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Medical School 2020, Year 1, Week 26

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From our anonymous insider…

“This is for 3,000 years of patriarchy!” exclaimed a female classmate as she slices off the penis. Today we are dissecting the external genitalia. We noted the three main regions of the penis: left corpus cavernosum, right corpus cavernosum, and corpus spongiosum.

Lectures introduced the female reproductive cycle, also known as the hypothalamus-pituitary-ovarian (HPO) axis.

This topic requires us to learn the derivatives of cholesterol and the enzymes that catalyze these conversions (graphic). Cholesterol is a 27-carbon structure that gives rise to numerous signaling molecules such as androgens, estrogens, progesterone, aldosterone (isoosmotic antidiuretic) and cortisol. When discussing cholesterol signaling, there are two questions: What enzymes are found in what cell? How much access does the given cell have to low-density lipoproteins (LDL) in circulation?

Two-thirds of the class is memorizing the names and important enzymes in First-Aid that will be tested on Step I. For example, they memorize 17-alpha hydroxylase deficiency will lead to increased aldosterone and cortisol levels with decreased sex hormones and ambiguous genitalia. They aren’t trying to learn the structure of cholesterol. I am wishing them good luck in retaining that information for next year.

The cells of the body have an ability to make fine distinctions among these related cholesterol-derived compounds. For example, aldosterone is very similar in structure to glucocorticoids (e.g., cortisol). So similar that kidney cells’ aldosterone receptors have an affinity to cortisol. However, the aldosterone receptor is typically near an enzyme that degrades cortisol into cortisone which has a lower affinity. In this clever way, the aldosterone receptor can maintain its high sensitivity (percent true positive) to aldosterone while increasing the specificity (percent true negative). [After you enjoy a bag of licorice, it is possible to have transient psuedohyperaldosteronism, including hypertension and hypokalemia from cortisol activating the aldosterone receptor; licorice inhibits the activity of the enzyme that degrades cortisol into cortisone.]

The menstrual cycle is divided into the ovarian cycle (follicular and luteal phase) and the uterine cycle (proliferative and secretory phase). Different regions in the hypothalamus release pulses of Gonadotropin-Releasing Hormone (GnRH) into the pituitary portal system. GnRH activates gonadotroph cells in the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) into the systemic circulation. FSH and LH act on ovarian follicles.

Each follicle is surrounded by granulosa cells that nurture a single dormant egg. Outside the granulosa cells are connective tissue called theca cells. LH binding to theca cell receptors initiates a signaling cascade that increases cholesterol uptake into the cell and increases transcription of the enzymes required to convert cholesterol into androgens. These androgens diffuse out of the cell and suppress further development of the follicle.

FSH binding to granulosa cell receptors upregulate aromatase, the enzyme that converts androgens into estrogens. Granulosa cells do not have the enzymes to synthesize androgens (estrogen precursor) themselves. Follicles are selfish. Once FSH has selected a follicle it will suppress other follicles from maturing, thereby ensuring only one follicle ovulates each cycle.

As FSH increases aromatase activity in granulosa cells, estrogen levels rise throughout the follicular phase of the ovary. Estrogen has many effects including proliferation of the uterine lining (proliferative phase of the uterus). Estrogen also has negative feedback on the neurons in the hypothalamus controlling GnRH release and negative feedback on the gonadotropins in the pituitary. Every 26-32 days in a healthy female, estrogen levels reach such high levels that the negative feedback switches to positive feedback. (The mechanism of this about-face remains a mystery to medicine.) The positive feedback produces the LH surge, a massive release of LH and FSH from the pituitary, initiating ovulation.

Ovulation is the rupture of the follicle. The oocyte or egg is released into the peritoneal cavity (space between abdominal wall and visceral gut organs) where the fimbriae of the fallopian tube sweeps it into the fallopian tube. Fertilization typically occurs in the ampulla of the fallopian tube and is carried into the uterus for implantation. An ectopic pregnancy occurs when a fertilized egg implants anywhere outside the uterus, most commonly in the fallopian tube. However, our embryology professor mentioned it is possible to have implantation in the peritoneal cavity on the the connective tissue of the gut.

After ovulation, the follicle enters the luteal phase. The ruptured follicle becomes the corpus luteum, a highly vascularized endocrine structure. Before, only the theca cells had adequate access to cholesterol in the bloodstream. Now, the granulosa cells have abundant access to cholesterol from LDL in the blood. Granulosa cells lack the enzyme to convert cholesterol into androgens. They are able only to convert androgens into estrogens and cholesterol into an androgen precursor, progesterone. Thus, progesterone levels spike initiating the secretory phase of the uterus. The uterus is ready for implantation of a fertilized egg. If fertilization occurs, the placenta secretes HCG (a close analog of LH) which preserves the corpus luteum production of progesterone. If fertilization does not occur, the corpus luteum involutes (degrades) causing progesterone withdrawal. This sudden decrease in progesterone causes shedding of the uterine lining or menstruation. The decline in progesterone and estrogen disinhibits the GnRH pulsations initiating the whole cycle again.

Two-thirds of the males had at best a fuzzy knowledge of the menstrual cycle. For example, how long is it? When do menses takes place in relation to ovulation? About half of the women did not know how their birth control works. Classmates argued about whether males should be given a handicap for the reproductive block: “You females have it easy. We’ve never seen this stuff before.”

Our patient case: Gina, 31-year-old overweight female presenting with amenorrhea (lack of periods) and hirsutism (hair growth on chin, armpits, etc.). A pregnancy test is negative. A hormone panel reveals high levels of estrogens, androgens and LH.

Gina suffers from Polycystic Ovarian Syndrome (PCOS). PCOS is named for the ultrasound appearance of small cysts in the ovary. Confusingly these fluid-filled sacs are not “ovarian cysts,” but simply mature follicles that are unable to ovulate. The elevated levels of androgens inhibit further maturation of follicles and ovulation and cause hair growth. The endocrinologist explained that hair growth, especially on the chin and neck, is what brings women to her office: “The amenorrhea is alarming but it is not what typically brings them in.”

PCOS affects about eight percent of reproductive age females, although there is not a standardized diagnostic criteria for PCOS and the causes are not fully understood. Diabetes and obesity are known risk factors: adipose (fat) tissue produces androgens, which interfere with follicle maturation. The inability to menstruate is serious. The uterus is stuck in proliferation mode, which vastly increases the risk of endometrial (lining of the uterus that regenerates every cycle) cancer.

How do we get Gina to ovulate? The endocrinologist explained how every woman’s HPO axis is different. “It’s really trial and error.” Gina, like many women with suspected PCOS or infertility issues, undergo a progesterone challenge. A high dose progesterone injection is given initiating the transition from the proliferative phase of the uterus (high estrogen, low progesterone) to the secretory phase of the uterus (high progesterone). Once progesterone is metabolised, progesterone withdrawal should initiate menses. This confirms that the problem is an inability to ovulate.

Gina is taking clomiphene, a drug also used to treat infertility. Clomiphene inhibits estrogen receptors in the hypothalamus to prevent estrogen negative feedback. Therefore, there continues to be release of GnRH and downstream release of FSH despite the presence of estrogen at levels which should cause negative-feedback . Clomiphene increases the risk of twins as multiple ovulations may occur. Gina also underwent what sounds like a barbaric procedure called ovarian drilling. A needle inserted laparoscopically destroys various follicles in a random array. Ovarian drilling is quite successful in decreasing androgen levels and inducing ovulation. Gina still is not on a normal cycle, but has been menstruating. She is trying to get pregnant with her husband.

[See also “Small-sample Behavioral Economics” for how clomiphene may be taken by women with normal fertility.]

Statistics for the week… Study: 20 hours. Sleep: 7 hours/night; Fun: 1 night. Example fun: One of our classmates recently moved in with two males in their 20s. Her new apartment is a bachelor pad equipped with a pool table, beer pong table, dart board and xbox. After two weeks of straight exam study, she was demonstrating her social skills by hosting a 26th birthday party for another classmate.

More: http://fifthchance.com/MedicalSchool2020

How do you spend $2.75 billion on signals for a subway system?

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Buried in this article on $100 billion in capital spending on the New York City subway system is the following:

the capital plan invests $2.75 billion to upgrade signals

If there are already signalling cables along the tracks capable of supporting TCP/IP, how is it possible to spend $2.75 billion on a set of lights driven by a few microprocessors? That’s enough to build two of the world’s largest passenger ships (see Symphony of the Seas), complete with water park, skating rink, thousands of cabins, accommodations for 2,175 crew members, etc. I don’t think the answer is “stuff purchased by the government costs a lot” because, according to the same article, they are going to get 1,000 subway cars for almost the same price ($3.2 billion).

[Separately, the Moscow Metro system was amazing by American standards. It is huge and growing every year. Trains on every line run every minute on weekdays and every two minutes on weekends. A 23-year-old native said that the longest she’d ever waited for a train was 12 minutes. That was at 1:00 am and the delay excited a lot of discussion among customers. The artwork is justly famous. I loved the aviation emphasis of the ceiling mosaics, which are designed to show what you might see if you looked skyward (some photos that I took a few hours after staggering out of the Moscow airport).]

What would that $100 billion spent by New York City buy in China? The World Bank says it costs China roughly $20 million per km to build a high-speed rail system. So $100 billion would suffice for 5000 km of track, stations, and trains(?). That’s 3,100 miles, or Boston to San Francisco.

Related:

Medical School 2020, Year 1, Week 25

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From our anonymous insider…

Five hour-long lectures over three days on calcium regulation to control neuronal activity, coagulation, heart function, and bone structure. One challenge is that calcium is a cation (positively charged ion) that can come out of solution. Too much calcium will cause calcium precipitation with various anions (negatively charged ions) potentially causing thrombosis of vessels, kidney stones, and coma. Too little calcium will cause hyperexcitability of neurons with the classic Trousseau sign.

Calcium in your body is governed by mass balance: What comes in must come out to maintain equilibrium levels (flux in = flux out). Calcium intake varies, so calcium efflux adapts accordingly. Two hormones, parathyroid hormone (PTH) and 1,25 dihydroxycholecalciferol (vitamin D) regulate calcium homeostasis through the gut, the kidney and the massive calcium reservoir of bones. (Calcitonin used to be thought to play an important role, but, at least in adulthood, appears secondary to PTH and vitamin D.)

The parathyroid glands, four small tissue regions within the thyroid in the neck, release PTH in response to decreased extracellular calcium. PTH instructs the kidney to increase calcium reabsorption and decrease phosphate reabsorption. The decrease in phosphate is thought to prevent precipitation of calcium-phosphate crystals.  Further, PTH increases the kidney’s conversion of inactive 25-hydroxycholecalciferol reserves into active vitamin D. Vitamin D primarily acts on the intestines to increase calcium and phosphate absorption. Both PTH and vitamin D act on bone cells to fine-tune bone maintenance.

Bone is an organized mesh of specialized bone cells, blood vessels, extracellular proteins and mineral crystals (primarily hydroxyapatite). There are three main types of bone cells: osteoblasts (bone-building cells), osteocytes (imprisoned osteoblasts), and osteoclasts (bone-destroying cells). Osteoblasts secrete various proteins, primarily collagen, into the extracellular environment that form osteons (nucleation site for mineral deposition). As the osteons become mineralized, the osteoblasts, now termed osteocytes, become imprisoned in this mineral matrix. Osteocytes communicate to each other with cellular foot processes, forming the elaborate osteocytic membrane.

The osteocytic membrane forms a cellular interface that separates the mineral deposits from the vascular network: bone on one side, blood vessels on the other. Therefore, the osteocytes can regulate the “bone fluid” to determine net bone resorption or deposition. If osteocytes pump calcium and phosphate from the blood into the bone fluid, net bone deposition occurs in this microenvironment; if the osteocyte membrane pumps calcium and phosphate out of the bone fluid into the blood, net bone resorption occurs in this microenvironment. Activated osteoclasts secrete enzymes and acid that degrade the osteon proteins and the mineral deposits, respectively. Although overactive osteoclasts lead to weakened bones, transient osteoclast activity is needed to make stronger bone by making room for more densely packed osteons. Perhaps next year I will understand enough to relate osteocyte and osteoclast activity.

Bone development and maintenance require adequate calcium input (1200mg/day), steady levels of vitamin D (greater than 30 IU/mL), and mechanical stress signals. One of the most overlooked bone health tools is weight-being exercise, the mechanical stress of which is sensed by the imprisoned osteocytes, inducing bone formation.

Our patient case: Lucy, 60-year old female artist with a history of kidney stones presents to the ED for a femur fracture after a fall. In addition to having broken the largest bone in her leg, a CT showed microfractures in several additional bones. Blood work showed extremely elevated PTH despite hypercalcemia  (high calcium levels in the blood). Presence of a parathyroid adenoma, a benign tumor that secretes PTH, is suspected. Physicians recommend the removal of Lucy’s parathyroid glands, a parathyroidectomy.

Lucy suffered from several psychological diseases in childhood and had become a fervent believer in holistic medicine. Lucy’s internist explained, “It’s always a challenge to emphasize how these complementary approaches are complementary, not supplementary. The Internet has introduced patients to a lot of information. Some good, some bad.” The internist explained that Lucy is one of her favorite patients despite the extra time required for each visit. “She would bring me stacks of articles on supplements I had never heard about. We would dig to find the active ingredient. I’ve learned a great deal from her.” Lucy tried several herbal, yoga and acupuncture therapies for osteoporosis and joint pain. A student asked the internist, “When do you draw the line if a patient does not want to follow your recommendation?” She responded, “If a patient is not following my advice I don’t boot them out. I ask myself, ‘Would another physician have a better outcome?’ The only patients I have kicked out were ones that forged my signature on prescriptions.” After several months of holistic treatment, Lucy elected to get the parathyroidectomy. Her calcium levels have come down and osteoporosis, measured by bone mass density, has improved. Although this was a success for our healthcare system, Lucy was diagnosed with breast cancer six months ago.

Instead of dissection (anatomy lab), we went to a radiology workshop. My classmates describe radiologists as “antisocial people who sit in a dark reading room all day with $40,000 monitors.” The consensus among our class is that this profession is at risk of being replaced by image-recognition algorithms. Only one of our classmates, a quiet Asian-American gentleman, admits he would like to be a radiologist. Our lecturer is a father of two whose phone repeatedly buzzed with a toddler’s voice saying “dada” as the ringtone. “I teach one class a month, and this is the day imaging blows up,” exclaimed the radiologist. The radiologist was quirky, but sociable and self-deprecating. He did mention his monitors at least twice: “they cost as much as your tuition!”

Although the software that can replace a radiologist with 12 years of training is purportedly around the corner, our workshop was derailed when we were not able to log into the Picture Archiving and Communication System (PACS) due to a recent software upgrade being incompatible with the browser. After the school’s entire IT staff swarmed in to update the browser, we were up and running. I greatly enjoyed investigating abdominal and pelvic anatomy on de-identified patient CT and MRI scans.

The radiologist showed a CT angiogram (CT with contrast agent injected into arteries) of “nutcracker” syndrome, in which the left renal artery is compressed by the superior mesenteric artery and aorta due to a lack of retroperitoneal fat. It turns out too little fat can be a bad thing! Nutcracker syndrome is diagnosed by radiologists and fixed by surgeons. He spent ten minutes examining different imaging planes to convey the complex anatomical relationships.

Statistics for the week… Study: 16 hours. Sleep: 8 hours/night; Fun: 1 night. Early bedtime for Jane and me. We competed in a 5k. We both got first place in our age group, perhaps because the competitive runners elected to do the 10k. Drinks with our favorite couple (classmate and his PA-student wife) that evening.

More: http://fifthchance.com/MedicalSchool2020

Verizon Wireless in Russia

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Verizon has a $10/day “travel pass” program that lets you use your U.S. plan minutes and data in most European countries. With both my old iPhone 6 Plus and now my iPhone 7 Plus, this has proved to result in 3G service in both London and Paris, so it isn’t practical for much besides text messaging and maps.

The situation in Russia is better from a technical point of view: you get LTE data rates. It is worse from a contract point of view, however. There is a $40/month option for which you must sign up explicitly in advance. This provides only 100 minutes of voice and 100 MB of mobile data. Public WiFi is fairly common in Moscow, but sometimes you need a Russian cell phone number to activate it.

Facebook is a huge background cellular data hog, so consider deleting it from your phone altogether. I went into the “cellular” settings and shut off access to cellular data for most apps except Uber (a great service in Moscow, though the Metro and buses will get you almost anywhere), Google Maps, and Phone (iMessage uses this one? There is no separate Messages app control). I also turned off the big “Background App Refresh” switch under “General” settings. (Facebook ended up displaying some alerts, which I don’t see how it could have generated unless it was somehow still able to access cellular data.) Maybe if Apple stops concentrating on its Social Justice War it can develop a decent user interface to settings, e.g., a “minimize cellular data” wizard that asks what you really need to accomplish with the device.

The iPhone disagrees with Verizon regarding the quantity of data used. Verizon sent a text message regarding a $25 additional charge for another 100 MB data block when the phone showed only 88 MB having been used (I was careful to reset this when getting off the plane in Moscow). So I paid $65 for a week of limited usage in Moscow. My Russian friend said that he is paying $8/month for a comprehensive voice, text, and LTE data plan. So one week of roaming cost as much as eight months of domestic service. How do we get in on this business?

Medical School 2020, Year 1, Week 24

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From our anonymous insider…

Reproductive lectures start this week. “Males will finally understand how much harder females have it,” joked a female classmate.

There are three main parts of the reproductive system: the internal genitals, external genitals and gonads (testis or ovary). A quick theme that emerges is female development is the default: unless some signal overrides this process, female parts will emerge.

Gonad (testes; ovaries): Primordial germ cells (PGCs) are some of the first cells that are formed after fertilization. PGCs have the potential to become any cell in the body including sperm and eggs. These cells end their migration at the genital ridge, a paired region in the right and left lower abdomen. Here, the PGCs interact with surrounding cells to form the gonad.

In females, each PGC differentiates into an oocyte (egg) that cannot replicate. The surrounding cells nurture each egg in a single follicle. These eggs lie dormant until puberty.

In males, the presence of a functional Y chromosome overrides ovary development. The SRY gene on the Y chromosome signals for the surrounding cells to form interweaving tubes of Leydig and Sertoli cells. Have you ever thought about why the testes are outside the body? Evidently, spermatogenesis (production of sperm) requires a lower temperature than body temperature. Thus production of testosterone by Leydig cells leads to the descent of the testes. My favorite embryology professor instructed, “Boys, don’t drive with the seat warmer on for a long trip. It’ll kill your sperm!” The testes are pulled out of the abdominal cavity through the inguinal canal (see prior chapter). This descent is typically complete a few weeks before birth, but may take as long as one year after birth. [At birth this canal is not sealed completely, which can cause an indirect hernia. Structures, typically small intestine, can squeeze through the inguinal canal and potentially into the scrotum! Infants are routinely checked for this disorder.]

Internal Genitalia (epididymis, vas deferens and prostate; uterus and fallopian tube): In females, an embryological remnant of the kidney forms the fallopian tubes, uterus and proximal (to cervix) vagina. These tubes must fuse together and the septum must be removed to form a normal uterus. Failure to remove the septum is not uncommon (~3%). A more serious defect is if the tubes fail to fuse completely resulting in a bicornuate uterus with two distinct cavities connected at the cervix. Both are still able to become pregnant but have a much higher risk for complications and miscarriages.

In males, a similar tube forms the epididymis, vas deferens and prostate. The vas deferens transports mature sperm from the testis through the inguinal canal into the abdomen. The vas deferens then descends into the pelvis to form an ejaculatory duct. The ejaculatory ducts open into the prostatic urethra (urethra section with the prostate surrounding it).

External genitalia (penis; vagina, labia minora, labia majora, clitoris, etc.): At six weeks post-fertilization, the undifferentiated external genitalia appear, namely the genital tubercle and genital swellings.  There is no way to differentiate male from female at this stage, just that normal development is occurring.This transformation all takes place in the perineum (square region formed from the pubis, ischial tuberosity (bone you sit on) and coccyx (pointy ). We quickly appreciate how crowded this area is — the rectum, bladder and, in females, vagina/uterus all lie in this small volume. Initially, the urinary tract and anus share a common lumen. A septum forms to separate these into the anus and the urogenital openings.

My classmates and I learn this dense region differently. I have found focusing on embryology helps me. Each component of the undifferentiated external genitalia gives rise to the respective female and male reproductive parts (see Netter’s, page 364). Therefore, each part has a homologue (typically with similar function) in the opposite sex. For example, the prostate in males which wraps around the urethra is analogous to the Gland of Skene in females (thought to be involved in female ejactulation). The genital tubercle will form into the glans of the penis or the glans of the clitoris. The glans is supported by erectile tissue and vascular tissue that engorges during sexual arousal.

Males fold each of these parts together as evidenced by the raphe, or ridge, noted on the ventral side of the penis all the way to the anus. Classmates laughed on learning that the anatomical terms for parts of the penis make sense only when the penis is erect: the ventral penis is the underside with the urethra; the dorsal penis faces up.

Looking at the above in real life: Anatomy lab was short. Most students left within an hour. We investigated the external structures of the male and female cadaver. One group found an undescended testicle that got stuck in the inguinal canal. It was far smaller than the descended testicle. The trauma surgeon did not notice any evidence of testicular cancer. She said, “He and his doctors most likely knew he only had one testicle. Today we would remove the undescended testicle at an early age.

In lecture, an internist introduced the male genitourinary (GU) exam before we practiced on dummies. He joked, “I still remember my introductory lecture on the GU exam. I remember the pictures. I was scarred by the pictures.” He continued this tradition by showing us images of foreskin infections and noted that “the most common reason 20-year olds come in to the office is for penis problems.”

The internist described a common reproductive defect: hypospadias is where the urethral meatus (opening of the urethra) in not at the tip of penis but along the shaft or even in the scrotum. He amplified on what we had seen in anatomy lab with 10 minutes on cryptorchidism, the failure of a testicle to descend into the scrotum at birth. An undescended testicle is infertile due to the higher temperature and carries an elevated risk of testicular cancer. If a testicle is not descended by age 1, the current standard of care is to remove it. The physician then asked the class, “What is the number one type of cancer in 20-year-old males?” Despite having been prompted by the lecture topic, nobody in the class was able to come up with the correct answer: testicular cancer.

We discussed 5-alpha reductase deficiency (5-ARD), a rare genetic disorder commonly referred to as güevedoce. The phallus of the penis forms under stimulation of 5-alpha dihydrotestosterone (DHT), a more activated form of testosterone (same compound that causes male baldness). DHT initiates enlargement of the paired vascular tissue (corpus cavernosum, crus of the penis) and the erectile tissue (bulb of the penis, corpus spongiosum). Females have analogous parts, just they have not folded onto each other, nor enlarged. 5-alpha reductase is the enzyme that converts testosterone into DHT. This prevents the enlargement of the phallus in utero. Las Salinas, Dominican Republic, is known for having a high prevalence of 5-ARD: 1 in 90 XY males are born with ambiguous genitals and raised as females. However, during puberty 5-ARD individuals have such high testosterone levels that the ambiguous clitoris enlarges into a penis. Hence güevedoce or “eggs at twelve”. The community holds coming-of-age parties for these chosen individuals. 5-ARD individuals can be fertile propagating this genetic defect through generations in the isolated village. On the bright side, these individuals do not worry about male baldness.

The most dreaded part of the male GU exam for physician and patient is the digital rectal exam. The prostate can be palpated by pushing on the anterior rectum with two digits. Enlargement or masses can be felt. However, the internist emphasized that only the lower third of the prostate can be felt. “The digital rectal exam cannot rule much out.” An ultrasound exam of the prostate can see much more without associated distress.

One student asked what the medical consensus is on circumcision. The internist replied, “There is no medical reason to get or not to get circumcision. The main medical argument is the increased risk of foreskin infection with poor hygiene. However, with good hygiene, there is no increased risk of infection.” He ended by asking, “Why do doctors ask patients to turn their head and cough?” The cough increases intraabdominal pressure that accentuates any inguinal hernia. “We ask patients to turn their head cause we don’t want to be coughed on…”
Statistics for the week… Study: 20 hours. Sleep: 8 hours/night; Fun: 1 night. Example fun: watched college basketball at the house of an M2 (second-year medical student). She is married to an engineer and they’re debating when to have kids. The current plan is for her to give birth during the third year of medical school so that she isn’t pregnant during residency.

More: http://fifthchance.com/MedicalSchool2020

Post Office sets brain on fire

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Here’s a stamp design that I didn’t expect to see from an enterprise that gets revenue from selling stamps: “Repeal of the Stamp Act, 1766”

(Of course, if Vladimir Putin selects me as dictator to replace the Trumpenfuhrer, I will make it illegal to mail letters unless an Elvis Presley stamp is affixed.)

Medical School 2020, Year 1, Week 23

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From our anonymous insider…

We began endocrinology, the study of hormones. Hormones are signaling molecules, namely peptides and cholesterol derivatives, that cause systemic changes in the body. The pea-sized pituitary gland sits in a small alcove at the base of the skull, right behind the nasal cavities near the optic nerve. This master regulator of hormones functions as the interface between the brain and the blood, secreting nine different hormones.

The pituitary is actually two separate organs. The posterior pituitary gland, more recently renamed the neurohypophysis, is a protrusion of neurons in the hypothalamus. These neurons release oxytocin and antidiuretic hormone (ADH) into systemic circulation (the blood). For example, ADH is released in response to an increase in the concentration of solutes in the blood, thus causing the kidneys to concentrate urine by reabsorbing free water into the blood.  Other neurohypophysis neurons release oxytocin (a.k.a. the love hormone) during labor causing uterine contractions and also while a baby nurses causing a “let down” (spray) of milk. (New mothers can have excruciating cramps from uterine contractions during nursing because of this oxytocin release).

The anterior pituitary or adenohypophysis is a broken-off extension of the mouth that wraps around the neurohypophysis. These cells also secrete hormones under the control of the hypothalamus. These hormones regulate everything from the thyroid and adrenal glands to the menstrual cycle and milk production. Thyroid issues are some of the most common adult ailments. The thyroid gland, located right under the “Adam’s apple” secretes thyroxine. Thyroxine increases metabolism and “energy”. Our endocrinologist says that many of her patient’s request synthroid (synthetic thyroxine) to help lose weight. Low thyroxine levels can not only be caused by an issue in the thyroid but also by the pituitary. The pituitary secretes thyroid-stimulating hormone (TSH) which tells the thyroid to release thyroxine. Without TSH, there will be no thyroxine even if thyroxine levels are abnormally low.

Our patient case: “Susan”, 22-year-old female presenting with fatigue, blurred vision, transient loss of vision, and a headache. Labs show abnormally low thyroid stimulating hormone (TSH) and low thyroxine and abnormally high prolactin levels for someone not breastfeeding. She was referred for a head MRI.

The MRI revealed a large mass in the pituitary. Susan had a prolactin-secreting adenoma of the adenohypophysis. The mass was squeezing her optic nerve causing the vision problems. She underwent transsphenoidal (through the nasal cavities) surgery to resect (remove) the pituitary gland. Her vision returned to normal, but she will require hormonal supplementation for life.

This presented an enormous challenge for Susan. Susan’s husband was on SSDI. Her children had health insurance through Medicaid. Susan was the only one working and also the only one without health insurance because she didn’t get it through her employer. Hormone supplements are expensive. Unless she withdraws from the workforce and qualifies for SSDI and/or Medicaid, she and her doctor will endure a lifelong struggle to decide what hormones to prioritize. Growth hormone? Synthroid? ADH?

An epidemiologist introduced clinical trial research. We investigated survival metrics and clinical trial studies on mesothelioma, a cancer of connective tissue, most commonly of the pleural membrane surrounding the lungs. Average survival is 12-20 months after diagnosis; five-year survival is less than 5 percent. The largest risk factor for mesothelioma is exposure to asbestos. Production of many industrial products such as paint, brake-pads and ships used to include asbestos fibers. “It isn’t only males who get mesothelioma,” explained the epidemiologist. “When Daddy got home from the shipyard, Mom and Daughter would run to the door and wring out Daddy’s coat. Asbestos was on that coat.”

We got on the subject of whether the National Institutes of Health (NIH) disproportionately funds cancer research. A traditional successful cancer drug trial finds a few months of additional life compared to the current standard of care, but if funded by a pharmaceutical company does not take into account quality of life.  For example, a clinical trial for a VEGF inhibitor in the treatment of renal cancer increases median overall survival (OS) from 21.3 to 23.3 months compared to IFN plus placebo. What if the quality of life for those 23.3 months is miserable compared to the quality of life for the 21.3 months under the current standard of care? “Patient-reported outcomes is the big buzz word in clinical trial research. Double-blind trials are essential for these subjective metrics.”

The whole school is abuzz about Trump’s seven-country immigration ban. Classmates post on Facebook about their immigrant roots (mostly grandparents or farther back in the family tree). One classmate posted a link instructing what to do if a “Customs” officer comes knocking on your door. The reply: “Did you mean immigration officer?”

Statistics for the week… Study: 25 hours. Sleep: 8 hours/night; Fun: 1 night. Example fun: class bbq followed by classmate’s performance at local coffeeshop! They performed a now class-favorite Twistin and Groovin from Leon Bridge’s Tiny Desk Concert.

More: http://fifthchance.com/MedicalSchool2020

A rare moment of personal restraint on Facebook

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A friend posted the following on her Facebook feed:

At the Computer History Museum new Fellow Induction Gala. Catching up with some of the most creative people on the planet.

I want credit for refraining from posting the following comment:

It was a joint event with some other industry?

Medical School 2020, Year 1, Week 22

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From our anonymous insider…

In anatomy lab, we investigated abdominal blood vessels. The descending aorta pierces the diaphragm at the aortic hiatus to enter the abdomen where it is now called the abdominal aorta. (The external iliac artery becomes the femoral when it passes into the leg***. Being a medical student is like driving in Massachusetts where roads adopt new names every time they cross over a town border.) The abdominal aorta gives off numerous branches: the arteries of the gut (celiac, superior mesenteric and inferior mesenteric), the paired renal arteries and the gonadal arteries (testicular or ovarian). At the umbilicus (belly button) the abdominal aorta bifurcates into the right and left common iliac arteries. Each common iliac artery branches again into the internal and external iliac, which supply the pelvis and the leg, respectively. One group from last week thought they had an aortic aneurysm that was causing all the organs to be pushed forward in the abdomen. It turned out to be cancer (source unknown). They could not find any of the structures in our lab manual as the cancer mass had engulfed everything.

Our trauma surgeon, a woman in her 60s, described a frequent patient case involving the portal system (vessels that direct blood from the gut to the liver), which we dissected this week. An alcoholic presents to the ED for severe rectal bleeding or esophageal bleeding. A CT scan (Computed Tomography or 3D X-ray reconstruction) reveals liver cirrhosis, an enlarged portal vein, and tortuous blood vessels all through his GI tract.

Most blood supply to organs drains into the inferior/superior vena cava which drain into the right atrium of the heart. In a healthy person, blood supplying the GI tract (colon, intestines, spleen, pancreas, stomach and distal esophagus) drains into the portal vein. The portal vein drains into the liver for detoxification. Blood leaves the liver through the hepatic (liver) vein, which drains into the inferior vena cava to join the normal circulation.

The patient’s liver cirrhosis (hardening of the liver) caused severe portal vein hypertension (high pressure). Blood seeking an outlet drains into the lumen of the gut tube instead of through the portal system. “Portal hypertension can cause bleeding worse than getting shot in the aorta,” said the surgeon. “This is a life-or-death situation.”

Lectures continued detailing transport processes of the renal system. We learned about several drugs to treat diabetes mellitus (not to be confused with diabetes insipidus, a hormonal disease preventing urine concentration). Diabetes is named for the accompanying diuresis (excessive urination). Diabetes mellitus (mellitus means honey-sweet) is named due to the high glucose levels present in the blood plasma and urine.The severity of diabetes can be categorized as “insulin-independent” and “insulin-dependent”. Insulin-dependent diabetics require injected insulin to keep glucose levels down.

One of the most effective drugs for diabetes mellitus is metformin, which inhibits natural production of glucose from energy stores (gluconeogenesis). Metformin, derived from the French lilac (Galega officinalis), can prevent or at least delay type 2 diabetics transitioning to insulin dependence. Since at least the 1800s, this plant has been used to treat individuals with polyuria (frequent urination). By far the most common complaint is the terrible breath from metformin. The toxicologist brought a small dummy infused with metformin breath. Sally the Future Surgeon was sitting next to the dummy and threw up after five minutes. “You try to go on a date with this breath,” exclaimed the toxicologist. “Good luck!” Metformin has terrible compliance rates.

(A few hours later we were surprised when the conference room we’d planned to use was occupied by the apparently-forgotten dummy. We vacated the premises, with the smell chasing us down the hallway.)

Farxiga (Dapagliflozin), approved in 2014, is a fascinating drug for the treatment of diabetes. Farxiga inhibits SGLT, a glucose pump protein, used to reabsorb glucose in the kidney back into the blood. Patients just pee out glucose as blood plasma spills into the urinary tract. Unfortunately, this leads to unbearable urinary tract infections; bacteria love sugar.

The toxicologist brought in various insulin pens and even bought a bottle of insulin and needles. Apparently low dose insulin can be purchased over the counter although it is quite expensive. Insulin is measured in standard insulin “units”. (One unit refers to the amount required to lower glucose a set amount.) $150 for a 10 mL bottle at 100 units/mL. This might last some patients a week, others a few days. “Some severe insulin resistant diabetics use 300 units a day.”

Our patient case: “Sherry”, a 50-year-old female who has had type 2 diabetes since her late twenties. Since childhood she has been overweight, but never obese. Her whole family had a history of type 2 diabetes.

Sherry’s poor management of her diabetes led to kidney failure.(Diabetic nephropathy, degradation of the glomerulus caused by hyperglycemia, is the number one cause of kidney failure.) She joined the ranks on the dialysis wards. Dialysis filters a patient’s blood by pumping the blood through a semipermeable membrane. On one side of the membrane is the patient’s blood; on the other is a dialysis fluid (basically saline). Solutes such as glucose and electrolytes diffuse down their concentration gradient into the dilute dialysis fluid. Each dialysis session can use up to 30-50 liters of water!

Sherry described how close she got with her dialysis group. She elected to do overnight sessions. “It’s hard to get much sleep with everyone chattering and all the noises from the machines. We had a good group.” Sherry initially went only three times a week, thus requiring a large volume of blood plasma to be removed (some people go five times per week). This caused terrible cramps and muscle weakness. Fortunately, Sherry’s federal employee insurance covered home dialysis treatment and she was able to switch to a five-times-a-week schedule in the comfort of her own home. An entire room in her house was dedicated to the fluid tanks, filled monthly by truck. Because most dialysis patients have a port (brachial artery-vein autogenous fistula) installed, at-home dialysis can be done without help from a technician, but the procedure is supposed to be done when someone else is in the house in case the patient passes out.

Sherry went through seven years of dialysis. “I was at the store when my doctor called me. ‘Can you get to the hospital in 24 hours?’. ‘Yes! Yes!’ I screamed.” Sherry matched. She had a kidney donor.

“You can only appreciate this gift once you have experienced dialysis for several years. I know several transplant recipients who quickly get their kidney and just throw it away after a year. They use their new life to drink, party and have sex. They end up back in the dialysis centers. No wonder why there is strong disapproval of kidney transplants at the dialysis centers.” Sherry had retired from the federal government due to the time commitment of dialysis, but now she works part-time.

Shadowing my physician mentor this week, our first patient turned out to be a classmate. I excused myself. I also diagnosed my first patient! A 45-year-old male presented with right leg pain worsening with exertion. I asked him to lie on the examination chair and remove his pants. I then palpated his sciatic nerve, which caused a terrible radiating pain down his leg. Diagnosis: Piriformis syndrome. The sciatic nerve exits the pelvis into the thigh through a tight hole called the greater sciatic foramen. Piriformis, a muscle used for lateral rotation of the leg, can become inflamed and enlarged. This constricts the sciatic nerve causing radiating pain. He asked, “How do you make it stop?” I replied, “Let’s ask the doctor when he comes in.” Turns out there is not a great remedy. Medicine is better at labeling problems than treating them. Anti-inflammatory medications such as Tylenol and ibuprofen may help. The key is rest. Unfortunately, “George” is a construction worker without health insurance. He makes too much to be on Medicaid, but not enough to afford Obamacare premiums. I felt terrible sending him home knowing that he couldn’t afford to rest and would soon be receiving a shocking bill from the clinic.

About 20 percent of the class, and some of the faculty, went to the local women’s march, and Type-A Anita ventured to Washington, D.C. for the main event, explaining that she was demanding “equal rights for women.”

At lunch after the march, there was what would have been a discussion among eight classmates about campus sexual violence (it fell slightly short of an actual “discussion” due to the lack of interest in hearing dissenting point of views or facts that didn’t fit preconceived opinions). All supported the school-run administrative tribunals that have been expelling accused students since the 2011 “Dear Colleague” letter from the Obama Administration. Several students argued that by matriculating at school you agree to abide by the school’s code of conduct. If the school’s tribunal or committee deems an accused guilty of violating that code, that individual can be expelled without violating due process. Two classmates compared this to accusations of sexual harassment in the workplace. “A business can fire an employee if he or she is accused.” Anita: “There are far more rape cases than false accusations. 1 in 5 female college students are sexually assaulted on campus. It would be unbearable for her to live in the same dorm and go to the same class as him.”

Statistics for the week… Study: 20 hours. Sleep: 7 hours/night; Fun: 1 night. Example fun: Late night bar shenanigans on the pretext of a classmate’s girlfriend arriving in town.

More: http://fifthchance.com/MedicalSchool2020

Fundamental Attribution Error on Parade in Massachusetts

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The Boston-area commuter rail system adapts the Japanese idea of trains that run every 1-2 minutes to American standards of efficiency. I.e., the trains run every 1-2 hours. A group of locals were having coffee at our town’s sole breakfast venue when we fell into a conversation with a woman from another town who had missed her train to Boston and was thus stuck waiting for 1.5 hours.

She was 53 years old, never married, and has just moved in with a 60-year-old man. He had 18- and 19-year-old children from a marriage that ended when the wife sued him under Massachusetts family law. An MIT Class of 1960 member cautioned her not to get married to her moderate-income boyfriend. Given her good career and relatively young age, she would be a prime target for a divorce-and-alimony lawsuit from this guy in the sunset of his career. She responded that both the boyfriend and everyone other divorced person that she knew in Massachusetts and New York (where she’d previously lived) had endured years of litigation with legal fees typically exceeding the cost of sending all of the children of the marriage through college. “I don’t understand why people who aren’t happy being married can’t just walk away with what they had earned,” our never-married newcomer said, “Why do they have to try to make money off their kids or their ex? One guy in New York had been cheating on his wife for three years and lying to her. Then he tried to get a share of her pension in the divorce. It took her 20 years to recover from that.”

Her model of the world was that people were fundamentally good and loving and considered their children’s welfare more important than getting maximum cash. But she had observed that all of the divorce plaintiffs with children whom she’d known were determined to get the last possible dollar for themselves out of their respective defendants, even if the result was a lot less total cash for the children (due to the legal fees and other transaction costs). How to account for the apparent discrepancy? “It is all the fault of the lawyers,” she said. “None of these people were that greedy until they hired a lawyer.”

I think this is a great example of the Fundamental attribution error, which research psychologists have shown is more prevalent among Americans than, e.g., people in India. From Wikipedia:

In social psychology, the fundamental attribution error, also known as the correspondence bias or attribution effect, is the claim that in contrast to interpretations of their own behavior, people place undue emphasis on internal characteristics of the agent (character or intention), rather than external factors, in explaining other people’s behavior.

She found it easy to believe in the evil character of all of the lawyers who had represented all of the divorce plaintiffs she knew about. She did not consider “external factors,” such as a legislative environment setting up a winner-take-all system for divorce litigants.

Related:

  • Divorce Litigation chapter (“Both attorneys are giving accurate estimates based on what they’ve heard from their respective potential clients. These irreconcilable expectations quickly turn into feelings of entitlement. People naturally get upset when they aren’t getting something to which they feel entitled. … Part of the reason that divorce litigation is so intense is what tends to happen at parties’ first meetings with attorneys. “A lawsuit never looks better than the day you file it,” one litigator told us. By definition the attorney who is interviewing only one spouse at the inception of a lawsuit hasn’t heard any of the other side’s facts. The result is that each litigant develops an expectation regarding the divorce lawsuit that is an unlikely best-case outcome.”)
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