HIV prevention drug called a "game changer"

On World AIDS Day, the focus in the U.S. is on educating people at risk for HIV about prevention. CBS News' Kenneth Craig has more on how a life-saving drug could turn the epidemic around.

From: http://www.cbsnews.com/videos/hiv-prevention-drug-called-a-game-changer/

Could early balding signal heart trouble in men?

Preliminary research looks at men's hair loss patterns for possible clues to future heart health

From: http://www.cbsnews.com/news/could-early-balding-signal-heart-trouble-in-men/

Lung cancer drug targets "hidden" HIV in promising case

In what researchers say is a first, a man's cancer treatment had an unexpected impact on HIV-infected cells

From: http://www.cbsnews.com/news/lung-cancer-drug-targets-hidden-hiv-in-promising-case/

Henry Schein, Leidos team up to modernize military health records

When the U.S. Department of Defense announced in 2014 it was looking to modernize military health records, the team at Henry Schein believed its dental practice management software, Dentrix Enterprise, would work.

From: By Jennifer Garvin and David Burger
http://www.ada.org/en/publications/ada-news/2017-archive/december/henry-schein-leidos-team-up-to-modernize-military-health-records

Cellphones, video games eyed in teen suicide study

New report appears to add weight to the argument that there's a link between the rise in suicide in young people and use of electronic devices

From: http://www.cbsnews.com/news/teen-suicide-study-cellphones-video-games/

Glasses were sold in Total Wine stores around the country.

Glasses were sold in Total Wine stores around the country.

From: https://www.webmd.com/a-to-z-guides/news/20171201/recall-libbey-bourbon-glasses?src=RSS_PUBLIC

HIV Is Gaining Resistance to Lifesaving Drugs

A new study warns of a potential return to the "bad old days" when there were no effective drugs to fight HIV, the virus that causes AIDS.

From: https://www.webmd.com/hiv-aids/news/20171201/hiv-is-gaining-resistance-to-lifesaving-drugs?src=RSS_PUBLIC

Lebanon Valley Dental Association donates $5,000 to help dental assistant students

Lebanon, Penn. — The Lebanon Valley Dental Association donated $5,000 to help dental assistant students afford the examination costs to receive radiology or infection control certifications, the Lebanon County Career and Technology Center announced Nov. 29.

From: http://www.ada.org/en/publications/ada-news/2017-archive/december/lebanon-valley-dental-association-donates-5000-to-help-dental-assistant-students

Gum Disease Tied to Yet Another Deadly Illness

Add one more reason to why you should brush and floss regularly: Gum disease bacteria are now tied to higher odds of esophageal cancer.

From: https://www.webmd.com/oral-health/news/20171201/gum-disease-tied-to-yet-another-deadly-illness?src=RSS_PUBLIC

FDA Approves Monthly Dose of Opioid Addiction Treatment

A once-monthly injection of the opioid addiction drug buprenorphine has been approved by the U.S. Food and Drug Administration.

From: https://www.webmd.com/mental-health/addiction/news/20171201/fda-approves-monthly-dose-of-opioid-addiction-treatment?src=RSS_PUBLIC

FDA approves first test for cancer gene profiling

The test looks for mutations in hundreds of cancer genes​ at once, giving a more complete picture of what's driving a patient's tumor and aiding efforts to match treatments

From: http://www.cbsnews.com/news/fda-approves-first-of-its-kind-test-for-cancer-gene-profiling/

Rye Bran Modified with Cell Wall-Degrading Enzymes Influences the Kinetics of Plant Lignans but Not of Enterolignans in Multicatheterized Pigs [Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions]

Background: Whole-grain intake is associated with a lower risk of chronic Western-style diseases, possibly brought about by the high concentration of phytochemicals, among them plant lignans (PLs), in the grains.

Objective: We studied whether treatment of rye bran with cell wall–degrading enzymes changed the solubility and kinetics of PLs in multicatheterized pigs.

Methods: Ten female Duroc x Danish Landrace x Yorkshire pigs (60.3 ± 2.3 kg at surgery) fitted with permanent catheters were included in an incomplete crossover study. The pigs were fed 2 experimental diets for 1–7 d. The diets were rich in PLs and based on nontreated lignan-rich [LR; lignan concentration: 20.2 mg dry matter (DM)/kg] or enzymatically treated lignan-rich (ENZLR; lignan concentration: 27.8 mg DM/kg) rye bran. Plasma concentrations of PLs and enterolignans were quantified with the use of targeted LC-tandem mass spectrometry. Data were log transformed and analyzed with mixed-effects, 1-compartment, and asymptotic regression models.

Results: The availability of PLs was 38% greater in ENZLR than in LR, and the soluble fraction of PLs was 49% in ENZLR compared with 35% in LR diets. PLs appeared in the circulation 30 min after intake of both the ENZLR and LR diets. Postprandially, consumption of ENZLR resulted in a 4-times-greater (P < 0.0001) plasma PL concentration compared with LR. The area under the curve (AUC) measured 0–360 min after ENZLR intake was ~2 times higher than after LR intake. A 1-compartment model could describe the postprandial increase in plasma concentration after ENZLR intake, whereas an asymptotic regression model described the plasma concentrations after LR intake. Despite increased available and soluble PLs, ENZLR did not increase plasma enterolignans.

Conclusion: The modification of rye bran with cell wall–degrading enzymes resulted in significantly greater plasma concentrations of PLs and the 4-h AUC, particularly syringaresinol, in multicatheterized pigs.

From: Bolvig, A. K., Norskov, N. P., van Vliet, S., Foldager, L., Curtasu, M. V., Hedemann, M. S., Sorensen, J. F., Laerke, H. N., Bach Knudsen, K. E. http://jn.nutrition.org/cgi/content/short/147/12/2220?rss=1

Ammonia Nitrogen Added to Diets Deficient in Dispensable Amino Acid Nitrogen Is Poorly Utilized for Urea Production in Growing Pigs [Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions]

Background: Including ammonia in low–crude protein (CP) diets deficient in dispensable amino acid (DAAs) increases nitrogen retention in growing pigs.

Objective: We investigated the absorption and metabolism of dietary ammonia nitrogen in the portal-drained viscera (PDV) and liver of pigs fed a diet deficient in DAA nitrogen.

Methods: Eight pigs with an initial mean ± SD body weight (BW) of 26.5 ± 1.4 kg were surgically fitted with 4 catheters each (portal, hepatic and mesenteric veins, and carotid artery). The pigs were fed (2.8 x 191 kcal/kg BW^0.60), for 7 d and every 8 h, a diet deficient in DAA nitrogen supplemented with increasing amounts of ammonia nitrogen (CP: 7.76%, 9.27%, and 10.77%; indispensable amino acid nitrogen:total nitrogen ratio: 0.71, 0.59, and 0.50 for control and low- and high-ammonia diets, respectively). The treatment sequence was based on a Latin square design with 3 consecutive periods. On the last day of each period, blood flows in the portal and hepatic veins were determined with a continuous infusion of -amino hippuric acid into the mesenteric vein. Serial blood samples were taken to determine ammonia and urea nitrogen concentration. Net balances of ammonia and urea nitrogen were calculated for the PDV and liver.

Results: Cumulative (8 h) ammonia nitrogen appearance in the portal vein increased (P ≤ 0.05) with ammonia intake (433, 958, and 1629 ± 60 mg ammonia nitrogen/meal for control and low- and high-ammonia diets, respectively). The cumulative hepatic uptake of ammonia nitrogen increased (P ≤ 0.05) with ammonia nitrogen supply. The cumulative urea nitrogen appearance in the hepatic vein tended to increase (P ≤ 0.10) only in high-ammonia treatment (–92.5, –59.4, and 209.7 ± 92 mg urea nitrogen/meal for control and low- and high-ammonia diets, respectively) and, relative to the control diet, represented –6.0% and 11% of ammonia nitrogen intake.

Conclusion: Dietary ammonia nitrogen is poorly utilized for urea production across splanchnic organs when pigs are fed diets deficient in DAA nitrogen.

From: Mansilla, W. D., Silva, K. E., Zhu, C. L., Nyachoti, C. M., Htoo, J. K., Cant, J. P., de Lange, C. F. http://jn.nutrition.org/cgi/content/short/147/12/2228?rss=1

Carbohydrate Taste Sensitivity Is Associated with Starch Intake and Waist Circumference in Adults [Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions]

Background: Recent studies have proposed that humans may perceive complex carbohydrates and that sensitivity to simple carbohydrates is independent of sensitivity to complex carbohydrates. Variation in oral complex carbohydrate sensitivity may influence food consumption.

Objective: This study aimed to investigate the associations between oral complex carbohydrate sensitivity, anthropometry, and dietary intake in adults.

Methods: We assessed oral sensitivity to complex carbohydrates (maltodextrin and oligofructose) by measuring detection thresholds (DTs) and suprathreshold intensity perceptions (STs) for 34 participants, including 16 men (mean ± SEM age : 26.2 ± 0.4 y; range: 24–30 y) and 18 women (age: 29.4 ± 2.1 y; range: 24–55 y). We also measured height, weight, and waist circumference (WC) and participants completed a 4-d food diary and a food-frequency questionnaire.

Results: Measurements of oral sensitivity to complex carbohydrates were significantly correlated with WC and dietary energy and starch intakes (DT: r = –0.38, P < 0.05; ST: r = 0.36–0.48, P < 0.05). When participants were grouped into tertiles, there were significant differences in WC and total energy or starch intakes for those who were more sensitive or experienced high intensity compared with those who were less sensitive or experienced low intensity. Being more sensitive or experiencing high intensity was associated with greater energy (7968–8954 kJ/d) and starch (29.1–29.8% of energy) intakes and a greater WC (88.2–91.4 cm) than was being less sensitive or experiencing low intensity (6693–7747 kJ/d, 20.9–22.2% of energy, and 75.5–80.5 cm, respectively).

Conclusion: Complex carbohydrate sensing is associated with WC and consumption of complex carbohydrates and energy in adults. This trial was registered at anzctr.org.au as ACTRN12616001356459.

From: Low, J. Y., Lacy, K. E., McBride, R. L., Keast, R. S. http://jn.nutrition.org/cgi/content/short/147/12/2235?rss=1

Long-Term Intake of a High-Protein Diet Affects Body Phenotype, Metabolism, and Plasma Hormones in Mice [Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions]

Background: High-protein diets (HPDs) recently have been used to obtain body weight and fat mass loss and expand muscle mass. Several studies have documented that HPDs reduce appetite and food intake.

Objective: Our goal was to determine the long-term effects of an HPD on body weight, energy intake and expenditure, and metabolic hormones.

Methods: Male C57BL/6 mice (8 wk old) were fed either an HPD (60% of energy as protein) or a control diet (CD; 20% of energy as protein) for 12 wk. Body composition and food intakes were determined, and plasma hormone concentrations were measured in mice after being fed and after overnight feed deprivation at several time points.

Results: HPD mice had significantly lower body weight (in means ± SEMs; 25.73 ± 1.49 compared with 32.5 ± 1.31 g; P = 0.003) and fat mass (9.55% ± 1.24% compared with 15.78% ± 2.07%; P = 0.05) during the first 6 wk compared with CD mice, and higher lean mass throughout the study starting at week 2 (85.45% ± 2.25% compared with 75.29% ± 1.90%; P = 0.0001). Energy intake, total energy expenditure, and respiratory quotient were significantly lower in HPD compared with CD mice as shown by cumulative energy intake and eating rate. Water vapor was significantly higher in HPD mice during both dark and light phases. In HPD mice, concentrations of leptin [feed-deprived: 41.31 ± 11.60 compared with 3041 ± 683 pg/mL (P = 0.0004); postprandial: 112.5 ± 102.0 compared with 8273 ± 1415 pg/mL (P < 0.0001)] and glucagon-like peptide 1 (GLP-1) [feed-deprived: 5.664 ± 1.44 compared with 21.31 ± 1.26 pg/mL (P = <0.0001); postprandial: 6.54 ± 2.13 compared with 50.62 ± 11.93 pg/mL (P = 0.0037)] were significantly lower, whereas postprandial glucagon concentrations were higher than in CD-fed mice.

Conclusions: In male mice, the 12-wk HPD resulted in short-term body weight and fat mass loss, but throughout the study preserved body lean mass and significantly reduced energy intake and expenditure as well as leptin and GLP-1 concentrations while elevating postprandial glucagon concentrations. This study suggests that long-term use of HPDs may be an effective strategy to decrease energy intake and expenditure and to maintain body lean mass.

From: Vu, J. P., Luong, L., Parsons, W. F., Oh, S., Sanford, D., Gabalski, A., Lighton, J. R., Pisegna, J. R., Germano, P. M. http://jn.nutrition.org/cgi/content/short/147/12/2243?rss=1

Lock Eyes With Your Baby, Synchronize Brain Waves?

Eye contact between parents and their infants actually helps synchronize their brain waves, researchers report.

From: https://www.webmd.com/children/news/20171201/lock-eyes-with-your-baby-synchronize-brain-waves?src=RSS_PUBLIC

The Couric-Jolie effect: The impact of celebrities’ medical advice

Follow me on Twitter @RobShmerling

Some called it the Katie Couric effect. Soon after her husband died of colon cancer in 1998, the journalist and television personality had a televised colonoscopy to promote the test. Rates of screening colonoscopies soared for at least a year. Or, call it the Angelina Jolie effect. In 2013, the actress wrote an editorial in the New York Times about the tests she had for genes (called BRCA) linked with breast and ovarian cancer, and how the positive result led her to have a double mastectomy. Soon after, rates of BRCA testing jumped.

Whatever you call it, the effect is real. When it comes to matters of health, celebrities can have an enormous impact.

It’s good when celebrities do good

The impulse to take a challenging or tragic medical experience and turn it into something that helps others is commendable. It may be easier to keep such matters private or avoid talking about them in public. But time and again, we see celebrities joining forces with health-promoting organizations, speaking out, and sharing their stories to help others avoid what they’ve experienced. Many have credited Katie Couric with removing the embarrassment associated with colonoscopy and showing how easy it is.

Is there a downside?

There are a number of ways celebrity pronouncements on matters of health can go wrong. For example, the information can be faulty or confusing. The forays of Jenny McCarthy (who claimed vaccines cause autism) and Gwyneth Paltrow (who recommended vaginal steams to “cleanse the uterus”) into matters of health and illness are examples of influence most doctors would consider unhelpful or even dangerous.

When I heard about Katie Couric’s colonoscopy, I thought it was brave and certainly a unique way to get her message across. But as well-intended as it may have been, she was 43 years old at the time. Since guidelines suggest people begin routine screening at age 50, I wondered if she was a good candidate for the test. Unless she had symptoms (such as intestinal bleeding), a strong family history of early colon cancer, or some other special circumstance that put her at higher than average risk for colon cancer, her colonoscopy could be considered unnecessary testing. And that could have led others to have unnecessary testing as well.

A recent study raises a similar concern about Angelina Jolie’s BRCA testing. It found that in the weeks after her editorial was published, testing increased by more than 60% (at an estimated cost of $13.5 million). However, mastectomy rates actually fell over the next two to six months, leading the authors to suggest that most of the additional women who had testing had negative results and therefore may have been poor candidates for testing in the first place. Of note, the study did not confirm whether those having the BRCA test had risk factors (especially a family history of early breast or ovarian cancer) that would make the test appropriate. Critics of the study have suggested that mastectomy rates within six months of testing is not an adequate measure of whether the tests were appropriate. Still, the point is worth considering. When a celebrity recommends a medical test or treatment, the audience is not limited to those who are most likely to benefit.

The bottom line

For any medical test or treatment, ask whether it’s likely to be helpful. The answer may be straightforward. For example, a well-studied and well-accepted screening test may be recommended based only on your age and gender. But in many cases, the answer may rely on a considerable amount of judgement based on how likely it is that you have a particular condition, the ability of the test to detect it, and the impact of the test result on treatment decisions. For example, if a person has knee pain that’s mild and well-controlled with exercises, it may make little sense to have an MRI, as the results are highly unlikely to affect treatment.

If your doctor recommends a test or treatment, make sure you understand why. And if it’s a celebrity making the recommendation, do yourself a favor: run it by your doctor.

The post The Couric-Jolie effect: The impact of celebrities’ medical advice appeared first on Harvard Health Blog.

From: Robert H. Shmerling, MD https://www.health.harvard.edu/blog/impact-celebrities-medical-advice-2017120112831

ADA 2017 exhibitors donate supplies to Hurricane Harvey-affected dentists

About two months after Hurricane Harvey hit eastern Texas, members of the dental community continue to offer support to dentists affected by the storm.

From: By Kimber Solana
http://www.ada.org/en/publications/ada-news/2017-archive/december/ada-2017-exhibitors-donate-supplies-to-hurricane-harvey-affected-dentists

Naloxone: An important tool, but not the solution to the opioid crisis

Every once in a while, I’ll have a terrible shift in the emergency department (ED) in which I have to pronounce yet another young person dead from an opioid overdose. I typically have to call their parents, who usually express sorrow but not surprise at the horrific news, as we all know how deadly opioid use disorder can be. But more frequently, the overdose patients I care for survive. Typically, they were found unresponsive by a friend or family member — 911 is called, the person is given the reversal agent naloxone, and is brought to the ED where my colleagues and I take over.

How naloxone works

Here’s the problemNaloxone is, in many respects, a wonder drug. It inhibits the opioid receptor in the brain (so it blocks the effect of an opioid) and, if there is an opioid already present, naloxone can knock it off a receptor. So, if a person overdoses on an opioid such as heroin, the naloxone pushes the heroin away and blocks the receptor but does not activate it, so the person can recover from their overdose. However, since its time of action is fairly short — shorter than the effect of many of the opioids people use — we watch patients for a few hours in the ED until we’re sure the opioids have completely cleared their system. Basically, we want to make sure that they don’t overdose again. After they sober, we offer to have them speak to a social worker (most refuse), or provide a list of detox facilities, and then they quietly leave the ED.

This status quo bothers me. In particular, I’m concerned that although naloxone is now readily available — carried by police, firefighters, basic life support ambulances, and even bystanders —overdose deaths continue to clim

b. I want to talk frankly with the patient who overdoses and survives, and specifically let them know their risk of dying should they not get treatment. I also want to make the case that better treatment options after an overdose are needed.

Our group at Brigham and Women’s Hospital therefore conducted a study, recently presented at the American College of Emergency Physicians national meeting in Washington, DC. In this study, we aimed to define how many patients who were treated with naloxone by an ambulance crew and initially survived were still alive after one year. Even though these patients are typically just observed in the ED hallway, allowed to sober while the ED staff is busy taking care of other patients with life-threatening emergencies like heart attacks, trauma, and strokes, our team hypothesized that the individual sobering in the hallway bed has perhaps one of the highest one-year mortality rates of anyone seen in the department.

Here’s how the study worked — and what we found

To perform the study, we took advantage of a special project in Massachusetts called the “Chapter 55” legislation which, for the first time, linked many previously separate state databases. We connected the Emergency Medical Services (EMS) database with the all-payer claims database and death records database for our study. In brief, we evaluated patients who received naloxone by EMS over a 30-month period. We then looked at death records one year beyond the first time they received naloxone.

During the study period, there were 12,192 naloxone administrations by EMS, which equals over 400 per month. Of these, 6.5% of patients died that same day and 9.3% died within one year. Excluding those who died the same day, about 10% of the patients who initially survived were dead at one year. Even more significant was that 51.4% of those patients died within one month. Also, apart from those who died the same day, about 40% of those who died within one year died outside of the hospital, highlighting the danger of overdosing before medical personnel can reach the victim and the need for bystander naloxone.

What does this mean about preventing deaths from opioid use disorder?

These results are disheartening: an opioid overdose patient who sobers in the hallway, is offered a detox list, and then is discharged has a one-in-10 chance of being dead within a year. And the highest risk is within one month. Naloxone is an important tool in fighting the opioid crisis, but is no solution. Patients who survive opioid overdose should be considered extremely high-risk. I believe that as a society, we should talk seriously about the resources that are available for people who overdose. We should counsel these patients and offer them buprenorphine (a medication used to help treat opioid use disorder) directly from the ED, provide recovery coaches, and create easily accessible treatment sites where they can go for ongoing care.

The post Naloxone: An important tool, but not the solution to the opioid crisis appeared first on Harvard Health Blog.

From: Scott Weiner, MD https://www.health.harvard.edu/blog/naloxone-tool-not-solution-opioid-crisis-2017113012800

Resistance to Popular Antibiotic Began Years Ago

Ampicillin, a broad-spectrum penicillin, is widely used to treat many bacterial infections, including bladder and ear infections, pneumonia and gonorrhea.

From: https://www.webmd.com/a-to-z-guides/news/20171130/resistance-to-popular-antibiotic-began-years-ago?src=RSS_PUBLIC

Scarlet fever makes a dangerous comeback

After decades of decline, cases of scarlet fever have surged to a 50-year high in England; could it happen here, too?

From: http://www.cbsnews.com/news/scarlet-fever-makes-a-dangerous-comeback/

5 Things You Should Know About Cervical Cancer

Death rates from cervical cancer have fallen by more than 50 percent in the past four decades as women have learned more about their risk and as increasing numbers have had Pap tests, which help doctors screen for the disease, the experts noted.

From: https://www.webmd.com/cancer/cervical-cancer/news/20171201/5-things-you-should-know-about-cervical-cancer?src=RSS_PUBLIC

New guideline on hypertension lowers threshold

Nearly half of American adults are at risk for major health problems because of high blood pressure, according to a new scientific guideline issued by the American Heart Association that redefines this often silent but potentially harmful condition and provides tactics for health care providers to detect it.

From: By David Burger
http://www.ada.org/en/publications/ada-news/2017-archive/november/new-guideline-on-hypertension-lowers-threshold

Could Your Coffee Habit Lengthen Your Life?

The finding, which applies to so-called "moderate" coffee drinking, stems from a review of more than 200 previous studies.

From: https://www.webmd.com/diet/news/20171130/could-your-coffee-habit-lengthen-your-life?src=RSS_PUBLIC

Resistance to Popular Antibiotic Began Years Ago

Ampicillin, a broad-spectrum penicillin, is widely used to treat many bacterial infections, including bladder and ear infections, pneumonia and gonorrhea.

From: https://www.webmd.com/news/20171130/resistance-to-popular-antibiotic-began-years-ago?src=RSS_PUBLIC

Zinc strengthens the jejunal barrier by reversibly tightening the paracellular route

During the postweaning period, piglets are prone to gastrointestinal infections. The resulting impairment of intestinal barrier function may cause diarrhea associated with growth retardation or even death of piglets. Orally applied Zn is commonly used to prevent and treat diarrhea, but its mode of action still needs to be elucidated. To analyze the molecular mechanism whereby Zn acts on porcine intestinal barrier function, ex vivo studies on piglet jejunum and accompanying in vitro studies on a porcine jejunal epithelial cell line, IPEC-J2/PS, were performed with electrophysiological tools. Feeding pharmacological Zn doses exerted no significant electrophysiologically ascertainable short- and long-term effects on jejunal barrier function ex vivo. However, in IPEC-J2/PS, basolateral Zn was cytotoxic since its application caused a release of lactate dehydrogenase and an irreversible breakdown of the epithelial barrier. In contrast, apical Zn application caused an immediate increase in paracellular resistance and a decrease in permeability to the paracellular marker fluorescein, reflecting overall barrier strengthening in vitro. Apical effects were fully reversible upon washout. This indicates that Zn supplemented to feed was completely washed out during ex vivo jejunum preparation. We conclude that there is no evidence for long-term barrier effects through prophylactic Zn supplementation and that extracellular Zn acts acutely and reversibly from the apical side via tightening the paracellular route, thus counteracting leak-flux diarrhea.

NEW & NOTEWORTHY Therapeutically administered Zn successfully treats diarrhea in veterinary and human medicine. Here we present data that Zn strengthens the porcine jejunal epithelial barrier by reversibly tightening the paracellular route for inorganic ions and small solutes. Acute or long-lasting Zn effects on transcellular transport (Cl^– secretion) were not detected. We therefore conclude that Zn is useful for acutely treating leak-flux diarrhea rather than secretory diarrhea. Suitability as prophylactic feed supplement, however, is questionable.

From: Zakrzewski, S. S., Fromm, M., Schulzke, J. D., Günzel, D. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G537?rss=1

Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation

Clinical studies in burn patients demonstrate a close association between leaky guts and increased incidence or severity of sepsis and other complications. Severe thermal injury triggers intestinal inflammation that contributes to intestinal epithelial hyperpermeability, which exacerbates systemic response leading to multiple organ failure and sepsis. In this study, we identified a significant function of a particular palmitoyl acyltransferase, zinc finger DHHC domain-containing protein-21 (ZDHHC21), in mediating signaling events required for gut hyperpermeability induced by inflammation. Using quantitative PCR, we show that ZDHHC21 mRNA production was enhanced twofold when intestinal epithelial cells were treated with TNF-α-IFN- in vitro. In addition, pharmacological targeting of palmitoyl acyltransferases with 2-bromopalmitate (2-BP) showed significant improvement in TNF-α-IFN--mediated epithelial barrier dysfunction by using electric cell-substrate impedance-sensing assays, as well as FITC-labeled dextran permeability assays. Using acyl-biotin exchange assay and click chemistry, we show that TNF-α-IFN- treatment of intestinal epithelial cells results in enhanced detection of total palmitoylated proteins and this response is inhibited by 2-BP. Using ZDHHC21-deficient mice or wild-type mice treated with 2-BP, we showed that mice with impaired ZDHHC21 expression or pharmacological inhibition resulted in attenuated intestinal barrier dysfunction caused by thermal injury. Moreover, hematoxylin and eosin staining of the small intestine, as well as transmission electron microscopy, showed that mice with genetic interruption of ZDHHC21 had attenuated villus structure disorganization associated with thermal injury-induced intestinal barrier damage. Taken together, these results suggest an important role of ZDHHC21 in mediating gut hyperpermeability resulting from thermal injury.

NEW & NOTEWORTHY Increased mucosal permeability in the gut is one of the major complications following severe burn. Here we report the novel finding that zinc finger DHHC domain-containing protein-21 (ZDHHC21) mediates gut epithelial hyperpermeability resulting from an experimental model of thermal injury. The hyperpermeability response was significantly attenuated with a pharmacological inhibitor of palmitoyl acyltransferases and in mice with genetic ablation of ZDHHC21. These findings suggest that ZDHHC21 may serve as a novel therapeutic target for treating burn-induced intestinal barrier dysfunction.

From: Haines, R. J., Wang, C. Y., Yang, C. G. Y., Eitnier, R. A., Wang, F., Wu, M. H. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G549?rss=1

Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling

The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P₄₅₀ 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. We have previously shown that microtubules are hyperacetylated in ethanol-treated polarized, hepatic WIF-B cells and livers from ethanol-fed rats. We have also shown that enhanced protein acetylation correlates with impaired clathrin-mediated endocytosis, constitutive secretion, and nuclear translocation and that the defects are likely mediated by acetaldehyde. However, the roles of CYP2E1-generated metabolites and ROS in microtubule acetylation and these alcohol-induced impairments have not been examined. To determine if CYP2E1-mediated alcohol metabolism is required for enhanced acetylation and the trafficking defects, we coincubated cells with ethanol and diallyl sulfide (DAS; a CYP2E1 inhibitor) or N-acetyl cysteine (NAC; an antioxidant). Both agents failed to prevent microtubule hyperacetylation in ethanol-treated cells and also failed to prevent impaired secretion or clathrin-mediated endocytosis. Somewhat surprisingly, both DAS and NAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone was prevented by DAS and NAC. These results were confirmed in ethanol-exposed HepG2 cells expressing only ADH or CYP2E1. Using quantitative RT-PCR, we further determined that ethanol exposure led to blunted growth hormone-mediated gene expression. In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity.

NEW & NOTEWORTHY Impaired growth hormone-mediated signaling is observed in ethanol-exposed hepatocytes and is explained by differential effects of alcohol dehydrogenase (ADH)- and cytochrome P₄₅₀ 2E1 (CYP2E1)-mediated ethanol metabolism on the Jak2/STAT5B pathway.

From: Doody, E. E., Groebner, J. L., Walker, J. R., Frizol, B. M., Tuma, D. J., Fernandez, D. J., Tuma, P. L. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G558?rss=1

Ammonia modifies enteric neuromuscular transmission through glial {gamma}-aminobutyric acid signaling

Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca²⁺ responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP::CreER^T2+/–/connexin43^f/f mice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABA_A receptor antagonists, and ammonia drove substantive GABA release as did the selective pharmacological activation of enteric glia in GFAP::hM3Dq transgenic mice. We propose a novel mechanism whereby local ammonia is operational through GABAergic glial signaling to influence enteric neuromuscular circuits that regulate intestinal motility. Therapeutic manipulation of these mechanisms may benefit a number of neurological, hepatic, and renal disorders manifesting hyperammonemia.

NEW & NOTEWORTHY We propose that local circuits in the enteric nervous system sense and regulate intestinal ammonia. We show that ammonia modifies enteric neuromuscular transmission to increase motility in human, pig, and mouse intestine model systems. The mechanisms underlying the effects of ammonia on enteric neurotransmission include GABAergic pathways that are regulated by enteric glial cells. Our new data suggest that myenteric glial cells sense local ammonia and directly modify neurotransmission by releasing GABA.

From: Fried, D. E., Watson, R. E., Robson, S. C., Gulbransen, B. D. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G570?rss=1

Age-related external anal sphincter muscle dysfunction and fibrosis: possible role of Wnt/{beta}-catenin signaling pathways

Studies show an age-related increase in the prevalence of anal incontinence and sphincter muscle atrophy. The Wnt/β-catenin signaling pathway has been recently recognized as the major molecular pathway involved in age-related skeletal muscle atrophy and fibrosis. The goals of our study were to 1) evaluate the impact of normal aging on external anal sphincter (EAS) muscle length-tension (L-T) function and morphology and 2) specifically examine the role of Wnt signaling pathways in anal sphincter muscle fibrosis. New Zealand White female rabbits [6 young (6 mo of age) and 6 old (36 mo of age)] were anesthetized, and anal canal pressure was measured to determine the L-T function of EAS. Animals were killed at the end of the study, and the anal canal was harvested and processed for histochemical studies (Masson trichrome stain for muscle/connective tissue) as well as for molecular markers for fibrosis and atrophy [collagen I, β-catenin, transforming growth factor-β (TGF-β), atrogin-1, and muscle-specific RING finger protein-1 (MuRF-1)]. The L-T was significantly impaired in older animals compared with young animals. Anal canal sections stained with trichrome showed a significant decrease in the muscle content (52% in old compared with 70% in young) and an increase in the connective tissue/collagen content in the old animals. An increased protein and mRNA expression of all the fibrosis markers was seen in the older animals. Aging EAS muscle exhibits impairment of function and increase in connective tissue. Upregulation of atrophy and profibrogenic proteins with aging may be the reason for the age-related decrease in anal sphincter muscle thickness and function.

NEW & NOTEWORTHY Our studies using a female rabbit model show age-related alterations in the structure and function of the external anal sphincter (EAS) muscle. We used endoluminal ultrasound to measure age-related changes in EAS muscle thickness. We employed Western blot and quantitative PCR to demonstrate age-related changes in the levels of important fibrogenic as well as atrophy markers. Our findings may have significant clinical implications, i.e., use of specific antagonists to prevent age-related EAS muscle dysfunction.

From: Rajasekaran, M. R., Kanoo, S., Fu, J., Nguyen, M.-U., Bhargava, V., Mittal, R. K. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G581?rss=1

Role of MicroRNA-423-5p in posttranscriptional regulation of the intestinal riboflavin transporter-3

Riboflavin (RF) is essential for normal cellular functions and health. Humans obtain RF from exogenous sources via intestinal absorption that involves a highly specific carrier-mediated process. We have recently established that the riboflavin transporter-3 (RFVT3) is vital for the normal intestinal RF uptake process and have characterized certain aspects of its transcriptional regulation. Little is known, however, about how this transporter is regulated at the posttranscriptional level. We address this issue by focusing on the role of microRNAs. Using bioinformatics, we identified two potential interacting miRNAs with the human (h) RFVT3-3'-UTR, and showed (using pmirGLO-hRFVT3-3'-UTR) that the hRFVT3-3'-UTR is, indeed, a target for miRNA effect. Of the two putative miRNAs identified, miR-423-5p was found to be highly expressed in intestinal epithelial cells and that its mimic affected luciferase reporter activity of the pmirGLO-hRFVT3-3'-UTR construct, and also led to inhibition in RF uptake by intestinal epithelial Caco-2 and HuTu-80 cells. Furthermore, cells transfected with mutated seed sequences for miR-423-5p showed an abrogation in inhibitory effect of the miR-423-5p mimic on luciferase activity. While miR-423-5p did not affect the level of expression of the hRFVT3 mRNA, it did lead to a significant inhibition in the level of expression of its protein. Similarly, miR-423-5p was found to affect the level of expression of the mouse RFVT3 in cultured intestinal enteroids. These findings demonstrate, for the first time, that the RFVT3 is a target for posttranscriptional regulation by miRNAs in intestinal epithelial cells and that this regulation has functional consequences on intestinal RF uptake.

NEW & NOTEWORTHY Our findings show for the first time that RFVT3 is a target for posttranscriptional regulation by miR-423-5p in intestinal epithelial cells, and this regulation has functional consequences on intestinal riboflavin (RF) uptake process.

From: Lakhan, R., Subramanian, V. S., Said, H. M. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G589?rss=1

A physics-based model for maintenance of the pH gradient in the gastric mucus layer

It is generally accepted that the gastric mucus layer provides a protective barrier between the lumen and the mucosa, shielding the mucosa from acid and digestive enzymes and preventing autodigestion of the stomach epithelium. However, the precise mechanisms that contribute to this protective function are still up for debate. In particular, it is not clear what physical processes are responsible for transporting hydrogen protons, secreted within the gastric pits, across the mucus layer to the lumen without acidifying the environment adjacent to the epithelium. One hypothesis is that hydrogen may be bound to the mucin polymers themselves as they are convected away from the mucosal surface and eventually degraded in the stomach lumen. It is also not clear what mechanisms prevent hydrogen from diffusing back toward the mucosal surface, thereby lowering the local pH. In this work we investigate a physics-based model of ion transport within the mucosal layer based on a Nernst-Planck-like equation. Analysis of this model shows that the mechanism of transporting protons bound to the mucus gel is capable of reproducing the trans-mucus pH gradients reported in the literature. Furthermore, when coupled with ion exchange at the epithelial surface, our analysis shows that bicarbonate secretion alone is capable of neutralizing the epithelial pH, even in the face of enormous diffusive gradients of hydrogen. Maintenance of the pH gradient is found to be robust to a wide array of perturbations in both physiological and phenomenological model parameters, suggesting a robust physiological control mechanism.

NEW & NOTEWORTHY This work combines modeling techniques based on physical principles, as well as novel numerical simulations to test the plausibility of one hypothesized mechanism for proton transport across the gastric mucus layer. Results show that this mechanism is able to maintain the extreme pH gradient seen in in vivo experiments and suggests a highly robust regulation mechanism to maintain this gradient in the face of dynamic lumen composition.

From: Lewis, O. L., Keener, J. P., Fogelson, A. L. http://ajpgi.physiology.org/cgi/content/abstract/313/6/G599?rss=1

World AIDS Day 2017

Statement by Dr Tedros for World AIDS Day, 1 December 2017

From: http://www.who.int/entity/mediacentre/news/statements/2017/world-aids-day/en/index.html