain-maps-micron-program-iarpa/

Here’s a quote from the article to whet your appetite.

“By the end of the five-year IARPA project, dubbed Machine Intelligence from Cortical Networks (Microns), researchers aim to map a cubic millimeter of cortex. That tiny portion houses about 100,000 neurons, 3 to 15 million neuronal connections, or synapses, and enough neural wiring to span the width of Manhattan, were it all untangled and laid end-to-end.”

I don’t think this will help us understand how the brain works any more than the above list of neurons and connections from AlphaGo. There are even more problems with such a list. Connections (synapses) between neurons come and go (and they increase and decrease in strength as in the neural net). Some connections turn on the receiving neuron, some turn it off. I don’t think there is a good way to tell what a given connection is doing just by looking a a slice of it under the electron microscope. Lastly, some of our most human attributes (emotion) are due not to connections between neurons but due to release of neurotransmitters generally into the brain, not at the very localized synapse, so it won’t show up on a wiring diagram. This is called volume neurotransmission, and the transmitters are serotonin, norepinephrine and dopamine. Not convinced? Among agents modifying volume neurotransmission are cocaine, amphetamine, antidepressants, antipsychotics. Fairly important.

So I don’t think we’ll ever truly understand how the neural net inside our head does what it does.

Is that mutation significant?

Face it, our genomes are a real mess. A study of just the parts of the genome coding for amino acids (2% at most) in about 2,500 people found an average of 205 variants which change the amino acid coded for IN EACH PERSON. Each person also had an average of 3 termination codons in the 15,000+ protein coding sequences they studied. So they are wandering around with 3 abnormally short proteins. You can read more about it in this old post –https://luysii.wordpress.com/2012/07/31/how-badly-are-thy-genomes-oh-humanity/

Here’s the problem — these people were healthy. Obviously, not a problem for them, but a big problem for physicians attempting to do genetic counseling. For how it affected epilepsy counseling see — https://luysii.wordpress.com/2011/07/17/weve-found-the-mutation-causing-your-disease-not-so-fast-says-this-paper/.

This brings us to Lynch syndrome (aka Hereditary NonPolyposis Colorectal Cancer — HNPCC). It is a familial cancer syndrome, and we now know what the problem is — mutations in any of four genes involved in a type of DNA mutation repair (there are many). The genes are called MSH2, MSH6, MLH1 and PMS2 (acronyms all whose names you don’t need to know) and the type of repair is called MisMatch Repair (MMR).

This isn’t academic at all. Suppose your aunt comes down with colon cancer and you get tested for mutations in one of the four, and a mutation is found. You’re fine now. The question before the house is — should you have your colon out? Colonoscopy won’t help because this kind of colon cancer doesn’t arise from polyps (which is what colonoscopy is looking for).

The problem is that the 4 genes are ‘peppered’ with missense variants (change the amino acid coded for). They are called VUS (Variants of Unknown Significance). The following paper [ Proc. Natl. Acad. Sci. vol. 113 pp. 3918 – 3820, 4128 – 4133 ’16 ] used a clever way to test a VUS for significance. This would have been impossible 5 years ago. What they did was use CRISPR to introduce the variant into the appropriate protein in mouse Embryonic Stem cells. Then they tested the manipulated stem cells for defects in MisMatch Repair. They tested 59 (yes fifty-nine) such VUSs and found that about 1/3 (19) produced MMR defects.

Fascinating time to be alive and reading about all this stuff.

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