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The differential for thrombocytopenia, or low platelets, is a classic. Are all the cell lines down? Usually bone marrow suppression due to anything from leukemia to Lyme disease. Is there new, severe thrombocytopenia and anemia? Make sure to rule out a microangiopathic hemolytic anemia (MAHA). Is there portal hypertension with splenomegaly? It’s probably sequestration. When platelets are low, there’s usually a reason we can find. How about when platelets are high? To be honest, most of us see thrombocytosis on a complete blood count and mutter something about it being “reactive” while hoping the number is normal on the next. Which, to be fair, is a reasonable answer, as platelets are an acute-phase reactant. But next time you see a platelet count of 600,000 on a CBC, add this to your differential: Iron deficiency.

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Now what does iron deficiency have to do with platelets? And if anything, why do platelet counts get HIGHER when iron is low and hemoglobin is dropping with it? To answer that, we first need to learn more about an unsung bloodline hero: The megakaryocyte. This platelet progenitor primarily lives in the bone marrow, where it makes up only 0.5% of all cells despite being 10 to 15 times larger than the average red blood cell. Of note, it’s been known since 1893 that megakaryocytes also inhabit the lungs, but it was only in 2017 that a mouse study showed them to be highly active and likely a major contributor to total-body platelet count. Each megakaryocyte produces a few thousand platelets a day, totaling over 100 billion new platelets daily. Why so big? Unlike most precursors, which continually divide and mature, megakaryocytes actually produce platelets by breaking off parts of the cell, like flinging drops of water from an ever-running fountain.

As the megakaryocyte breaks off platelets, it must constantly replicate its DNA, but not divide. It accomplishes this through endomitosis, a modified cell cycle where it begins mitosis, but doesn’t complete normal cell division by completing cytokinesis. This results in impressive polyploidy, or DNA copying. Each copy is referred to as “N,” such that a cell (like most human cells) which copies its DNA twice is “2N.” Megakaryocytes (literally “big nucleus cell” in Greek) are usually 16N, although some reach 32N or 64N. Platelets themselves don’t have nuclei or DNA (which is why they aren’t, strictly speaking, “cells”). However, each platelet needs mitochondria, alpha granules, and dense granules. These granules store polypeptides and proteins, including clotting factors, von Willebrand factor, growth factors like VEGF, and cytokines. The megakaryocyte needs all that extra DNA to continuously produce the machinery that thousands of platelets require but cannot make themselves.

Some of you may remember that platelets and red blood cells share a myeloid progenitor. For years the teaching has been that as the iron-deficient body produces more of those progenitors to help produce RBCs, some of them become megakaryocytes by accident. We now know that this is no accident. Evolutionarily, the body senses iron deficiency as a sign of bleeding. To support hemostasis, it diverts megakaryocytic-erythroid progenitors (MEPs) away from erythroid production and towards megakaryocyte production. Furthermore, even if total megakaryocytes are not increased, iron deficiency increases the polyploidy of the new megakaryocytes, making them capable of producing more platelets. The multiple mechanisms for prioritizing platelet production are the reason by thrombocytosis is seen in up to a third of iron-deficient patients, and is even associated with increased risk of thrombosis.

In iron deficiency, it seems like the body is acting on a “plug the drain before refilling the bath” principle. But why not do both, especially since platelets aren’t full of iron like red blood cells? It’s true that 60–70% of total body iron is incorporated into hemoglobin, making red blood cell production by far the largest consumer of this mineral. However, many enzymes in the body, especially mitochondrial ones, require iron to function. If the body responded to iron deficiency by prioritizing RBC production, total-body stores would be rapidly depleted, leaving other cells, including platelets, functioning less well. A temporary down-shift is fine, because as we learned in episode 82, we need far less hemoglobin than you’d think to maintain normal oxygen delivery.

Take Home Points

• Iron deficiency is a known cause of thrombocytosis.

• Iron deficiency leads to a megakaryocytic-erythroid progenitor lineage commitment shift towards megakaryocytes. One of the key changes is an increase in megakaryocyte ploidy.

• Platelets are produced in the lung too!

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Credits & Suggested Citation

Episode written by Tony Breu
Show notes written by Tony Breu and Giancarlo Buonomo
Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Cooper AZ, Buonomo G, Manna, M. Ironing Out More Platelets. The Curious Clinicians Podcast. July 25th, 2026.

Image Credit : Wikimedia

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Congratulations to Rana for making the USA Today Bestseller list!

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Achoo! Ever thought about why you sneezed when you stepped into sunlight? Well, this same question plagued even Aristotle himself, so much so that in The Book of Problems, he asked, “Why is it that one sneezes more after one has looked at the Sun?” His answer was that sneezing resulted from a chain of physical events in which the sun heated the nose, eventually triggering a person to sneeze. But, as you can probably guess, the story is a bit more complicated than that.

Aside from Aristotle being a very curious person (among many other examples, The Book of Problems is essentially an ancient FAQ about everyday life), this question probably arose, to some extent, from the metaphysical view the Greeks held of sneezing. For example, in The Odyssey, while Penelope is harassed by the suitors and Odysseus is still away, their son Telemachus lets out a loud sneeze. Penelope then interprets this sneeze as a positive and divine omen, in which the suitors were doomed to die. In Historia animalium, Aristotle frames sneezing as a sacred act, one that was tied even to prophecy. Additionally, in ancient Greek philosophy, a potential location of the soul was the head, with the nose serving as a portal of entry. We see echoes of this in how we respond when someone sneezes. We say “bless you,” “God bless you,” or “Gesundheit,” which means “good health,” after someone sneezes.

Funny enough, this phenomenon of sneezing in response to sunlight is aptly named ACHOO syndrome. It dates back to 1978, when four physicians–Collie, Pagon, Hall, and Shokeir–wrote an outstanding paper called ACHOO syndrome: Autosomal dominant Compelling Helio-Ophthalmologic Outburst. They proposed using this acronym to name photic sneezing – a suitably fitting name for a surprisingly common phenomenon. One 2017 study from Germany, published in the European Archives of Otorhinolaryngology, surveyed 1,000 patients in the ENT department at Saarland University Hospital. In this group of patients, 57% reported sneezing in response to sunlight exposure. Other studies have found a prevalence in the 25%-40% range. Interestingly, Japanese cohorts may be one exception, with prevalence lower in that population. Photic sneezing tends to be heritable, with an inheritance pattern consistent with autosomal dominance and variable penetrance.

About 1,800 years after Aristotle, Francis Bacon made an observation that was a helpful step in the right direction. Born in London in 1561, Bacon held the title of The Right Honourable First Viscount St Alban in the court of King James I. He was an early proponent of what we now consider to be the scientific method, and in that vein he brought an empirical approach to sunlight sneezing. He basically conducted a self-experiment by observing what would happen when he opened versus closed his eyes in bright sunlight. He found that he would sneeze when his eyes were open, but wouldn’t when they were closed. Instantly, he disproved Aristotle’s “nasal heat theory” and suggested that the eyes are involved.

Sneezing itself is actually a reflex involving the forceful exhalation of air, and its technical term is “sternutation”, which is derived from Latin. Sneezing occurs in two phases: the first phase is a spasm that leads to a sharp inhalation of air, the “AH” in ACHOO. The second is an oral-nasal expiratory phase, which is the “CHOO” portion.

So, where does this sneeze reflex come from? It’s less clear where sneezes come from in humans, but the best data for the existence of a brainstem sneeze center is actually in cats, who have been found to have one in their medulla. However, there is a case report that suggests that humans might have a sneeze center of some kind in the medulla. The paper 2005 and it involved a 66-year-old man who had what the authors called a “strategic infarct” in the right lateral medulla, close to the trigeminal tract. He had the expected symptoms, like ataxia and right-sided neurologic deficits, but he also had something else that was odd. His medical team could induce sneezing by stimulating his left nostril, but they couldn’t elicit any sneezing when stimulating his right nostril. They theorized that his stroke had knocked out a putative sneeze center in that spot.

1. Cat Sneeze 2. Sneeze related area in the medulla: localisation of the human sneezing centre?

From the case report, the man’s stroke was right adjacent to the trigeminal tract (CN V), which is integral in the sneezing response. The sensation of something irritating your nose or face is actually routed to your brain through the trigeminal nerve. And that seems to be the key to this reflex, via an entity theorized to be optic-trigeminal summation. It is theorized to involve activation of the trigeminal nerve when the optic nerve (cranial nerve II) is stimulated by light. Because there are connections between the optic and trigeminal nerves in the brainstem, bright sunlight ends up stimulating the trigeminal nerve. This means light, rather than common triggers like dust, pollen, or odors, can cause a person to sneeze. There is also speculation that parasympathetic signaling might be playing a role as well.

But photic sneezing is more than just some odd physiological quirk. An interesting case report in 2023 described a patient whose sneezing interfered with a slit-lamp eye examination. This phenomenon also affects pilots who are routinely exposed to sunlight while flying. There was a paper written in 1993 that explored this concern under a fascinating title, “The Photic Sneezing Reflex as a Risk Factor to Combat Pilots”.

Take home points:

1. Photic sneezing aka sneezing as a result of sunlight exposure is home to an epically good acronym - Autosomal dominant Compelling Helio-Ophthalmologic Outburst, or ACHOO

2. The mechanism about this has been wondered about for thousands of years, from Aristotle to Francis Bacon

3. It actually is theorized to relate to something called optic-trigeminal summation, where light stimulates the trigeminal nerve like dust or pollen would, leading to a sneeze

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Credits & Suggested Citation

◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Millennium Manna
◾️Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Buonomo G, Cooper AZ, Manna M. The Sunlit Sneeze. The Curious Clinicians Podcast. June 10th, 2026.

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Read the feature published in The New York Times Magazine: Inside the Interstitium, the Human Body’s Hidden Pathways - The New York Times

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What is umami? Who discovered it?

Umami is the flavor of savory deliciousness (it means savoriness in Japanese), and is separate from the other four types of taste that we all learned about in school. The term was coined by the chemist Kikunae Ikeda, who may have been the first to describe/discover umami (though the late 19th century French chef Auguste Escoffier deliberately used umami flavor with things like veal stock several years before Ikeda codified it. Escoffier, however, didn’t describe the flavor scientifically).

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In 1907 Ikeda was sitting down for dinner with his family and he was eating a bowl of dashi broth made from bonito and kelp. He found it to be particularly delicious and perceived its savory flavor. He called this flavor umami and since he was a chemist he went about isolating the source of the flavor, which he eventually found was glutamate.

By 1909 he had extracted crystals that delivered a pure umami flavor. He called them ajinomoto, which means “origins of flavor” in Japanese but we know this compound today by its chemical abbrevation, MSG, or mono-sodium glutamate.

What is umami’s ‘mechanism’?

For years there actually was some controversy about whether umami was a distinct flavor. This was probably because the umami receptor hadn’t yet been identified. In 2003, a group of researchers knocked out the glutamate receptor complex known as T1R1+3 in mice. This eliminated the mice’s response to umami stimulation! This simultaneously both proved umami’s existence and identified its mechanism.

There are other sources of umami, as well, including most prominently inosine monophosphate (IMP). IMP is a purine nucleotide that signals through the same umami receptor, T1R1+3, though it binds at a different site than glutamate.

Can we use this information to become better cooks?

Some umami-rich foods only contain glutamate (e.g., tomatoes and cheese) while others have glutamate and IMP (e.g., bonito and beef). One key idea is that you can get more intense umami flavor by combining different umami sources.

When you combine glutamate and IMP, the signal strength through the T1R1+3 receptor synergistically increases about 30-fold due to conformational receptor changes. The result: an umami bomb!

This synergistic signaling explains how cooking with different umami sources like soy sauce and shitake mushrooms (which have glutamate) with chicken or beef or sardines (which have IMP) can be so delicious.

Is there an evolutionary explanation?

There are a number of physiologic purposes that umami serves:

1. Umami signaling increases saliva production and you get a similar synergy when glutamate and IMP are combined.

2. Glutamate is the most common amino acid in breast milk.

3. Umami appears to be the way we sense the presence of protein in food (just like saltiness signals minerals).

Here is one fascinating theory offered in a paper by Paul Breslin.

Thousands of years ago our early Homo sapien ancestors started to cook and ferment food. This provided a major survival advantage compared to other human species as cooking releases micro/macronutrients and kills parasites. Hydrolysis from cooking and fermenting breaks down protein and nucleotides, which releases glutamate and IMP. In effect cooking can accelerate release of umami flavor and may have incentivized early humans to eat healthier cooked or fermented food.

Are there other clinical correlates?

Not surprisingly, given what we have learned about IMP as a purine and a source of umami, a low purine diet for gout control is also low in umami. This may explain why it is notoriously hard to adhere to. But there are umami-rich foods that are not high in purines (which would be those that get their umami flavor exclusively from glutamate), such as tomatoes, red peppers, shitake mushrooms, or parmesan cheese. And of course MSG.

There is also interesting data around umami and, ironically, appetite suppression. One study found that rats who received MSG in their diet, in comparison to rats not exposed to MSG, actually had reduced leptin levels, lower weight gain overall, and smaller amounts of abdominal fat.

There’s also some human data suggesting appetite suppression and reduced postprandial hunger with the use of umami.

Take home points

1. Glutamate and inosine monophosphate are the mediators of umami flavor by way of the T1R1+3 taste receptor

2. Umami signaling has several physiologic roles, including increased salivation, signaling the presence of protein in food, and possibly inducing postprandial satiety

3. The enhanced umami flavor yielded from cooking or fermenting food may have had an adaptive advantage for early humans

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Credits & Citation

◾️Episode written by Avi Cooper
◾️Audio edited by Hannah Abrams
◾️Show notes by Tony Breu and Avi Cooper

Cooper AZ, Breu AC, Abrams HR. Why is umami so delicious? The Curious Clinicians Podcast. September 16, 2020. https://curiousclinicians.com/2020/06/03/episode-9-why-is-umami-so-delicious/

Image credit: http://bcbstwelltuned.com/2018/03/28/the-science-of-taste/tongue-taste-areas-sweet-sour-salty-bitter-umami/

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Early on in medical training, you learn to separate a patient’s oxygen from their carbon dioxide. A COPD patient can be heard wheezing from across the ward with a pCO₂ of 80mmHg and actually have a stable O₂ saturation, while their neighbor with interstitial lung disease will be barely maintaining their oxygen on six liters and have a pCO₂ of 40mmHg. The thinking, simply put, is that O₂ is about air “in” and pCO₂ is about air “out.” That makes sense, until you think about what is actually happening in the lung. Someone with ILD is hypoxemic because their interstitium is so fibrotic and thick that diffusion of O₂ into the pulmonary capillaries is impaired. But just as O₂ needs to diffuse into the blood to be absorbed, CO₂ needs to diffuse out of it to be exhaled. So why doesn’t that patient with ILD also have a high pCO₂?

The answer lies in that dreaded term: The gas laws. Don’t worry, this will all make sense by the end. We need to start with Henry’s Law, named after the 18th century English chemist and physician William Henry. It states that the concentration of a dissolved gas is proportional to its partial pressure and to the solubility coefficient. The higher the coefficient, the more soluble it is. The solubility coefficients of O₂ and CO₂ are quite different: O₂ has a coefficient of 0.024, while CO₂ has one of 0.57. This makes CO₂ about 24 times as soluble as O₂.

Why such a big difference? Two reasons. First, our blood is mostly water, and H₂O is a highly polar molecule. Although CO₂ is overall nonpolar, its polar C=O bonds allow favorable interactions with water. O₂, by contrast, is completely nonpolar and does not interact well with H₂O. Second, CO₂ doesn’t just interact with water, it reacts with it, forming carbonic acid, which in turn is converted to bicarbonate and a hydrogen ion. As the CO₂ is converted into carbonic acid, chemical equilibrium then favors more CO₂ dissolving. This is a demonstration of Le Chatelier’s principle, named for the 19th-century French chemist Henry Louise Le Chatelier. This reaction explains why only about 7% of the CO₂ carried in the blood is actually dissolved CO₂ – the vast majority is carried as bicarbonate.

Ok, so this all explains pretty well why CO₂ is so much more soluble in the blood than O₂ is. But in the end, we’re breathing out CO₂, not bicarbonate, and these laws don’t seem to be the passport that lets CO₂ into the United States of Alveoli while O₂ is languishing in the customs line on the other side. For that, we turn to Fick’s Law of Diffusion, a name many physicians may only know from cardiac catheterization. Named for Adolf Fick, a German-born physician and physiologist, this law states states that the rate at which a gas moves across a membrane is proportional to the solubility of the gas, the surface area of the membrane, and the difference in partial pressures across the membrane, and inversely proportional to the membrane’s thickness and the molecular weight of the gas. In other words, the smaller and more soluble gas is, it moves more easily across a given membrane. CO₂ is, obviously, a bit heavier than O₂, but it is much more soluble, and on balance already moves across the alveolar membrane more easily.

We can then return to Le Chatelier’s principle that if a system at equilibrium is disturbed, the system shifts to counteract that change. On its journey from the tissues to the lungs, an equilibrium exists between the reactions that convert CO₂ to carbonic acid and that in turn to bicarbonate and a hydrogen ion. When the blood reaches the alveolar membrane, the dissolved CO₂ starts to slip across it, which then favors the production of more CO₂ in the blood to try and restore the previous equilibrium, and that then escapes, and the cycle continues. Since Fick’s Law says diffusion is also proportional to the partial pressure difference across the membrane, as more CO₂ is created in the blood, the pressure gradient favors it passing into the alveoli.

So there’s our answer! Almost. One thing you need to know about that CO₂/carbonic acid system is that it’s very, very slow, at least in the biochemical sense. It takes several seconds to react to changes and reach a new equilibrium. Given that the transit time of a red blood cell across an alveolus is under one second, there’s simply not enough time for that crafty little use of Le Chatelier’s to have any real effect. And then comes carbonic anhydrase. This enzyme, which is in red blood cells, takes the system from one reaction every five seconds to a million every one second. When venous blood first reaches tissue, carbonic anhydrase ensures that CO₂ is rapidly converted to carbonic acid, which creates a positive gradient for continued CO₂ diffusion out of cells. At the end of the journey, it reverses roles and allows for CO₂ to be continually produced so it can diffuse across the membrane. Carbonic anhydrase is so vital to these processes that acetazolamide, a carbonic anhydrase inhibitor used to treat idiopathic intracranial hypertension, edema and many other conditions, can actually cause severe respiratory acidosis in patients with COPD.

The strongest evidence, in a sense, for how unaffected CO₂ is by things like interstitial thickening or alveolar filling is the equation for its partial pressure in arterial blood. It’s proportional to tissue CO₂ production and inversely proportional to alveolar ventilation. As long as air is entering and leaving the alveoli, CO₂ will diffuse across the membrane. That’s why our patient with COPD, who can’t get enough air out, has a high pCO₂, but our ILD patient, who has enough air in and out of the alveoli and just can’t get the O₂ across the membrane, doesn’t have to add hypercapnia to their list of problems.

Take Home Points

1. We don’t typically see hypercapnea in interstitial lung disease, even though we see hypoxemia.

2. The reasons for this difference are that carbon dioxide is about 24 times more soluble than oxygen, plus the gradient for alveolar diffusion is maintained by the ultrafast carbonic anhydrase reaction.

3. This allows for continued CO₂ diffusion across a thickened interstitium

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Credits & Suggested Citation

◾️Episode written by Tony Breu
◾️Show notes written by Tony Breu and Giancarlo Buonomo
◾️Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Cooper AZ, Buonomo G, Manna, M. One of the Fast Reactions in the Body. The Curious Clinicians Podcast. April 1st, 2026.

Image Credit : Adobe

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When we think of antibodies, such as monoclonal antibodies that target specific diseases, we often think of them as blocking receptor-ligand interactions or binding to pathogens to neutralize them. Yet in Graves’ disease, we actually find the opposite of what we would normally expect: an antibody actually activates the receptor rather than inhibit it.

Although Graves’ disease was first described in 1786, the condition was actually initially described by a physician from England, Caleb Parry. He gathered a case series of patients during his clinical practice in Somerset, and these patients had clinical symptoms that fit with the disease we now call Graves’ disease. According to Parry’s description:

“The part swelled was the thyroid gland; the eyes were protruded from their sockets, and the countenance exhibited an appearance of agitation and distress, especially on any muscular exertion, which I have rarely seen equalled.”

Parry’s descriptions from the late 1700s were published posthumously in 1825 by his son, Charles Parry. Parry was a very curious and observant person, as evidenced by his extensive writings on rabies, which he called ‘canine hydrophobia.’ While Parry described Graves’ first, the Irish surgeon Robert Graves published a case report in 1835 about a man with enlarged eyes, difficulty shutting them, and an enlarged thyroid. Graves himself was a remarkable and fascinating individual, ahead of his time on many topics, including the adoption of the newly invented stethoscope, the use of the second hand on a watch to measure heart rate, and feeding febrile patients, which was thought to be harmful at the time. Several years later, Armand Trousseau suggested naming this syndrome “Graves’ disease,” and that stuck, although William Osler recognized that Parry had been overlooked and should have had priority in naming.

Despite Parry’s clinical observations in the late 1700s, it wasn’t until 2 centuries later, in the 1950s, that the pathophysiology of Graves’ disease began to be unpacked. Most of the work was done by two researchers named Adams and Purves. Their work was based on the observation that injecting thyroid-stimulating hormone (TSH) into guinea pigs led to the thyroid gland producing thyroid hormone. The effects of TSH would peak about 3 hours after administration. However, when they injected these guinea pigs with serum samples from patients with hyperthyroidism or thyrotoxicosis, they noticed that something in the samples stimulated the thyroid gland, with effects peaking at about 24 hours. Though much more delayed than TSH, they also noticed it lasted longer in the system. They initially called this non-TSH thyroid-stimulating substance “long-acting thyroid stimulator.” Further work then identified that it was an antibody. Interestingly, at the time they made this discovery, the TSH receptor had not yet been discovered. The TSH receptor was discovered in 1973, and the following year, this thyroid-stimulating factor was shown to be an antibody that binds the TSH receptor very tightly and was labelled the thyrotropin receptor antibody.

So, why is it that antibodies activate rather than inhibit their receptor in Graves’? This is because the TSH receptor has a repeating domain that is rich in leucine that extends from the transmembrane portion of the receptor. This leucine-rich repeat in the schema looks like the head of a lacrosse stick, the part that catches the ball. The TSH receptor binds this head, activating G protein-coupled signaling in thyrocytes. A study published in the journal Thyroid by a group of biochemists from the United Kingdom in 2007 used X-ray crystallography to examine how the TSH receptor and a thyroid-stimulating antibody in Graves’ disease interact at the molecular level. They found that the thyroid-stimulating antibody binds to the TSH receptor at essentially the same location and configuration as TSH itself, even though they do not look alike. They also noted that the thyroid-stimulating antibody binds very tightly and dissociates slowly, which explains the significantly longer TSH receptor activation time compared with TSH itself.

While this antibody can bind the receptor, the results are not uniform because multiple types of anti-TSH receptor antibodies are produced in Graves’ disease. Some stimulate the receptor and activate the thyroid; some are neutral in their effects; and some actually block TSH from binding but don’t stimulate the thyroid, as we typically associate antibodies with antagonism. These would be considered thyroid-blocking antibodies instead of thyroid-stimulating antibodies. So any given patient with autoimmune thyroid disease could potentially produce a combination of these different antibody types.

Graves’ ophthalmopathy, also known as Graves’ orbitopathy, is due to edema and fibrosis of the extraocular muscles and tissues of the eye orbit. This clinical phenomenon occurs because TSH receptors are also found on the cell surfaces of orbital fibroblasts. TSH receptor antibodies stimulate orbital fibroblasts to produce glycosaminoglycans and collagen in the tissues around the eyes, and induce an inflammatory reaction in the orbits themselves, causing edema and inflammation of the extraocular muscles. The result is what we see clinically: protrusion of the eye, known as exophthalmos.

Take Home Points

• Graves’ disease results from thyroid-stimulating antibodies binding to the TSH receptor in essentially the exact same location and configuration as TSH itself does, even though they don’t look anything alike.

• Patients with autoimmune thyroid disease also can produce that block the TSH receptor instead of stimulating it.

• Graves’ ophthalmopathy results from activation of orbital fibroblasts that also express TSH receptor

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Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation

◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Millennium Manna
◾️Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC, Buonomo G, Manna, M. Graves. The Curious Clinicians Podcast. March 19, 2026.

Image Credit: Endocrine Society

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Although the erythrocyte sedimentation rate (ESR) is typically high in active lupus, C-reactive protein (CRP) is often normal. What’s particularly cool about this finding is that it lends insights into the mechanism of lupus and potentially its cause.

The earliest report alluding to this discordance was published in 1951 by Alan Hill. He wondered whether CRP could be used to track disease activity in various non-infectious inflammatory conditions, ranging from rheumatoid arthritis to dermatomyositis to lupus. For rheumatoid arthritis, the CRP was elevated in 56 of 84 cases, or about two-thirds. There were far fewer lupus cases. But of the four he did examine, none had an elevated CRP unless there was a concurrent infection. In 1979, a larger cohort found that CRP was elevated in 85% of patients with active RA and only 4% of patients with active lupus. In a more contemporary study, from 2019, a CRP of about 7 mg/L was found in inactive lupus and 12 mg/L in active lupus. But if you had active lupus with infection, the CRP rose to over 40 mg/L.

ESR, on the other hand, is typically elevated. And this difference has led some to suggest that the ESR-to-CRP ratio may help distinguish flares from infection: a high ESR-to-CRP ratio suggests a flare alone, while a lower ratio might suggest active infection as well. In the 2019 study, an ESR:CRP ratio of 15 or more was almost always active lupus alone, without concurrent infection.

To understand the discordance between ESR and CRP in active lupus, it helps to consider the immune response in various conditions. To do this, imagine a trigger, a receptor that senses it, and the characteristic cytokine signature it promotes upon activation. Ultimately, the cytokine signature determines whether CRP, ESR, or both are elevated.

A good example is gram-negative sepsis, a classic inflammatory state. Here, the trigger is often lipopolysaccharide, also known as endotoxin. This protein activates toll-like receptor 4 (TLR4). TLR4 activation results in a robust cytokine profile characterized by tumor necrosis factor, IL-1, and IL-6. It’s the IL-6 that is mainly responsible for the marked increase in CRP production by the liver. And CRP is usually very high in gram-negative sepsis. In one study, the mean CRP was greater than 100 mg/L. Recall that in active lupus, the values were closer to 10 mg/L.

This same inflammatory cascade also leads to an increase in fibrinogen and immunoglobulins, which promote the aggregation of red blood cells and their sedimentation in a test tube.

Epstein-Barr virus provides a good example of the immune response to a viral infection. Viruses consist of either DNA or RNA enclosed in a protein coat. So, unsurprisingly, the immune trigger in a viral infection is either DNA or RNA. EBV is a DNA virus, so DNA is a trigger. More specifically, unmethylated CpG-rich DNA. This type of DNA activates toll-like receptor 9 (TLR9). TLR9 activation results in a distinct cytokine profile, with a pronounced IFN-α response. Interferon was named for its ability to interfere with viral replication, so it makes sense that we see this sort of response during a viral infection.

Interferon, particularly type I interferons like IFN-α, suppresses CRP production. The primary mechanism involves interferon-α-induced shedding of membrane IL-6 receptors, leading to the release of soluble IL-6 receptors. This ultimately reduces the amount of IL-6 reaching the liver to stimulate CRP production. Additionally, type I interferons appear to have direct inhibitory effects on hepatic CRP synthesis, independent of IL-6 modulation. It should therefore be unsurprising that EBV is only associated with minimal elevations in CRP, consistent with an interferon-based immune response.

Some viral infections do have an IL-6 signature. COVID-19 is one example. We even use tocilizumab, a monoclonal antibody against IL-6, in some cases. In one of the largest randomized trials of tocilizumab in COVID-19, the median CRP was about 150 mg/L. But in these cases, the immune response isn’t just to the virus; it is also responding to the marked tissue damage and activation of TLR4, the same toll-like receptor we saw in gram-negative sepsis. This makes the cytokine profile resemble that seen in bacterial sepsis, at least in some cases. But COVID-19 also demonstrates how our attempts to put things into silos like “viral,” or “bacterial,” or “inflammatory” oversimplify. Still, we necessarily do this to understand the key features of diseases.

In lupus, the body is creating antibodies against nuclear components, including double-stranded DNA. It should come as little surprise that the immune cascade we observe is similar to that observed in a double-stranded DNA virus such as EBV. In lupus, the same TLR is activated as in EBV. And the immune cascade is nearly identical in lupus as in EBV. The trigger is dsDNA, which activates TLR9. TLR9 initiates a profound IFN-α response, as with EBV.

The interferon-based immune response is what dampens the CRP elevation we might otherwise see in the setting of immune activation. Unless a concomitant bacterial infection activates the IL-6 arm, the IFN arm predominates in active lupus, keeping the CPR normal or only modestly elevated. That’s one of the mechanisms that explain the high ESR but low CRP in active lupus. There are a few other mechanisms. For example, some patients have auto-antibodies directed against CRP. There are also genetic polymorphisms that may play a role.

The similarities between EBV and lupus are interesting because there may be a causal relationship between the two. First, EBV seropositivity in those with lupus is 100%, compared with approximately 92% in controls. Patients with lupus also have high rates of EBV reactivation. It could be that EBV leads to reprogramming of autoreactive B-cells to induce autoimmunity in those who are otherwise predisposed. Despite this, it’s too simplistic to say that EBV causes lupus, even if it is in the causal chain for some, or even all, patients. But lupus looks like what would happen if the immune system believed EBV was permanently present and could never be cleared.

Other conditions with an interferon gene signature are also associated with a high ESR but normal CRP. These include Inflammatory myopathies, primary Sjögren’s syndrome, and systemic sclerosis. The reverse is also seen: ERS is low and CRP is high. Thinking back to the patient with gram-negative sepsis, if they also have disseminated intravascular coagulation (DIC), they might have a markedly elevated CRP but a very low ESR. Fibrinogen, which typically cross-links red blood cells, leading to faster fall and a higher ESR, is low, resulting in less cross-linking and a normal or even low ESR.

Multiple myeloma often presents with a markedly elevated ESR and normal or minimally elevated CRP. Here, red blood cell aggregation isn’t due to fibrinogen but to immunoglobulins produced by plasma cells. That’s what causes the elevation in ESR. The high ESR has even been suggested as a marker for early detection of multiple myeloma.

Take Home Points

1. Active lupus is characterized by an elevated ESR but a normal CRP, an example of ESR:CRP discordance.

2. The low CRP is primarily driven by a predominantly interferon-mediated immune response in active lupus.

3. The cascade observed in active lupus is very similar to that seen in EBV, a dsDNA virus linked to the pathogenesis of lupus.

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Credits & Suggested Citation

Episode written by Tony Breu
Show notes written by Tony Breu and Giancarlo Buonomo
Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Cooper AZ, Buonomo G, Manna, M. When CPR Goes Missing. The Curious Clinicians Podcast. February 11, 2026.

Image Credit: https://en.wikipedia.org/wiki/C-reactive_protein

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In July 1953, freight brakeman John Hageman’s doctors faced a scenario that might feel familiar to anyone who has ever done preoperative medicine consults. Hageman had planned to undergo a partial gastrectomy for peptic ulcer disease, but his preoperative tests showed a prolonged clotting time. In the 1950s, we knew about other diseases with prolonged clotting times; hemophilia in particular, which at the time referred to what we now know as hemophilia A (Factor 8 deficiency) and hemophilia B (then known as Christmas disease and now known as Factor 9 deficiency). But Oscar Ratnoff and Joan Colopy, two scientists who investigated the case further, found a few things that made it clear Hageman didn’t have either condition. So why did he have a prolonged clotting time without any bleeding symptoms?

First, Ratnoff and Colopy noted a few tests and observations that distinguished Hageman’s condition from hemophilia. First, Hageman’s clotting time improved with the addition of even small amounts of blood from people with factor 8 or factor 9 deficiencies, indicating that neither was the missing piece. If the missing step in forming a clot was either factor 8 or factor 9, then that blood would not have corrected the issue. Second, Hageman’s apparent condition did not act like any of these classic deficiency states. And last, perhaps most importantly, John Hageman wasn’t bleeding! He was an asymptomatic (at least as related to bleeding/clotting) 37-year-old man being assessed in a preoperative clinic. His bleeding time was normal, and he had previously undergone a tonsillectomy, a dental extraction, and a traumatic hand injury as a kid, all without bleeding. This is not the experience of someone with hemophilia.

Fortunately, this asymptomatic lab test ultimately did not keep Hageman from getting his surgery. In 1954, the same year Ratnoff and Colopy published their observations on Hageman and two other people with the same condition, he underwent a partial gastrectomy and gastrojejunostomy without excessive bleeding or wound healing complications. However, he was transfused pre-emptively during and after the case.

To understand how a prolonged bleeding time might not place one at risk for bleeding, it helps to compare it with severe hemophilia A. Those with hemophilia have a near-complete lack of factor 8. Because factor 8 is a component of the intrinsic coagulation cascade, their labs will show a prolonged partial thromboplastin time (PTT) with a normal prothrombin time (PT) and thrombin time (TT). These tests allow one to ‘localize the lesion’ to the intrinsic clotting cascade.

As with hemophilia A, Hageman’s PT and TT were normal, and mixing his plasma with plasma that contained any missing factor corrected the problem. So it looked like classic hemophilia. But when Ratnoff and Colopy performed other tests, they found unusual results. The first thing they did was to measure the overall clotting time. This meant putting whole blood in a tube and measuring how long it takes to form a clot at a given temperature. When they did this with Hageman’s specimen, it took 87 minutes for whole blood to clot in a glass tube. To examine whether this was a platelet issue or a plasma issue, they separated the two and ran the test again. When they did that, the plasma in a glass tube absolutely did not clot, for at least 5 hours.

Two other strange things happened. Rafnoff and Colopy wondered whether the glass might be playing a role. So they added 100 mg of crushed-up glass to a tube. When they did this, Hageman’s sample did clot, but instead of the 87 minutes, it took 182 minutes. Then, with 500 mg of crushed-up glass, it took 144 to clot. Finally, they found that diluting the whole mixture could also improve clotting time, down to 113 minutes.

What does all of this mean? Because the addition of normal plasma corrected the bleeding time, we can conclude that Hageman had a factor deficiency. But adding glass and diluting are not consistent with a factor deficiency. So there must be something more to it. Ratnoff and Colopy concluded that “the defect was at an early stage in the clotting process,” with the idea that perhaps all this occurred somewhere in the clotting process that then later affected what they then knew as anti-hemophilia factor, now known as factor 8. This idea of “early” and “late” stages in the clotting process led to the modern understanding of the coagulation cascade.

We now know that John Hageman lacked factor 12. And Hageman remains the namesake of the Hageman trait, also known as factor 12 deficiency. But why didn’t Hageman bleed?

Turns out that factor 12 is an enzyme that can autoactivate itself after contact with artificial surfaces, like glass or bacteria, and can then start a clot by activating factor 11. Factor 12 does not appear to be involved in regular day-to-day clotting in the human body. Instead, clots can initiate through the extrinsic pathway by exposure of tissue factor. Then the intrinsic cascade can propagate downstream of factor 12, with thrombin activating factor 11a as a loop that essentially bypasses 12. So, when Hageman had his tonsils out, those alternate ways of starting the cascade would have served him just fine. In fact, Hageman himself died of a pulmonary embolism, which occurred after he had a boxcar accident and fractured his pelvis, requiring multiple weeks of immobility. Going back to the original experiments, adding all that glass might provide tons of surface area to allow clotting to begin and maximize the use of any factor 12 in the sample.

If factor 12 doesn’t play a significant role in clotting, what does it do? This is a research question that has now been studied for about 70 years. In 2016, the Journal of Thrombosis and Haemostasis published a review that began with “Factor XII is a mysterious plasma protein without a clear physiologic function. It was identified as a clotting factor, but has no clear role in hemostasis.” The contemporary understanding is that factor 12 plays a role in inflammation and may also participate in wound healing through multiple mechanisms.

And factor 12 deficiency is not uncommon. Although we don’t know the true prevalence because most people are asymptomatic. There is a wide range of prevalence estimates, but in one study of healthy blood donors, 1 in 300 had severe factor 12 deficiency, and another 6 in 300 had moderate deficiency.

In the modern era, factor 12 may have more to teach us. Just a few months before we recorded this episode, Tem Bendapudi published a detailed characterization of clotting in both humans and mice that are heterozygous for factor 12. They found that in a sample of over 700,000 people from the United Kingdom and the United States, being a factor 12 carrier was associated with a significantly decreased risk of venous thromboembolism (HR = 0.648) without an increased risk of bleeding or sepsis. This would challenge how we typically think of inheritance for clotting factor deficiencies and point to the existence of a distinct ‘haploinsufficient‘ state -- just another way that John Hageman continues to teach us about the world of clotting.

Take Home Points

1. Hageman factor deficiency, also known as factor 12 deficiency, is an asymptomatic condition characterized by a prolonged PTT but no increased risk of bleeding.

2. Factor 12 helps start coagulation in vitro because it’s able to activate on the glass surfaces of the test tube, but in vivo we have other ways to initiate clotting.

3. Early studies on factor 12 laid the foundation for the modern coagulation cascade, and very recent studies suggest that there may be factor 12 haploinsufficient states, which would challenge how we commonly think about coagulation factor inheritance.

Sponsor

This episode was sponsored by FIGS. FIGS is offering 15% off your first purchase. Just go to wearfigs.com and use the code FIGSRX at checkout.

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CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation

◾️Episode written by Hannah Abrams
◾️Show notes written by Hannah Abrams and Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com

Abrams HR, Cooper AZ, Buonomo G, Manna, M, Breu AC. The Forgotten Factor. The Curious Clinicians Podcast. January 7, 2026.

Image Credit: https://www.thebloodproject.com/ufaq/what-is-the-clotting-cascade/

We often think of sleep as a state of brain rest and restoration, but it also has significant physiological implications for the whole body. Chronic insomnia has been linked to an increased incidence of infections, as sleep optimizes immune regulation and balances pro- and anti-inflammatory states. Sleep also impacts cardiovascular health. Interestingly, when we look at the fall and spring daylight saving time changes, there appears to be a protective effect on mortality immediately after the fall time change (when people can get an extra hour of sleep) among elderly people, those with dementia, those with chronic respiratory disease, and those with cancer. It’s not a strong association, but people die less often the day after gaining an extra hour of sleep, and the effect persists for 8 weeks after the time change. Unsurprisingly, sleep deprivation also causes cognitive impairment and mood effects.

Sleep is not unique to complex animals such as vertebrates; almost all animals require some form of restorative sleep, including insects. There is evidence that bacteria can engage in cyclical metabolic rest that’s not necessarily sleep, suggesting that living things in general need to rest periodically. An interesting phenomenon is the light-dependent, full-day cycle of photosynthetic cyanobacteria, which oxygenated the early Earth’s atmosphere, beginning about 2.5 billion years ago. As photosynthesizers, they depend on sunlight for their metabolism; at night, they essentially shut down until morning, when they awaken as part of a 24-hour circadian rhythm.

Familial fatal insomnia is a neurodegenerative prion disease that was first reported only 38 years ago, in 1986, in the New England Journal of Medicine. Nine physicians from Italy published the case of a 53-year-old man who had a sharply progressive course of insomnia and signs of dyautonmia, followed by dreamlike mental states, dysarthria, tremor, and myoclonus, which subsequently led him to a coma and death after nine months. What made the case particularly interesting was that other members of his family exhibited similar symptoms and courses of illness. Someone in the family was a physician and observed a pattern of “a peculiar, fatal disorder of sleep” and had been compiling a family history. They were able to trace this syndrome back to the early to mid-1800s, with multiple family members experiencing a neurodegenerative syndrome involving insomnia.

D.T. Max wrote a family profile in the New York Times Magazine in 2001 and later wrote a book about the family. In his Times piece, Max wrote about a man named Giacomo, who lived near Venice, Italy, who suddenly developed insomnia, becoming bedbound and delirious before he died months later at age 45. Over the last two and a half centuries, dozens of family members were similarly affected, and it came to be known as a “family disease” in that part of Italy. As a result, they’ve experienced social isolation, and when Max interviewed a contemporary descendant of Giacomo, she noted that members of the family have trouble getting life insurance.

In the 1986 New England Journal case report, they did not know what had caused this inherited disorder, but they noticed some distinct pathological patterns in the patient’s brain as well as the brain of his sister, who had died of the same disease. The authors found neuronal death in specific thalamic regions in both brains. They wondered whether this could be a form of Creutzfeldt-Jakob Disease (CJD), but felt that this Italian family’s presentation did not align with what is typically seen in CJD.

FFI is also a prion disease, similar to CJD. Inherited mutations in the prion gene PRNP cause FFI. There are sporadic cases too, where a PRNP mutation arises de novo. It’s separate from CJD, scrapie, or mad cow disease – the so-called transmissible spongiform encephalopathies. There actually is a physiologic version of prion proteins known as PrP. PrP is a type of protein that we all have that’s bound to cell membranes and transports copper, and it is necessary for the function of neurons in particular.

In the case of pathologic prions, a change in the folding pattern leads to disease. Proteins fold on themselves. The primary structure of proteins is the amino acid sequence that determines how the protein folds. This is followed by secondary folding, which involves two types of patterns called motifs: beta-sheets or alpha-helices. With these neurotoxic prion proteins, either a genetic mutation or an acquired infectious prion protein initiates a cascade of conversion of alpha-helices to beta–sheets. The proteins then start to stack and roll into themselves as their secondary structures all snap into alignment with each other.

With neurons, this cascade leads to neurotoxicity and neurodegenerative symptoms. Acquired prion diseases can be caught by eating infected nervous tissue, such as beef from affected animals, which can cause mad cow disease, also called variant Creutzfeldt-Jakob disease. Exposure to brain matter or cerebrospinal fluid of an affected person, whether from contaminated surgical instruments or from body fluid exposure after a lumbar puncture, can also cause it. These occurrences are exceedingly rare due to safety regulations in the food supply and healthcare facilities.

So, why are people with FFI unable to sleep? This actually has to do with the location of where these abnormal prion proteins are forming. As noted earlier, in the 1986 case report, the authors found thalamic degeneration at autopsy. This anatomic pattern has been confirmed with subsequent case series as well, with the consistent finding that familial fatal insomnia is ultimately a thalamic disorder. Below is a PET scan example from the brain of someone with FFI. There is no metabolism in the thalamus; that part of the brain shuts down.

Since the thalamus is a primary regulator of the sleep-wake cycle, from wakefulness to non-REM to REM sleep, its localization is reasonable. The thalamus is hyperconnected to the rest of the brain, like an old-school phone switchboard operator, and one of the many things it regulates is sleep. It is not fully understood why the thalamus is uniquely susceptible in individuals with a PRNP gene mutation, compared with other brain regions that carry the same mutation. There’s two plausible mechanistic theories that we can briefly review. The first was that there might be specific receptors for these abnormal prions that are present only in the thalamus. One proposed candidate is the limbic associated membrane protein or LAMP, which is a type of cell membrane receptor that only exists on neurons in parts of the brain within or closely associated with the thalamus. Another theory is that different degrees of prion glycosylation inside the thalamus could affect how these prions function.

Currently, FFI has no cure but doxycycline is being tested to see if it will slow down the disease or prevent it from arising altogether. Doxycycline has two effects that may be beneficial in FFI: it blocks the formation of abnormal prion protein and increases its proteolytic degradation. A 2021 paper out of Italy published in the journal Neurobiology of Disease found that giving prophylactic doxycycline to mice in an in vivo familial fatal insomnia model did minimize memory and sleep issues that the animals would have otherwise developed, however they still experienced fatal neurodegeneration. From a clinical standpoint, a 10-year preventive doxycycline trial testing in families affected by the disease concluded recently, but the results have not yet been published.

Additionally, a couple of avenues have been pursued, leveraging the observation that a very small percentage of people are what’s called “PRNP heterozygous”, having only one copy of the PRNP gene, and so make less than normal amounts of prion protein. They seem to suffer no ill effects. One approach is to silence the abnormal prion gene using an epigenetic editor. The name for this is CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase), as reported in a 2024 paper in the journal Science from Harvard and MIT that tested this technology in a mouse model. The researchers used a viral vector to deliver CHARM to the mice’s brains, thereby silencing prion genes by inducing DNA methylation at those sites. This can offer therapeutic avenues for other prion diseases besides just familial fatal insomnia. Another method is to edit the PRNP gene itself to definitively silence it in vivo using CRISPR technology, which the same group of researchers found could decrease prion protein expression in PRNP-mutated mouse brains by 50% and extend survival by the same margin.

The author list of the two papers cited above, which are significant advances in prion research, includes Dr. Sonia Vallabh as the second-to-last author. She is a neuroscientist at Harvard Medical School who also found out that she inherited a PRNP mutation after her mother died of familial fatal insomnia in 2010. She and her husband, Dr. Eric Minikel, run a lab studying prion disease therapeutics at the Broad Institute in Boston. Here is a link to a 2025 Harvard Gazette article that highlights their incredible story.

Take Home Points

• Familial fatal insomnia is a neurodegenerative prion disease that leads to, among many clinical symptoms, progressive insomnia. Misfolded prion proteins accumulate in the thalamus

• Thalamic prion accumulation then causes disruption in the sleep-wake cycle and an inability to fall asleep

• It is not fully understood why this thalamic specificity exists, but it may result from different glycosylation of prions in the thalamus or because of prion receptors that only exist in that part of the brain.

• There are fascinating potential therapies being studied and under development, including prophylactic doxycycline, epigenetic prion gene silencing, and gene editing technologies using CRISPR

Listen to the episode!

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation

◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Millennium Manna
◾️Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC, Buonomo G, Manna, M. No Sleep for the Weary. The Curious Clinicians Podcast. December 10th, 2025.

Image Credit: Pexels.com

Original tweetorial source: https://x.com/AvrahamCooperMD/status/1837872885018341658?s=20

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Other than when there’s Thai food at noon conference, it’s the best part of the day on inpatient medicine. A patient comes in with ascites, they get a diagnostic paracentesis, you look at the fluid albumin and subtract it from that serum albumin that you pray you remembered to order before the tap. This is the serum ascites-albumin gap (SAAG). You google that chart that you’ve somehow never remembered to bookmark, and, unlike most other lab values in medicine, it gives you a clear answer: If the SAAG is ≥ 1.1 g/dL, the ascites is due to portal hypertension, and your differential has just been narrowed to cirrhosis ... and then cirrhosis ... and then cirrhosis ... and then finally some other causes like heart failure and various types of thrombosis.

SAAG is mercifully easy to calculate and use. But how many of us actually know why all of our patients with cirrhosis have a high SAAG? That’s why we’ve devoted a whole episode to understanding how this small number tells us an enormous amount about a patient’s pathophysiology.

To understand SAAG, we first need to understand ascites, and to understand ascites we have to understand capillaries. There are three basic types of capillaries in the body: Continuous, fenestrated and sinusoidal. Continuous capillaries have an uninterrupted endothelial lining joined by tight junctions and supported by a complete basement membrane, which makes them ideal for spaces like skin, lungs and the central nervous system where you don’t want too much leakage. Fenestrated capillaries, which have small pores (fenestrations), are in places like the glomeruli of the kidney where rapid, but controlled, filtration and absorption of molecules needs to happen. Sinusoidal capillaries have more of an “open-door policy.” Also known as discontinuous capillaries, they are large and have irregular lumens with wide gaps between endothelial cells and minimal basement membrane. This allows for much freer passage of large molecules like proteins. These capillaries exist primarily in the spleen, bone marrow and, pertinent to this episode, the liver.

“Hold on,” you may be thinking. “This makes no sense. High SAAG means that the ascites has less albumin. If the liver capillaries are leakier than a papier-mâché canoe, and portal hypertension is usually from liver disease, shouldn’t the fluid coming out of them be chock-full of albumin, making the SAAG low, not high?”

It’s a great question, and relates to the next one we need to answer: Where does portal-hypertensive ascites actually come from? Leading into the 1950’s, the thought was that ascites was simply due to a buildup of hydrostatic pressure in the portal system, and this pressure eventually backed up into the mesenteric vessels of the abdomen. Unlike the liver capillaries, mesenteric capillaries are continuous, and so the pressure would force out fluid but not much albumin.

It was a very logical conclusion, but not the whole picture. To be sure, excess pressure in the portal system can definitely cause ascites: Most cases of hepatic vein (Budd-Chiari syndrome) or inferior vena cava thrombosis produce ascites even in the absence of underlying liver disease. However, when just the portal vein is occluded (like in portal vein thrombosis), which should theoretically cause pressure buildup in those mesenteric vessels, we don’t often see large-volume ascites, and sometimes we see no ascites. Schistosomiasis (a parasitic infection and one of the leading causes of portal hypertension worldwide) can cause terrible portal vein fibrosis due to inflammation from egg deposition. Patients may have many classic signs of portal hypertension such as splenomegaly and varices, but rarely have significant ascites.

What’s going on here? Look closely at the diagram above and think about the diseases we just discussed. In Budd-Chiari syndrome and IVC thrombosis, the pressure backs up directly into the liver, whereas in portal vein thrombosis and schistosomiasis, the liver itself isn’t “feeling” the pressure. There are some old experiments where the liver was surgically moved to above the diaphragm and the IVC ligated to simulate portal hypertension. The resulting fluid accumulated in the chest, not the peritoneal cavity. Overall, this suggests that portal hypertensive ascites is coming from the liver, not the mesenteric vessels.

“Wait a second,” you’re probably saying. “This all literally proves my initial point. If the ascites if coming directly from the liver and the liver has all those leaky capillaries, shouldn’t the ascites in cirrhosis have just as much albumin as normal serum?”

Again, a very good question, and this leads us to our final area of exploration. Those leaky liver capillaries are organized in small beds called sinusoids, which connect the portal and central veins. In cirrhosis, a process called “capillarization” occurs. First described in 1963 by by Fenton Schaffner and Hans Popper, capillarization refers to a chronic inflammatory sequela in which hepatic stellate cells deposit extracellular matrix in the Space of Disse. This fibrosis impedes the exchange of proteins, including albumin. As cirrhosis progresses, capillarization worsens, and the hepatic sinusoids essentially turn into continuous capillaries.

Does this mean we can track the progress of cirrhosis using SAAG? Unfortunately, this is not a well-studied question. One 1968 study by Charles Witte and William Cole tracked the total protein content of ascites as cirrhosis worsened and found that as liver fibrosis increased, the ascitic protein went down. SAAG was not invented at this point, but as albumin is a protein, the total protein is a good enough proxy.

So, there’s the basic answer to our initial question: Cirrhosis causes both portal hypertension and capillarization of hepatic sinusoids, leading to leakage of low-albumin fluid. Of course, the ultimate answer may be more complicated. Remember those ultra-tight mesenteric vessels that we seemed to dismiss? Some researchers argue that while cirrhosis patients with relatively high ascitic protein content but still high SAAG (i.e., low ascitic albumin) probably have ascites purely coming from the liver, as disease progresses, splanchnic arterial vasodilation also does, which causes the mesenteric capillary hydrostatic pressure to rise enough to eventually force albumin-poor fluid out as well.

There are a million other questions to answer about ascites. For example, why do heart failure and IVC thrombosis also cause high SAAG if those diseases don’t necessarily causes hepatic fibrosis? And why do we use total ascitic protein to help us distinguish them from cirrhosis? Those are questions for another day. For now, we hope that this episode helps you the next time you pore over paracentesis results and wonder why that patient with jaundice, a swollen belly and a long history of alcohol use has a SAAG of ≥ 1.1 g/dL.

Take Home Points

1. A non-cirrhotic liver contains the leakiest of all capillaries, known as sinusoidal capillaries.

2. Despite this, the ascites of cirrhosis has a low albumin content.

3. The main reason for this is capillarization of the sinusoidal capillaries, in which fibrosis restricts the movement of plasma proteins.

4. As cirrhosis progresses, the continuous capillaries of the mesentery also contribute to high-SAAG ascites.

Sponsor

This episode was sponsored by FIGS. FIGS is offering 15% off your first purchase. Just go to wearfigs.com and use the code FIGSRX at checkout

Listen to the episode!

https://directory.libsyn.com/episode/index/id/39189005

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation

◾️Episode written by Tony Breu
◾️Show notes written by Tony Breu and Giancarlo Buonomo
◾️Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Cooper AZ, Buonomo G, Manna, M. On Sinusoids and SAAGs. The Curious Clinicians Podcast. November 26th, 2025.

Image Credit: Wikimedia Commons

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What comes to mind when we say tiny but mighty? Well, if Deinococcus radiodurans didn’t cross your mind, maybe it will earn your respect after this segment, so much so that it may come to mind the next time someone asks you that question. In our previous episode, “Wherefore Iodine?”, we learned about why iodine administration was a key public health intervention in Eastern Europe following the Chernobyl disaster. Then, in a follow-up episode, “The Mold that Eats Radiation for Breakfast”, we covered how various species of black radiation-eating fungi are not only surviving, but thriving within and around Chernobyl. In that episode, we discussed the concept of radioresistance, which refers to the degree to which an organism can withstand various levels of radiation exposure. And that brings us to this segment: how does the most radioresistant organism on the planet, a tiny bacterium called D. radiodurans, withstand extreme levels of radiation?

D. radiodurans is an extremophile, a term used to describe an organism that can live and even thrive in the most extreme environments. And as mentioned in a previous episode, bacteria are the most tolerant of environmental extremes among any form of life. The term “extremophile” was coined in 1974 by R.D. MacElroy, a scientist at NASA, when he described the microbes that exist in harsh environments that most forms of life cannot tolerate, such as extremes of temperature, pH, pressure, or radiation exposure. Fascinatingly, Koki Horikoshi and Alan Bull, in their book Extremophiles Handbook, note “definitions of extreme and extremophile are of course anthropocentric; from the point of view of the organism per se, its environment is that to which it is adapted and thence is completely normal.” In other words, what we humans view as extreme is entirely normal to an extremophile bacterium like D. radiodurans.

D. radiodurans is just remarkably resilient to radiation damage. Just to put it into perspective, according to the CDC, humans have an LD50/60 (dose at which ~50% die within 60 days after an entire body high dose penetrating radiation) of about 2.5–5 Gy, whereas D. radiodurans can survive 5,000–15,000 Gy of acute ionizing radiation with no loss of viability. Apparently, it has been nicknamed “Conan the Bacterium” due to its ability to survive such extreme conditions. It was discovered in 1956 when it was isolated from cans of meat that had gone through sterilization using high-dose radiation bursts.

So, how does D. radiodurans survive these conditions? To answer this, we will draw from a 2005 review in Nature, titled “Deinococcus radiodurans – The Consummate Survivor,” by Michael Cox and John Battista. In a very general sense, this bacterium’s superpower involves resistance to DNA damage. Radiation damages DNA by causing a double-stranded break where that double helix strand of DNA fully ruptures. Like other bacteria, D. radiodurans employs double-stranded DNA repair mechanisms, where a homologous region on another intact segment of DNA serves as a template for repair. However, D. radiodurans also possesses different forms of certain DNA repair enzymes, which enable more efficient and accurate repair compared to other bacteria.

Additionally, D. radiodurans has redundancy built into its genome, comprising approximately 3,000 individual genes. It accomplishes this by having at least four copies of its genome, so even if a DNA break damages one copy of a gene, it still has at least three other copies of that gene. These extra copies also make D. radiodurans better able to repair DNA strand breaks when they arise, because they can be used as a template to patch the rupture. However, Cox and Battista point out that this mechanism is more speculative because other bacteria, which are not equally radioresistant to D. radiodurans, can also increase their gene copies during phases of active cellular division. Nonetheless, it does make sense that having more gene copies in general would help an organism better absorb damage from ionizing radiation.

Furthermore, D. radiodurans organizes its DNA into a circular ring, which is a fairly standard arrangement for bacteria. However, it also has a more condensed genome, which some molecular biologists have theorized might help keep breaks closer together rather than separating within the cell, making its DNA more radioresistant. Finally, D. radiodurans also has more manganese in its DNA than other types of bacteria. Since it is a positively charged cation, it may act as a protective agent by serving as a reactive oxygen scavenger or by facilitating further condensation of the DNA.

Radiation doesn’t only damage DNA though, it also oxidizes proteins hindering their function. A 2010 paper by Anita Krisko and Miroslav Radman, published in the Proceedings of the National Academy of Sciences, found that D. radiodurans is exceptionally adept at preventing radiation-induced protein oxidation through an unknown mechanism, but they presumed the involvement of a cytosolic antioxidant compound.

Is there any advantage to this type of extreme radioresistance? We discussed in “The Mold that Eats Radiation for Breakfast” that some of these microbial radioresilience features might relate to the environment that life had to contend with on the early Earth, where radiation levels were higher. However, Cox and Battista theorized that the primary reason might be that having hardier, sturdier, and easier-to-repair DNA is itself beneficial, regardless of whether radiation, changes in pH, temperature, or desiccation damage that DNA. They drew a connection in particular with desiccation, arguing that the evolutionary pressure to be able to survive DNA damage from drying out for a bacteria is really strong, and it may be that the ability to tolerate extremely high doses of ionizing radiation may simply be a byproduct of resistance to desiccation. Resilient DNA is the underlying theme there, and presumably proteins as well. This is an example of exaptation, where a feature evolves for a particular reason but then gets used to serve a different purpose altogether. In “The Mold that Eats Radiation for Breakfast,” we also discussed how NASA is exploring the use of radioresistant fungi as potential radiation shields for a future human mission to Mars. These non-human forms of life are often far more resilient than we are at withstanding environmental and physiological extremes.

But this also begs the question, if D. radiodurans is that hardy, do we have to worry about it or other extremophiles potentially colonizing other planets? This is the inverse of the so-called panspermia hypothesis, which posits that the essential ingredients for life on Earth arrived on our planet from a meteor impact. The term for this concern is interplanetary contamination, and it is a real concern. In 2001, an article titled “Infecting Other Worlds” was published in the magazine American Scientist by Richard Greenberg, where he noted that the Apollo 12 mission, which was of course the first to land on the moon, retrieved probes that had been sent to the moon years earlier. Upon returning to Earth, live bacteria were found to be living inside the machinery, despite the machinery having been on the moon’s surface. As we continue to explore the Solar System, Greenberg frames this as an ethical quandary that we must grapple with as a scientific community and as a species.

As cool as this tiny bacteria is, the melanin in fungi also serves a similar purpose, where extreme radioresistance might be an epiphenomenon related to being able to protect DNA from any source, including desiccation. This paper from the fungal world suggests that melanin in fungal cell walls serves a function beyond simply protecting against radiation. Having melanin in a fungus’ cell wall just makes it sturdier in general, including being more resistant to things like desiccation, heat, and physical damage to cell walls. It protects fungi against the human immune system, thus making melanized fungi more pathogenic.

Take Home Points

• Deinococcus radiodurans is an example of an extremophile, and is perhaps the most resilient organism on the planet

• Mechanisms for its radioresilience involve genome construction, efficient DNA repair, and resistance to radiation-induced protein oxidative damage

• This capacity for radioresistance may be a byproduct of resistance to DNA damage from desiccation

• Melanin in fungi increases their virulence and pathogenicity via resistance from immune-mediated destruction

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CME/MOC

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Credits & Suggested Citation

Episode written by Avi Cooper
Show notes written by Avi Cooper and Millennium Manna
Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC, Buonomo G, Manna, M.

Image Credit: https://doi.org/10.1038/nrmicro1264

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We are thrilled to welcome Dr. Mike Todorovic, friend of The Curious Clinicians, renowned online educator who makes complex concepts in physiology, biophysics and pharmacology more accessible for students and clinicians alike, back to the podcast! Along with his partner Dr. Matt Barton, Dr. Mike has written a new book: The Body A-Z: A fun, fascinating and family-friendly manual for the most important thing you own.

This amazing book is a must-read for anyone who wants to learn more about the wonders and mysteries and quirks of the human body.

On this episode, we discussed 3 fascinating questions (of many) that Dr. Matt and Dr. Mike tackle in the book:

1. Why might riding a bike be easier for someone with Parkinson’s Disease than buttoning a shirt?

2. Why do we hiccup?

3. Why does rigor mortis follow shortly after death?

You can order the book here: https://www.readings.com.au/product/9781923046320/the-body-a-z–matthew-barton-michael-todorovic–2025–9781923046320

Kindle version: https://www.amazon.com/Body-Z-fascinating-family-friendly-important-ebook/dp/B0FJMQH87X

Listen to the episode!

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation
Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Todorovic M, Abrams HR, Breu AC. Dr. Mike Todorovic and the Wonders of the Na+/K+ ATPase Pump. The Curious Clinicians Podcast. August 21, 2024.

Dr. Matt & Dr. Mike’s podcast: https://drmattdrmike.com.au/dr-matt-mikes-medical-podcast/

Dr. Matt & Dr. Mike’s YouTube channel: https://www.youtube.com/@DrMattDrMike/featured

Image Credit: https://www.simonandschuster.com/books/The-Body-A-Z/Matthew-Barton/9781761639784

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Ah, serum ammonia. A lab that is often sent and often a head-scratcher. Sometimes an altered patient with cirrhosis and the most textbook asterixis will have a normal serum ammonia. And other times a patient has a sky-high ammonia and you have no idea why. Have you ever stopped and check if their on valproic acid?

Valproic acid (VPA) is a commonly-prescribed anti-seizure medication. It was was first synthesized in 1881 by the American Chemist Beverly Burton, but only found clinical use nearly a century later, and by accident. In Grenoble, France, a researcher named Pierre Eymard was studying the anti-convulsant properties of various herbal compounds and he used VPA as a solvent. He found that all of the herbal compounds prevented seizures in his animal subjects, so he then tested VPA on them and realized that VPA itself was the therapeutic agent. Within a few years, the same group that had made the initial observations also reported the effect in patients with epilepsy and VPA quickly became a wisely-used anti-epileptic drug (AED) in Europe. It wasn’t approved for use in the USA until 1978 (possibly because the anti-emetic thalidomide, which we discussed in Episode 83, had also seemed safe in animal models and ended up causing birth defects in thousands of babies).

To be clear, VPA is also well-known to cause neural and cardiac defects in fetuses and is mostly contraindicated in pregnancy. But some early studies on VPA occasionally noted some strange side-effects in adults. A 1974 study published in The British Medical Journal noted that “drowsiness occurred in eight patients, two becoming so drowsy as to be nearly stuporous.” All the patients were receiving other anticonvulsants, so the thought was that combining AEDS was the cause. However BMJ published the first randomized controlled trial of VPA the following and none of the 20 patients had severe side effects. In 1979, a case series of several patients again reported “stupor,” like a 37-year-old on 1,750 mg per day of VPA. However, they were also given phenytoin, carbamazepine, and primidone. After stopping VPA, the patient returned to baseline, only to become altered when they resumed VPA. All of these studies seemed to indicate that combining AEDs (especially with VPA) was the cause of altered mental status. A very reasonable theory, as polypharmacy is widely known to cause cognitive impairment, especially in our older patients.

In the above-mentioned case series, the authors wrote that “it is unlikely that stupor was caused by metabolic disturbances, since in each case the serum glucose, blood urea nitrogen, [AST], LDH, and alkaline phosphatase were normal.” Who did they neglect to check amongst the usual rogues gallery of altered mental status (AMS)? Ammonia.

Around that time, David Coulter and Richard Allen from the University of Michigan Medical Center observed increased plasma glycine and propionic acid concentrations in patients with valproic acid toxicity. Elevations in these compounds are rare and usually a sign of a inherited metabolic disorder. Coulter and Allen noted that the levels weren’t nearly as high as one would expect in those diseases. However, they’d also recently seen a patient on VPA with altered mental status who had hyperammonemia without any history of liver disease (the usual suspect as the liver is the main clearer of ammonia in the body). They wondered if there was a connection between these four compounds: VPA, ammonia, glycine and propionic acid. The next time a patient on VPA presented with AMS and hyperammonemia, they stopped the VPA and the ammonia levels and mental status improved. After giving the same patient a load of VPA, he glycine, propionic acid, and ammonia concentrations all increased and they became altered yet again.

We’re hinting (if that) at a connection between VPA and ammonia. But why does that happen? Dust off your biochemistry textbooks because we’re going to talk about the urea cycle (don’t worry, we’ve put a diagram below so you can follow along).

The primary role of the urea cycle is to convert toxic ammonia (which is produced both by cells and also bacteria in the gut) into urea, a non-toxic compound excreted in urine. One of the metabolites of VPA inhibits N-acetyl-glutamate synthase, also known as NAGS. As its name implies, NAGS is essential for synthesizing N-acetyl-glutamate, a required activator of carbamoyl phosphate synthetase I, the first and rate-limiting enzyme of the urea cycle. With NAGS inhibited, the urea cycle is impaired and toxic ammonia builds up. Elevated glycine ( a precursor molecule to ammonia) and propionic acid are signs of an impaired urea cycle. On an interesting side note, propionic acidemia, a rare inborn error of metabolism, can similarly cause hyperammonemia because one of the precursors of propionic acid is also a NAGS inhibitor!

To make matters worse, VPA depletes carnitine, which alters valproic acid metabolism, generating toxic metabolites that further inhibit ammonia elimination. In fact, carnitine supplementation is one of the mainstays of VPA-induced hyperammonemia treatment, as multiple studies have shown it to help reduce ammonia levels and improve mental status. Other things that researchers have shown to be effective include carbapenem antibiotics, which work by irreversible inhibition of acylpeptide hydrolase, a compound that helps convert VPA metabolites back to the active form.

VPA-induced hyperammonemia is not the most common of diagnoses. But it’s not as rare as you might think. Between 17% and 28% of patients on VPA have hyperammonemia. And since symptomatic encephalopathy occurs in about 3-5% of patients with hyperammonemia, it’s always good to pause when you see VPA on a med list and wonder if it’s wandered into unintended biochemical territories

Take Home Points

1. Valproic acid can lead to an increase in serum ammonia levels in approximately a quarter of patients, although most remain asymptomatic.

2. The primary mechanism is through inhibition of the urea cycle

   Listen to the episode!

https://directory.libsyn.com/episode/index/id/38518945

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation

◾️Episode written by Tony Breu
◾️Show notes written by Tony Breu and Giancarlo Buonomo
◾️Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Cooper AZ Buonomo G, Manna, M. Ammonia Rising. The Curious Clinicians Podcast. October 8th, 2025.

Image Credit: Safebuyer

Mark is a hospitalist and physician leader in California, but is best known as an extraordinarily talented podcast interviewer and inspiring speaker. If you’ve listened to Mark’s podcast, Explore The Space, you’ll know that he has a knack for finding compelling stories in a wide range of areas (and he has produced a mind-boggling 336 episodes to date!). Our conversation with Mark touched on cutting through tension, cultivating human connections in healthcare, improvisational interviewing, artificial intelligence, climate change, serendipity, and how to laugh and and cry in the same podcast episode.

We also highly recommend Mark’s TEDx talk titled “Making Friends as an Adult”:

Finally, Tony appeared as a guest on Episode 151 of Explore The Space back in 2019, discussing the importance of curiosity in medical education. Check it out!

Listen to the episode!

https://sites.libsyn.com/270773/115-the-art-of-the-question-with-dr-mark-shapiro

Credits & Suggested Citation

Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC, Shapiro M. The Art of the Question, with Dr. Mark Shapiro. The Curious Clinicians Podcast. September 24, 2025.

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This episode was sponsored by FIGS. FIGS is offering 15% off your first purchase. Just go to wearfigs.com and use the code FIGSRX at checkout.

Image Credit: Mark Shapiro

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In recent Curious Clinicians episode about the tragedy of Chernobyl and the public-health effort to distribute iodine pills to the victims, we mentioned that the reactor that exploded (and even some of the wider fallout area) is now host to a curious organism: A black fungus that apparently eats radiation. How does radiation, which usually kills living things, end up sustaining something?

Much of this episode is derived from a fabulous article entitled "Ionizing Radiation: How Fungi Cope, Adapt, and Exploit with the Help of Melanin" by Ekaterina Dadachova and Arturo Casadevall, published in Current Opinion in Microbiology in December 2008. This story begins back in the years immediately following the Chernobyl accident, when it was noticed that there were plentiful amounts of black-colored fungi both proliferating around reactor #4 and even outside the reactor within the so-called exclusion zone, which is the 30 km of restricted area around Chernobyl because of radiation contamination. This isn't a one-off mutant: Over 200 species of fungi have been isolated from the reactor and the highly-radioactive Red Forest, including Cladosporium cladosporioides, Penicillium lanosum, Penicillium roseopurpureum, Paecilomyces lilacinus and even cryptococcus neoformans.

It appears that these fungi aren't just surviving the radiation, they're thriving in it. The technical term is "radiotropism," meaning the fungi grow towards the most radioactive areas. Even more amazing is that these fungi seem dependent on radiation to grow, a process called "radiostimulation." The researchers we mentioned above took fungal samples from Chernobyl and found that they accelerated spore production when exposed to radioactive isotopes. Control fungi taken from areas that were uncontaminated did not start to make more spores after exposure to radiation. This suggested that the Chernobyl fungi had effectively undergone rapid evolution to not just tolerate but benefit from the radioactive environment in which they existed.

How is this possible? Aren't Twinkies supposed to be the only thing that survives radiation? Well, let's go back to the title of the article we cited: It had the word melanin in it. And what has radiation in it? Sunlight. Do you see where we're going with this?

This is all speculative, but the idea is that the fungi are black because they have evolved to produce tremendous amounts of melanin, the same compound that causes humans to tan when exposed to the ultraviolet radiation of the sun. Melanin is effective at absorbing radiation, and the fungi are protected from DNA damage in their highly radioactive environment.

That explains how the fungi survive in Chernobyl, but not how they thrive. Why are they actively growing towards radiation? Again, this is all theoretical, but some scientists believe that the fungi perform "radiosynthesis" in the way that plants do photosynthesis. Plants use chlorophyll to absorb the radiation from sunlight and turn it into energy to power ATP production. Fungi may use melanin in the same way. One experiment showed that melanized fungi exposed to radiation showed enhanced growth compared to both melanized fungi not exposed to radiation and fungi that did not have melanin. When they looked metabolically at the fungi, the researchers found that the radiation changed the spin of the electrons on melanin, and it had 4 times as much capacity to donate an electron or reduce NADH when compared with melanin that hadn’t been exposed to radiation.

So, it seems that the Chernobyl fungi are indeed some of the hardiest beings on earth (even more so than cockroaches!). However, they aren't even the toughest organisms when it comes to radiation. Remember Pinky, that Manatee-like creature from "The Magic School Bus"? He was a Tardigrade, a microscopic animal that can withstand up to 4,000 grays of radiation (the Chernobyl fungi can tolerate up to 1,000 grays). And even they aren't the true champions – Deinococcus radiodurans, a bacteria, can withstand 15,000 grays!

It's hard to imagine any organic material from the Chernobyl fallout being useful to humanity (in fact, a shipment of edible mushrooms from Belarus had to be recalled in France several years ago because they were still radioactive). But given how effective the Chernobyl fungi are at absorbing radiation, NASA has started experimenting to see if they could be cultivated on a mission to Mars as a potent shield for spacecraft on the harsh red planet.

Take Home Points

1. Various species of black radiation-eating fungi are growing in and around the Chernobyl site

2. The mechanism of this radiostimulation may be energized electron transfer by melanin

3. This might have relevance for a future mission to Mars

4. But the most radio-resilient being in existence, the bacteria Deinococcus radiodurans, stands alone

Sponsor

This episode was sponsored by FIGS. FIGS is offering 15% off your first purchase. Just go to wearfigs.com and use the code FIGSRX at checkout

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https://sites.libsyn.com/270773/114-the-mold-that-eats-radiation-for-breakfast

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Credits & Suggested Citation

◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Giancarlo Buonomo
◾️Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC, Buonomo G, Manna, M. The Mold that Eats Radiation for Breakfast. The Curious Clinicians Podcast. September 3rd, 2025.

Header image Credit: Wikimedia Commons

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Ever heard of bone forming inside blood vessels? Even if you haven’t heard it expressed in those exact words, you most likely have come across the concept of vascular calcification. And in certain instances, fully formed bone is precisely the endpoint of calcium deposition in vessels.

The earliest recording of this discovery was made in 1863 by the German physician/scientist Rudolf Virchow, who described his observations within the blood vessel as “an ossification, not a mere calcification.” Then, in 1904, the pathologist CH Bunting was stunned to discover bone in the aorta of a man who died preoperatively of an infection. He noted that “at the base of this atheromatous nodule and lying directly adjacent to the calcified media are two masses of true bone…a capillary vessel surrounded by a layer of cells resembling osteoblasts closely applied to the wall of bone, the whole appearing to represent a Haversian canal.” He hypothesized that there was a metaplasia of connective tissue cells into osteoblasts.

As both scientists observed many years ago, it turns out that smooth muscle cells in blood vessel walls can indeed undergo osteogenic transformation to take on roles similar to those of osteoblasts, the cells responsible for forming new bone. Although these cells are differentiated, they can undergo a process called transdifferentiation – the direct switch from one differentiated state to another without reversing to a pluriotent state.

The primary cause of vascular calcification is chronic inflammation. Oxidative stress causes vascular smooth muscle cells to start expressing osteogenic markers, while dying cells also begin to act as a nidus for calcium phosphate deposition, thereby initiating microcalcifications. This calcification is then followed by bone formation around the inflamed atherosclerotic lesion.

You might be wondering about the reason behind this, given that the elasticity and flexibility of blood vessel walls are crucial for blood vessel compliance. It has to do with the fact that calcification strengthens blood vessels that are under heightened stress. This is thought to be done in a biphasic process – microcalcification and macrocalcification.

Microcalcifications are typically less than 50 μm in diameter, and they are often located within the fibrous cap or necrotic core of atherosclerotic plaques. They are associated with inflammation and unstable lesions, and histopathological studies of coronary and carotid arteries show that microcalcifications are most related to acute rupture or erosion. However, the calcium isn’t necessarily the factor contributing to plaque instability.

On the other hand, macrocalcifications are large, sheet-like calcium deposits, often exceeding 1 mm in size. These are usually seen in advanced plaques and are associated with a healing response to chronic inflammation. In all kinds of arteries, macrocalcification is a hallmark of stable plaques. In a histopathological analysis of coronary arteries, acute thrombotic lesions displayed much less calcification, while fibrocalcific plaques and healed plaque ruptures showed maximum calcification. Ossification, the process of bone formation, signifies the conclusion of the reparative process and is linked to a state of quiescence, absence of inflammation, and a significantly lower likelihood of acute rupture. Of note, the calcification areas visible on coronary artery calcium CT likely represent safer zones, while the more fragile microcalcifications actually go undetected.

Since calcium is an essential component of bone, it is perhaps not surprising to learn that people with vascular calcification have lower bone mineral density and a higher risk of fractures, since it’s being deposited in the blood rather than bone. However, the dynamic is much more complex than that, and there’s an overlapping of molecular pathways and risk factors between vascular calcification and osteoporosis that contributes to this finding.

Take Home Points:

1. Vascular calcification begins as a response to chronic inflammation.

2. Vascular calcification involves the transformation of vascular smooth muscle cells to osteoblasts.

3. Microcalcifications, which are hard to see on conventional CT, represent areas of increased risk. Macrocalcifications, which can more easily be seen on CT, represent areas less prone to rupture.

Listen to the episode!

https://directory.libsyn.com/episode/index/show/curiousclinicians/id/37710925

CME/MOC

Click here to obtain AMA PRA Category 1 Credits™ (0.5 hours), Non-Physician Attendance (0.5 hours), or ABIM MOC Part 2 (0.5 hours).

As of January 1, 2024, VCU Health Continuing Education will charge a CME credit claim fee of $10.00 for new episodes. This credit claim fee will help to cover the costs of operational services, electronic reporting (if applicable), and real-time customer service support. Episodes prior to January 1, 2024, will remain free. Due to system constraints, VCU Health Continuing Education cannot offer subscription services at this time but hopes to do so in the future.

Sponsor

This episode was sponsored by FIGS. FIGS is offering 15% off your first purchase. Just go to wearfigs.com and use the code FIGSRX at checkout

Credits & Suggested Citation

Episode written by Tony Breu
Show notes written by Tony Breu and Millennium Manna
Audio edited by Clair Morgan of nodderly.com

Breu AC, Abrams HR, Buonomo G, Cooper AZ, Manna M. From Vessel to Bone. The Curious Clinicians Podcast. August 6th, 2025.

Image Credit: News from Karolinska Institutet

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Chernobyl. Even those who don’t actually know where it is or what happened there use the word as a metaphor for catastrophe and irrevocable destruction. At 1:23 in the morning on April 26, 1986, in the northern Ukranian city of Pripyat, a nuclear power plant called Chernobyl exploded and sent an enormous radioactive plume into the atmosphere, spreading radiation for hundreds of miles. You may be wondering why we're discussing a famous disaster on a medical podcast. As the radiation spread, one of the first public health actions taken was to distribute iodine tablets and solutions to people in its path. Why did they do this?

Even if you've seen the HBO mini-series, knowing a bit about how the disaster happened is helpful. Nuclear reactors need to be constantly cooled to function, and early that April morning the power plant engineers were running a safety check on Reactor 4 to see if it could withstand a temporary loss of power and therefore temperature regulation. How exactly it happened is complex, but the basic facts are that over a long safety check with personnel shift changes and faulty equipment, the reactor reached a critical temperature and exploded. Someone fishing nearby in a pond reported seeing this eerie blue haze shooting up into the sky, the effects of an enormous blast of radionuclides that were ionizing nitrogen and oxygen atoms in the air all around the reactor, specifically iodine-131, caesium-134 and caesium-137. The protective lid above the reactor literally blew off because of the force of the explosion and released all of this radioactivity into the atmosphere, spreading over not just Ukraine but large swaths of Russia and Eastern Europe.

28 people died soon after of acute radiation poisoning. But millions of people across Eastern Europe were exposed to the isotopes, both from breathing in the toxic air and then eating food and drinking milk which had been produced in radioactive soil, even months after the disaster. These are the people who iodine helped to save. How exactly did that help?

The answer, surprisingly, has to do with preventing thyroid cancer. Over 6000 cases were linked to radiation exposure, with a dose-response relationship between how much radiation someone was exposed to and their risk of developing thyroid cancer. Many more cases would probably have developed if public-health officials hadn't rushed to distribute iodine to millions of people after the disaster. Iodine works, essentially, by preventing the thyroid from absorbing radiation, and therefore from accumulating the cellular damage that leads to tumors.

Iodine doesn't usually get the same attention as potassium or magnesium, but it's an essential micronutrient, meaning the body can't produce it (which is why table salt is often iodized). T3 and T4, the main thyroid hormones, contain iodine. The thyroid ends up absorbing much of the iodine we eat to make them, using a specialized natrium iodide symporter. When people breathed or ingested the iodine-131 from the Chernobyl cloud, their thyroid's couldn't distinguish it from "normal" iodine, which put that organ at unique risk of harm.

Enter something you probably haven't heard since medical school: The Wolff-Chaikoff effect. It's named after two biochemists,Jan Wolff and Israel Lyon Chaikoff, who observed this effect back in 1948 at UC Berkeley. When they gave that radioactive iodine-131 isotope to rats, iodine uptake into their thyroids nearly completely stopped once the serum iodine level rose by 20-35%, and then quickly resumed again once the iodine levels returned to baseline. They wrote in their paper: “These results, therefore, suggest that plasma inorganic iodine acts as a homeostatic regulator in the formation of the thyroid hormone. This regulator probably serves to prevent the formation of excessive amounts of hormone by the gland when the body is suddenly flooded with iodine.” In other words, if the thyroid starts absorbing too much iodine, it shuts the symporters down to prevent excess thyroid hormone production. In fact, iodine-131 (in very controlled doses) is still used to treat certain thyroid cancers and hyperthyroid disorders.

The iodine distributed after Chernobyl was a very simple, but elegant, way to protect people from thyroid cancer. By ingesting large doses of "normal" iodine, their thyroids couldn't absorb as much radioactive iodine. In experimental models, just 100mg of potassium iodide lead to a 95% reduction in radioactive iodine uptake, with subsequent 15mg of daily consumption keeping absorption to less than 10%. It's impossible to say how much iodine helps in a Chernobyl situation, where the amount and duration of radiation exposure is quite variable, but one paper estimates that it reduces thyroid radiation absorption by at least 40%.

Like Pompei, Pripyat is frozen in time. Thousands of people fled in 1986 and could never return, the town forever poisoned with radiation. As the buildings crumble and plants grow everywhere, papers are still strewn on school desks and an amusement park still has a rusting ferris wheel. Chernobyl itself was sealed in a sarcophagus of steel and concrete. The area is so toxic that a new substance has been identified, a compound of zirconium silicate crystals and uranium fittingly named Chernobylite. No amount of iodine can ever make that better.

Take Home Points

1. Radioactive iodine-131 was one of the isotopes released from the Chernobyl nuclear disaster in 1986

2. One of the first public health responses involved mass distribution of iodine pills

3. This was done to protect against thyroid cancer via the Wolff-Chaikoff effect, whereby flooding the thyroid with iodine leads to a temporary shutdown in iodine into the gland

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Credits & Suggested Citation

◾️Episode written by Avi Cooper
◾️Show notes written by Avi Cooper and Giancarlo Buonomo
◾️Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC, Buonomo G, Manna, M. Wherefore Iodine?. The Curious Clinicians Podcast. July 23rd, 2025.

Image Credit: Wikimedia Commons

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