Truth and Consequences

(by whizbang) Apr 26 2016

This morning I saw a blurb in one of my newsfeeds about "potential new treatment target for deadly brain cancer."

It was indeed a new study on the cellular biology of glioblastomas, the type of cancer in my husband's head. We just finished the first round of radiation and chemotherapy. The next 4 weeks will be blissfully treatment-free. Instead, we will devote his time to weekly fasting lab studies and a whole bunch of doctor appointments. Oh, and he gets to go to the dentist this week.

This discovery involves the basic cell biology of these cancer cells, and may help explain why they are so resistant to treatment. They interview the author of the study, Dr. Arezu Jahani-Asl, who explains why she chose to study glioblastoma:

"The fact that most patients with these brain tumours live only 16 months is just heartbreaking,"

That's a particularly heartbreaking reminder with which to begin my day.

Keep plugging away, scientists. It's only through your efforts that we have hope. We also have no idea who will find the key piece of information that leads to improved survival or even a cure; it may be someone studying insects in the rainforest rather than a neuroscientist looking at this tumor. That's why we need to fund as much science as we can.

So we all can have hope.

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Non-Apologies

(by whizbang) Apr 18 2016

This post is an apology of sorts to new commenters. I have things set so that once you have an approved comment on my site, all future comments will ultimately appear immediately. Even with an effective, aggressive spam filter, two or three inappropriate things try to get through every week or so. To know that there are comments awaiting moderation, I have to sign into my site.

I no longer do this every day because, life.

Anyway, that's why some of you, even though your comment was inoffensive and even welcome, saw a lag before it made its public debut. I am sorry for that, but not sorry enough to change my moderation habits.

In other words, deal with it (although you're likely on the good list now)!

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For Better, For Worse

(by whizbang) Apr 14 2016

Today I took my husband to Grand Rounds, a Pediatric Educational Lecture (for my non-MD readers). I noticed on the announcement yesterday that a person he knew well from our St. Louis days was giving a named lectureship in honor of the retirement of a colleague here at Oklahoma. I asked if he wanted to go; he said he would.

He arrived bright and early, and quickly impressed people who knew of his illness and issues with his stamina and resilience. He paid enough attention to the lecture to get upset when I scrolled through non-emergent messages on my phone. He chatted with colleagues at the reception afterwards, until I retrieved my bag and took him home.

He slept most of the afternoon (while I went to the dentist for a tooth repair), ate a quick dinner, and then retired again for the night.

During the marriage vows, one typically swears in front of god-and-everybody to stay together through a number of circumstances, including for better or for worse. So far, 2016 has been a butt-load (to use the technical term) of for worse. Today, I finally saw some for better, even if it did wear him out.

I will take what I can get right now.

8 responses so far

Random Thoughts From the Restroom

(by whizbang) Apr 11 2016

Yesterday while picking up some groceries and assorted items, I required a trip to a public restroom that contained 10 stalls. As I took my seat I noticed nice shoes under the partition next door. Now, these shoes looked feminine, but frankly, I have no idea what the chromosomes or genitalia of that person were. I could not tell, even at those close quarters, if this person had a vagina or penis. For all I know, they might have been cursed with two penises or a persistent cloaca! They might have been XX, XY, or some other combination of DNA units. I don't know if this person was doing #1, #2, or something else in there.

All I know is that their outer appearance, based on shoes, was female. AND NONE OF THE REST OF THIS MATTERS ONE BIT WHILE I'M PEEING!

If someone presents themselves to the world as a woman, they get to use the women's restroom. And vice versa.

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Cures and Consequences #expbio

(by whizbang) Apr 06 2016

Pulmonary and Systemic Vascular Responses in Rats Exposed to Perinatal Hyperoxia

Greiner T, et al.

Ventilated premie

Ventilated premie

Premature infants used to die of lung immaturity. With surfactant treatment and ventilation, they have a much better survival rate. However, these interventions come with a cost. High oxygen causes retinopathy of prematurity which can lead to blindness. It may also have long-term effects on the cardiovascular system. In humans, teasing out the effects of the oxygen and the barotrauma (the pressure pushing the oxygen into the lungs) can be tricky.

The humble Sprague-Dawley rat is born at a stage of organ development similar to a premature infant. The lungs are saccular; the terminal ventilatory sacs have formed, but have not yet matured into alveoli. Exposing rat pups to high oxygen at birth can allow study of just the oxygen toxicity on the vascular function.

At birth, rats and mothers were housed in room air (21% oxygen) or 80% oxygen for two weeks.  Three to six months later they were exposed to a hypoxic challenge (12% oxygen) and systemic and vascular responses were studied.

Hypoxia resulted in an increase in pulmonary vascular pressure; however, this observation was not primarily due to an increase in pulmonary resistance. Most was due to an increase in flow from an elevated stroke volume.

This model offers promise for understanding oxygen toxicity in the neonatal lung. Clinicians have assumed that barotrauma is responsible for much of the chronic lung and reactive airway disease seen in ex-premies. Challenging these rats with bronchoconstrictors could let us determine what role hyperoxia may play in these conditions.

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Androgens and Angiotensin #expbio

(by whizbang) Apr 06 2016

Chronic Flutamide Treatment Alters Intrarenal Renin Angiotensin System Expression in Intrauterine Growth Restricted Female Rats

Designer JH, et al.

For many years, a relationship has been demonstrated between low birth weight and later development of cardiovascular and kidney disease in humans and in animal models. One model involves tying off uterine arteries late in rat pregnancy, effectively starving the pups. Female animals in this model develop hypertension as they age, as well as elevated testosterone levels and premature cessation of estrus cycling.

Mr. T, aka Testosterone

Mr. T, aka Testosterone

Post-cycling female IUGR rats underwent treatment for 2 weeks with vehicle or flutamide, an androgen receptor antagonist. This treatment blocked the development of hypertension in this model, as does renin-angiotensin blockade. The intrarenal renin-angiotensin system (RAS) was examined in these animals. Hypertensive  females had elevated angiotensin receptors in the kidney. Flutamide treatment prevented this rise in receptors, suggesting that androgen-induced activation of the intrarenal RAS is the mechanism of hypertension in this model.

One criticism of this model is its severity; certainly further translational work is needed before we start treating postmenopausal women with flutamide for hypertension.

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Kidney Function for the Birds #expbio

(by whizbang) Apr 05 2016

The Integration of Gastrointestinal and Renal Function in Nectar-Feeding Birds

McWhorter TJ.

King of the Feeder

King of the Feeder

Regular Whizbangers know that I love hummingbirds. I spent hours watching these tiny feathered warriors at our feeder last summer. When I came across an abstract about their kidney function, it had to be blogged.

Most birds we encounter have very little fluid in their diets. They primarily ingest seeds and bugs, and they maximally retain water from their food. Nectar-feeding birds have an all-liquid diet. Hummingbirds, sunbirds, and honeyeaters must deal with high water loads during their daylight hours. For example, a hummingbird requires the calories in an amount of nectar 1.6 times the bird’s body weight during ideal environmental conditions to meet minimum metabolic needs. With cool temperatures or other stresses, intake may go as high as 3.3 times its body mass. Imagine the mythical 70 kg male drinking more than 200 liters of fluid each day! My kidney stone patients freak out about 2.5 to 3 liters daily!

Birds have much different anatomy than mammals as well (see diagram below). Food enters the crop where digestion begins, then moves into the proventiculus or stomach. After a pass through the gizzard, it hits the intestine where absorption occurs. The remaining material passes into the cloaca from where it leaves the body. Water absorbed from the intestine can be filtered by the kidney. Urine passes into the cloaca. From there it can be directed into the lower intestine for more processing or pass directly out of the body.

From Beuchat 1990 Physiological Zoology 63:1059

From Beuchat 1990 Physiological Zoology 63:1059

These birds have different renal structures from mammals as well. Two types of nephrons occur in birds, looped or mammalian nephrons which reach into medullary pyramids and produce a countercurrent multiplier system for concentrating urine, and reptilian nephrons without loops. Hummingbird kidneys consist primary of unlooped nephrons, so their kidneys are built for maximal urine dilution.

This paper shows that the two classes of nectar feeding birds have different strategies for dealing with massive water intake. Both groups of birds drop their filtration rate to zero overnight when they do not feed. It then increases again during the day as they drink. Hummingbirds primarily absorb water and filter it out via their kidneys, while Passeriformes (those sunbirds and honeyeaters) reduce gastrointestinal water absorption. Imagine instrumenting tiny 4.5 g birds to see how much fluid remains in the intestine as they eat more. Yup, this group did it! The hummingbirds had stable intestinal water excretion across all levels of intake, while water absorption decreased dramatically with higher intake in the Passeriformes, allowing them to send it straight on through the intestine.

These birds have evolved different strategies to handle the same problem, namely high water intake. There are interesting physiological lessons here. And besides, birds are fun! And bird kidneys? Well, what more could you want in a blog post...?

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Damage Control in the Cortical Collecting Duct #expbio

(by whizbang) Apr 04 2016

Vasopressin-Escape Does Not Involve marked Changes in the Ratio of Intercalated-to-Principal Cells in the Cortical Collecting Duct

Chou C-L, et al.

Vasopressin, also known as anti-diuretic hormone (ADH), promotes absorption of water from the kidney’s cortical collecting duct. Under certain conditions, ADH can be inappropriately secreted, resulting in excess water retention and lowering of the body’s osmolality. Changes in osmolality can be quite dangerous, especially for the brain, so it is not surprising that the collecting duct can “escape” the effect of ADH to limit low plasma sodium and osmolality. This group previously showed that such vasopressin-escape occurs in association with lowered levels of expression for aquaporin 2 (AQP2), a water channel that allows ADH to do its job.

Autocrine and paracrine regulation of collecting duct principal cell ENaC and AQP2. Much commonality exists in regulation of ENaC (left) and AQP2 (right). Flow stimulates ATP, PGE2, and ET-1, which act on their cognate receptors to inhibit Na and water reabsorption. Similarly, bradykinin, adenosine, and NE act on their receptors to inhibit ENaC and AQP2. Flow-stimulated EET uniquely inhibits Na, but not water, transport. Compared with the wide variety of inhibitors, relatively few autocrine or paracrine factors stimulate ENaC and/or AQP2 activity. Renin, ultimately via AngII, as well as PGE2 binding to EP4 receptors, are potentially capable of augmenting principal cell Na and water transport. TZDs (via PPARγ) and kallikrein (via cleavage of an autoinhibitory domain in ENaC) may increase Na reabsorption. See the text for more detailed descriptions of each regulatory factor. ACE, angiotensin-converting enzyme; AGT, angiotensinogen; Ang, angiotensin; AQP, aquaporin; EET, eicosataetranoic acid; EP, PGE receptor; ET, endothelin; NE, norepinephrine; NO, nitric oxide; PPARγ, peroxisome proliferator–activated receptor-γ; TZD, thiazolidinedione.

Autocrine and paracrine regulation of collecting duct principal cell ENaC and AQP2. Much commonality exists in regulation of ENaC (left) and AQP2 (right). Flow stimulates ATP, PGE2, and ET-1, which act on their cognate receptors to inhibit Na and water reabsorption. Similarly, bradykinin, adenosine, and NE act on their receptors to inhibit ENaC and AQP2. Flow-stimulated EET uniquely inhibits Na, but not water, transport. Compared with the wide variety of inhibitors, relatively few autocrine or paracrine factors stimulate ENaC and/or AQP2 activity. Renin, ultimately via AngII, as well as PGE2 binding to EP4 receptors, are potentially capable of augmenting principal cell Na and water transport. TZDs (via PPARγ) and kallikrein (via cleavage of an autoinhibitory domain in ENaC) may increase Na reabsorption. See the text for more detailed descriptions of each regulatory factor. ACE, angiotensin-converting enzyme; AGT, angiotensinogen; Ang, angiotensin; AQP, aquaporin; EET, eicosataetranoic acid; EP, PGE receptor; ET, endothelin; NE, norepinephrine; NO, nitric oxide; PPARγ, peroxisome proliferator–activated receptor-γ; TZD, thiazolidinedione. Click image to access full review article.

Their current question centers on how AQP2 gets down regulated. It could be an intracellular mechanism or remodeling of the collecting duct, with a change in the ratio of principal and intercalated cells in that structure. Principal cells regulate sodium, potassium, and water reabsorption in the collecting duct, while intercalated cells influence acid-base balance. Decreasing the number of principal cells could decrease the effect of ADH. A full review of principal function can be found here; the image above comes from this paper.

After micro dissecting cortical collecting duct segments from animals in the early phases of vasopressin escape, the investigators probed them with a marker for all cells; an antibody to H+-ATPase, a marker of alpha intercalated cells; and an antibody to pendrin, found in in beta intercalated cells. They could then calculate the number of principal cells and intercalated cells to see if the principal cells decreased to explain the diminished AQP2 expression.

The cellular ratios did not differ between normal and vasopressin-escape animals.

So what intracellular process could be involved? Further exploration suggests a shift in cell cycle from G0 (resting) to mitosis. How this reduces AQP2 expression is not yet clear.

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Why I Am (Still) a Physiologist #expbio

(by whizbang) Apr 04 2016

A few years ago when my spouse took his current position, I decided to “gracefully” close down my laboratory. I enjoyed studying and writing about puberty, sex, and the kidney for twenty years, but lack of funding finally brought me down. I was lucky; being an MD, I had other skills to keep my faculty position.

I no longer play with new scientific gizmos in the lab. I do miss exploring questions of the how and why the kidneys do what they do. I still have some clinical studies going, but my days mostly consist of caring for children with kidney disease.

So why do I still belong to the American Physiological Society? Why do I work on their committees? And why do I attend Experimental Biology?

Because medicine is physiology.

Let’s take a common healthcare example. You go to your doctor because of seasonal allergies. Your symptoms of runny, itchy nose make you crazy, interfering with your sleep and work. Whatever your allergen, it triggers the release of histamine which induces itching and swelling in the nasal passage. These physiological changes can be ameliorated by blocking the histamine. Such drugs (Benadryl; Claritin; Zyrtec) form the first-line therapy. If they do not get the job done, other physiological systems of nasal inflammation can be blocked. Glucocorticoids (Flonase; Nasocort), the anti-inflammatory steroids, can be given as nasal sprays. Montelukast (Singular) blocks leukotriene receptors and prevents the allergic inflammatory response through another pathway. Now some individuals would say this example was immunology or pharmacology, but I would argue that understanding how the body responds to an allergen falls under the umbrella of physiology. We also have to know this physiology before we can design the pharmacology.

Perhaps my example has not convinced you. Who am I, after all? Just a random pediatric nephrologist who likes to write online. You want an opinion from recognized authority, damn it!

Remember, the Nobel Prize is for Physiology or Medicine. If the Nobel committee considers these fields so closely bonded, then who are we to question it?

That is why I am in San Diego, blogging a very basic science meeting. It’s not just for fun; it will make me a better physician.

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Starling 2016 at #ExpBio

(by whizbang) Apr 04 2016

David Pollock of University of Alabama - Birmingham gave the Starling Lecture for the APS Water and Electrolyte Homeostasis Section on Sunday, April 3. Live tweets of the event are summarized below.

 

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