My Crowded Nightstand: A Cry for Help

(by whizbang) May 25 2017

My bedside table is getting too crowded, and I need to get something off of it. This could be best accomplished by eliminating my clock radio. After all, I have an iPhone that has to be there when I'm on call. It has an alarm. It has access to my favorite radio station. In short, it can do everything my clock radio does.

Except wake me to a radio stream.

The system's built-in alarm can access music and playlists, but not radio streams that are present in the Music App. This seems to be the case for the third-party clock radio apps in the store.

If anyone out there knows how to make this happen, I would love to hear about it.

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Another Aspect of Pediatric Disease

(by whizbang) May 02 2017

Jimmy Kimmel gave an emotional monologue this week about his newborn son’s congenital heart disease and the implications it has for his life with a preexisting condition. His pleas for coverage of all children with repairable conditions are important; as he says:

If your baby is going to die, and it doesn’t have to, it shouldn’t matter how much money you make.

Now stories of babies will get the crowd going, and most of the poor will be covered by Medicaid, at least for their initial care. It’s actually more difficult for those with some money and some coverage.

Insurers often require the use of provider networks. There may only be a single hospital in your state that provides the sort of pediatric specialty care we are discussing here. Are they in your network? If not, new parents could face thousands of dollars out-of-pocket, even with “good” insurance.

I understand insurers trying to limit their  expenses through limited contracts. For well child care and a number of other conditions, there may be enough providers distributed about to make networks a good solution. For pediatric specialty care, that often is not the case.

I would like to see network requirements and penalties not be enforced when there is no appropriate provider in network. Perhaps we can get that added to those basic health coverage requirements.

Oh wait, never mind. This is one more thing to eliminate.

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#ExpBio - Cannaboids and the Injured Kidney

(by whizbang) Apr 26 2017

Cannabinoid receptors exist in many tissues, not just those fun neurological areas we all think about. The kidney contains type 2 receptors (CB2), and experimental data suggests they might play a role in acute kidney injury. With unilateral ischemia-reperfusion injury (IRI) CB2 receptors are dramatically upregulated after 72 hours, returning to baseline after 168 hours (7 days).

Could activating these receptors help the kidney heal itself?

Pressly et al used a novel CB2 agonist (SMM-295) in bilateral IRI, administering it just after ischemia and every 24 hours after. Kidney function and structure were examined 24 and 48 hours after injury.

Animals treated with SMM-295 did not have elevated creatinines after IRI. NGAL, a marker of tubular damage, also remained lower with treatment. Tissue analysis showed decreased staining for PCNA and TUNEL, demonstrating reduced apoptosis. Tubular damage and casts were reduced by 50% with CB2 agonist treatment.

Acute kidney injury is a major problem in hospitalized patients, especially those undergoing cardiac surgery requiring cardiopulmonary bypass. Any agent that shows this much promise deserves further study, even if it won't give you the munchies!

Click author name above for full abstract.

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#ExpBio - The Problem with Spinach

(by whizbang) Apr 26 2017

Spinach and other dark, leafy greens can bomb the human body with oxalate, a major causative factor for kidney stones. Stones also predict chronic kidney disease, making them more than an inconvenient pain.

Spinach smoothie

Mitchell et al, Urologists from the University of Alabama-Birmingham, have found that patients with recurrent oxalate kidney stones show impaired monocyte mitochondrial dysfunction in response to stress in vitro. The present study examined this phenomenon in healthy subjects 21 to 31 years of age with no prior history of stones. Blood for monocyte isolation and oxalate levels was drawn before and 5 hours after an oxalate load delivered as a spinach smoothie.

Blood for monocyte isolation and oxalate levels was drawn before and 5 hours after an oxalate load delivered as a spinach smoothie.

As expected, blood and urine oxalate increased after the spinach smoothie. Overall, mitochondrial function decreased after oxalate loading, with ~60% of participants showing responses similar to the stone-forming population. The remaining participants had preserved monocyte mitochondrial function.

So oxalate may impair monocyte function in people. Could the 60% with abnormal responses represent future stone-formers? Are these the ones more predisposed to chronic kidney disease after stones? Only time will tell.

In the meantime, I plan to avoid green smoothies on principle. And disgust...lots of disgust.

For abstract, click link on author names above.

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#ExpBio - Counterintuitive Results from Framingham

(by whizbang) Apr 25 2017

Framingham is the small city that researchers will not leave alone. We are now into the Framingham Offspring Study, examining relationships between some dietary factors and blood pressure control. The study population included 2632 individuals 30-64 years of age who were not on blood pressure medication at the start of the 16 years of follow-up. In the first 5 years of the study, all kept a 6-day diet diary which was used to estimate daily intake of sodium, potassium, magnesium, and calcium. All analysis corrected for age, gender, smoking, activity level and the other usual suspects.

Results were similar for systolic and diastolic blood pressures, so I will just show systolic here:

Systolic blood pressure according to sodium intake among individuals not taking blood pressure lowering medication. Results were adjusted for sex, age, education, height, weight, physical activity, cigarettes per day and alcohol intake.
Credit: Lynn L. Moore, Boston University School of Medicine

How can that be? We have advised healthy individuals to lower salt intake forever to avoid hypertension, yet these folks make that look like exactly the wrong advice. Could there be a confounding diet variable? Let's throw potassium into the mix:

Systolic blood pressure according to the combined intakes of sodium and potassium among individuals not taking blood pressure lowering medication. Results were adjusted for sex, age, education, height, weight, physical activity, cigarettes per day and alcohol intake.
Credit: Lynn L. Moore, Boston University School of Medicine

So low sodium, with or without high potassium intake, produced higher blood pressures than higher sodium plus high potassium intake. Similar results were found for intake of calcium and magnesium, other ions in the diet that seem to ameliorate hypertension.

There are some caveats here, like with every research study. First, even though this is a large, longitudinal study, these are people who are second or third generation research subjects. Being in cardiovascular research likely makes them more health conscious, so their level of sodium intake may not reflect the general US population. Also, these are healthy, non-hypertensive people. Findings might be quite different in people with high blood pressure or salt-sensitivity. They also have no biomarkers of intake; all diet data is from a 6-day diet diary in the initial years of the study. How eating patterns may have changed over time is just not known. Citizens of Framingham get the same health news as the rest of us; did many start green juicing or go paleo?

This study does bring into question reducing sodium intake for the general population. Those of us with hypertension probably need it, but it may not be important for the majority of people. Intake of other minerals may be far more important for general health (check this post out for more on the interrelationships between Na and K transporters in the kidney).

The bottom line? We should all eat a varied diet, avoiding junk food and focusing on fruits, veggies, and dairy with lean protein sources. That DASH-type diet has been shown to reduce weight and blood pressure.

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#ExpBio - It's a Nose, It's a Tongue, It's a Kidney!

(by whizbang) Apr 25 2017

For several years I have blogged about the kidney "smelling" stuff. Shepard and Pluznick have now updated their work on kidney olfactory receptor 1393 and it's role in diabetic nephropathy. In mice with this receptor knocked-out, Sglt1 is reduced in the proximal tubular lumen, This results in glycosuria with improvement in glucose tolerance.


They then took these mice and fed them a high fat diet. Even with the development of obesity, the knock-out mice maintained better glucose tolerance and did not develop an elevated glomerular filtration rate as wild-type counterparts did. Insulin tolerance was similar between the groups. Mice lacking the olfactory receptor also accumulated less fat in the liver than their wild-type brethren, even though body weights were similar.

There's still more to learn from these animals, but this is exciting work for sure!

This year, we also learned that kidneys can taste! Sweet receptors have been found in the pancreas and other areas of the gut beyond the tongue. They can regulate function of these organs in response to sugars and artificial sweeteners. Kassem, Ares, and Ortiz now show that sweet receptors T1R2/T1R3 are present in the kidney! They localize to the thick ascending limb and increase the presence of NKCC2 on the surface in response to fructose feeding. Gumarin, an antagonist of the receptor, blocks this response to fructose. The knock-out mouse for this sweet receptor shows diminished levels of NKCC2 in the tubular surface; these mice also have increased urine output with decreased osmolality, consistent with diminished efficiency of loop function.

The study only addressed effects of fructose, but given interactions of artificial sweeteners in the gut, there will be a lot more exciting information coming up, I'm sure.

The kidney: it tastes, it smells, it pees. Makes you think twice about eating that asparagus, huh?

Abstracts linked to author names above.

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#ExpBio - Oh, K!

(by whizbang) Apr 25 2017

I live tweeted this lecture, so the post is my Storify. Got a bit lost during the talk in a string of critical phosphorylations midway through. If you want to know that much about the topic, go read Welling's work!


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#ExpBio - Short Term Diet Restrictions for Obesity

(by whizbang) Apr 24 2017

Obesity and its complications raise major challenges for US healthcare, so better understanding its pathophysiology may help a great many people. Traditional caloric restriction has poor long-term outcomes because very few people can stick to dietary limitations forever. Other approaches have similar problems.

Click for image source

This group from the University of Wisconsin took a new tactic with short-term restriction of a single nutrient. Methionine is an amino acid that has high levels in beans, nuts, beef, turkey, pork, fish, eggs, and dairy. The study started with 6-week-old mice fed a high-fat western diet for ten weeks to induce obesity, hepatosteatosis, and hyperglycemia. Some mice continued on this diet, while others received an isocaloric high fat diet without methionine for 5 weeks.


At the end of that time, mice with methionine restriction showed decreased body weight, decreased body fat, less fat in the liver, and improved blood sugars. They looked more like mice on standard chow than high-fat fed mice. Remarkable, considering they were still getting a high-fat diet!

Would this work in people? I don't know if I could do a stringent methionine restriction for a month; look at that food list in the second paragraph! Other strategies might be in order, like swearing off this amino acid one or two days each week or month.

As always, only more research will tell us what might work!

Abstract here.

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#ExpBio - Why Do We Eat THAT?

(by whizbang) Apr 24 2017

Continue Reading »

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#ExpBio - More Medulla Please

(by whizbang) Apr 24 2017

Structure of Metformin

Newly diagnosed patients with type 2 diabetes generally start the drug metformin. Through a number of metabolic effects, this medication improves hyperglycemia. Over time, most drugs prove to have effects other than those initially identified. Metformin seems beneficial to the kidney, but how does that happen?

Once again we will ponder medullary hypoxia. In yesterday's post, the hypoxia occurred acutely, during heart surgery; now, we will address chronic hypoxia due to diabetes.

In this study, rats were made diabetic with streptozotocin. Some were treated with metformin. After approximately 1 month, kidney function and oxygenation in the cortex and medulla were measured under anesthesia. Cortical and medullary tissue were studied for mitochondrial function.

Metformin did not prevent elevation of glomerular filtration rate, a known phenomenon of diabetes. While oxygenation, measured as the partial pressure of O2, was lowered in both the cortex and medulla of control animals, metformin improved oxygenation in the medulla of diabetic animals.

Diabetes also promotes oxidative stress in the kidney. As a defense against this, the mitochondria become less efficient. An uncoupling protein (UCP2) allows respiration to continue but without ATP formation. In the present study, uncoupled respiration doubled in the medulla in diabetic animals, while metformin treatment returned this parameter to normal.

Metformin increases medullary oxygenation in animals, perhaps via inhibiting UCP2. More study is needed to characterize this effect and what it means for diabetic kidney disease. It also points out our ignorance of the medulla on the clinical side of things. When we biopsy a kidney, we examine the cortex. Our attention has been so focused on the glomeruli and the tubules surrounding them that we may be missing the real action.



Michael Christensen1, Tomas Schiffer2, Rikke Nørregaard1, Fredrik Palm2. 1Aarhus University, Aarhus N, Denmark, 2Uppsala University, Uppsala, Sweden


Metformin is the first choice treatment of type 2 diabetes where it can lower the level of blood glucose by inhibiting hepatic gluconeogenesis and increase cellular glucose uptake. Besides the effect on blood glucose metformin has also shown protective effects in several renal diseases including diabetic nephropathy. The development of hypoxia in the kidney is suggested to be an important driving force for the development of diabetic nephropathy and we therefore wanted to investigate how metformin affects the oxygenation levels and mitochondrial function in the diabetic kidney.


Sprague Dawley rats were injected with streptozotocin (STZ) (50 mg/kg) and when rats were diabetic, metformin (250 mg/kg) was administrated in the drinking water. Rats were prepared for In†Vivo†measurements 25-30 days after STZ injection. Rats were anesthetized, placed on a heating pad, tracheotomized and a catheter was placed in the left femoral vein for infusion of Ringer solution containing H-inulin and Paraaminohippurate. The left femoral artery was catheterized for blood pressure measurements and blood sampling. The left kidney was exposed by a subcostal flank incision, immobilized in a plastic cup and catheters were placed in the left ureter as well as bladder for collection of urine. Intrarenal pO2 was measured in kidney cortex and medulla by oxygen microsensors. To assess mitochondrial function, mitochondria were isolated from kidney cortex and medulla and analyzed by highresolution respirometry (Oroboros, O2K)

Important findings

Diabetic rats showed increased glomerular filtration rate (GFR), which was not affected by metformin treatment. PO2 was lower both in the outer medulla as well as cortex in the diabetic animals. Metformin treatment elevated PO2 in the outer medulla both in the control animals as well as in the diabetic animals. Isolated mitochondria from the outer medulla of diabetic rats showed a significantly higher GDP dependent respiration which was normalized by metformin treatment indicating inhibition of uncoupling protein 2 (UCP2) activity.


Metformin increases PO2 in the outer medulla both in control and diabetic animals, this could in part be mediated by inhibition of UCP2.


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