Archive for the 'Uncategorized' category

Toilet Police

Aug 23 2016 Published by under Uncategorized

ToiletLoveFor many years I have ridiculed self-flushing toilets. What problem do they solve? They seem to go off at random, at least on some occasions becoming a bidet in the process. What a waste of water.

Then I overheard this conversation in a public restroom:

Mother: All done?

Child:  Yes

Mother:  No, do not flush. That handle is dirty.

They then left the waste floating while they left. They did wash their hands.

I just wanted to scream at them! How many people will now avoid that stall because it might be out of order? Do you think public establishments have someone who just runs around flushing the toilets periodically? You need to wash your hands anyway after wiping your naughty bits, so touching the flush handle is not going to harm you. If you're that skittish, wrap some toilet paper around your hand and then throw it in the trash before you wash your hands.

This behavior is why we need toilet police, not stalking!

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Damage Control in the Cortical Collecting Duct #expbio

Apr 04 2016 Published by under EB2016, Uncategorized

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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It's All About the K

Apr 04 2016 Published by under Uncategorized

Despite the title of this year's Gottschalk lecture, it really was all about the potassium...

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Welcome to #ExpBio 2016

Apr 03 2016 Published by under EB2016, Uncategorized

San Diego once again proves itself to be an absolutely lovely city. The sun is out, it is 70 degrees, and a light breeze tickles us as we stroll from hotel to convention center. I feel refreshed, both by the locale and a gathering of friends.  The science starts in ernest tonight with the Cannon Lecture when Amira Klip of the Hospital for Sick Children in Toronto presents her work on muscle-immune cell crosstalk in the genesis of insulin resistance. 

I will be live tweeting her talk using the hashtag #Cannon16 if you want to follow along. If not, I will present my notes/tweets here at a later time. Also be on the lookout for my take on today’s APS Communication Workshop, Setting the Record Straight for Science: How to Write to Local and National News Outlets.

Now I have to put some juice in my phone and get ready for the address. 

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Ups and Downs

Mar 25 2016 Published by under Uncategorized

Chronic disease includes periods of relative “health” and intervals of exacerbation. The health problems my spouse and I suffered, until recently, meant taking some medications and monitoring parameters. We always had to remember our limits, like a tickle in the back of our minds, but otherwise life felt normal.

This brain tumor has other ideas. Since March 1, my spouse has spent 7 nights at home. Today I fetched him home again, following a procedure that I hope will keep him out of the hospital for a nice long while.

As hopeful as I am, I know that we are highly likely to achieve inpatient status again in the near future. It’s the nature of the beast for now. I do have new empathy for my patients and their families, especially when an acute illness means ruining a vacation or birthday or other event. 

Good luck to everyone dealing with chronic disease. Even if you are in the relatively healthy, silent phase, you still have to be wary.

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Before and After

Jan 27 2016 Published by under Uncategorized

Life contains a number of events that define turning points. "Before graduation", "after I had kids", and "once I got promoted", for example.

Last week now stands as one of those events. My husband developed a major mental status change. Within 24 hours we diagnosed his brain tumor and had it out the next day. He is much better now mentally, but we have a long road ahead of us.

In those first days, adrenaline kept me going. I had to notify family and get through the immediate issues. (By the way, 140 character twitter updates are the perfect length for anyone in a surgery waiting room. Cute animal photos also make a nice break in the tension.) Post-op, he was sitting up in the ICU talking to us again. Every time I saw him over the next 5 days he was more fluent and seemed more like himself.

Now the relatives have gone and the bouquets are fading. He manages his own medications again. He does not yet feel like he should drive (and he is grounded till his neurosurgery follow-up in 2 weeks), but he wants to use our OKC Thunder tickets this Friday. His progress is not as fast, but we both hope it will continue.

We no longer have any idea what our future holds. For now, we are dealing with stuff as it happens. Be warned - this blog will likely feature some intense introspective naval-gazing in the coming weeks and months.

Welcome to After.

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Calling Biochemists

Dec 01 2015 Published by under General Health, Uncategorized

WTF?

WTF?

For ten minutes every morning I entertain myself with fashion magazines while my hair gets dry. The December issue of In Style greeted me with the advice to the right.

It has been a few years since doctor school, but metabolism of ethanol does not seem to have changed much (discussion here). I have seen a number of theories on hangovers through the years, with most focusing on volume loss and intermediaries of the metabolic process.

Downing a cup of water between overindulging and sleeping it off might help with dehydration. I am at a loss to explain how a tablespoon of vinegar or a drop of raw honey would be of value here.

Here is a link to Nikki Ostrower's integrative nutrition center.

While this concoction certainly will do no harm, I am not conviced that it would prove superior to just chugging water or other fluid. I would also love to see evidence that it facilitates alcohol metabolism.

Your turn, biochemists. Educate me!

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A Doctor Deals: Metformin

Jul 14 2015 Published by under Diabetes, Uncategorized

Structure of Metformin

Structure of Metformin

The first-line treatment for type 2 diabetes (DM2) is Metformin. First synthesized in the early 1920s, the discovery of insulin a few years later eclipsed these agents, at least for a time. In the latter part of the 20th century medicine rediscovered these drugs, and they entered clinical use. Despite becoming the standard of care for DM2, it took 30 years to figure out how Metformin works!

Human studies show that its major action is reduction of glucose production in the liver. When we eat, nutrients of all types enter the bloodstream and make a first stop in the liver for metabolism. The liver can convert these other molecules to glucose, our circulating fuel for cells, via a process called gluconeogenesis (literally new glucose).  Patients with DM2 have twice the rate of gluconeogenesis in the liver as nondiabetic people. Metformin for 3 months can normalize this process.

Metformin also has beneficial effects on levels of fats in the bloodstream and uptake of glucose by muscles. Unlike many therapies for DM2, patients usually do not gain weight with Metformin; indeed, many experience weight loss.

AMPK-regulated enzymes circled

AMPK-regulated enzymes circled

One documented cellular mechanism involves AMP-activated protein kinase (AMPK), a protein that functions in a number of metabolic processes. These include lipid (fat) synthesis, muscle glucose uptake, and control of a number of enzymes in the gluconeogenesis process (diagram to the right).

Zhou et al showed that Metformin activated AMPK in liver cells, leading to decreased fatty acid and lipid production (which in turn increases the sensitivity of the liver cell to insulin). Inhibition of AMPK blocks Metformin's beneficial effects on gluconeogenesis, so activation of AMPK also provides an explanation for this beneficial effect.

So have we answered the mystery of Metformin? Of course not!

Metformin has one obvious, often troubling, side effect: diarrhea. For myself and a number of friends who take it, the first dose induced events not unlike the clean-out for a colonoscopy (ask your 50+ year-old friends about the joy of colonoscopy prep). Some folks have ongoing diarrhea that limits therapy with the drug; in most patients, like yours truly, the problem eventually resolves (or becomes less problematic).

Why does Metformin cause intestinal problems? We really do not know. Some have suggested that it reduces intestinal absorption of glucose which could contribute to changes in stool pattern. Its effects on the liver may also change stuff downstream in the gut. Some have suggested that these intestinal effects may be beneficial as well, through changes in the microbiome.

For a drug that's a century old, there is still a lot we do not know about Metformin. At least we know it works!

 

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Finally!

Jun 19 2015 Published by under Uncategorized

logo-aamc.gif-dataI have finally dug into the latest AAMC dataset on the status of women in academic medicine. The website AWEnow (Academic Women for Equality Now) will be featuring these updates over the coming weeks. Today I posted the overall scores for the nation.

Good news: The overall share of women in leadership has increased over 4 years (3 datasets).

Bad news: At this rate, I will be 94 when women hold half the leadership positions in academical centers.

Go see my pretty graph here!

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A Doctor Deals: Thoughts from #2015ADA

Jun 08 2015 Published by under Diabetes, Uncategorized

Boston revere 220x175

As usual for this time of year, I am at the annual scientific sessions of the American Diabetes Association. For four days I have been hobnobbing with others interested in diabetic nephropathy, learning about new stuff, and hanging out with my spouse in Boston.

This year brought a new perspective. I am now living with diabetes myself.

The diagnosis provided no big surprise. My fasting glucose levels had been “impaired” for about 10 years, a clear indicator that this could happen. I would start a diet, compulsively recording every bite and calorie I ate. This resulted in a few pounds coming off, but as soon as I failed to track food, it came right back. I had generally resigned myself to plus sizes for the rest of my life.

A few months back I established care with a new doctor. Basic lab work showed a somewhat higher glucose than before. Oops. I got back on the wagon to try and fix that by my next labs. I had some additional motivation as well. My daughter got engaged at Christmas, and I really wanted to drop some tonnage before taking family photos. I thought I would get it all fixed.

Unfortunately, I failed. Or at least my pancreas did. My HbA1c, a measure of the amount of hemoglobin with glucose glommed onto it, was 6.8%. Anything above 6.5% means you have diabetes.

Knowing stuff like this does not help

Knowing stuff like this does not help

My brain spent a few minutes in denial. Perhaps if I got more aggressive and lost some more weight, this would go away…? Luckily, I had put on my big girl panties and dealt with it by the time the doctor came in to discuss my next steps.

So this was my first year attending the diabetes meetings as a doctor, a scientist, and a patient living with the disease. In the near future I will write more about dealing with diabetes. It's especially sobering when you know stuff about your pathology...

 

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