Ramachandra R. Sista, M.D.: Pulmonologist - Mayo Clinic

From: Mayo Clinic https://www.youtube.com/watch?v=TkZiQuDm5ZQ

Improve Your Odds During Infertility Treatments

There's a better chance that in vitro fertilization (IVF) will lead to pregnancy if fresh donor eggs are used instead of frozen eggs, a new study suggests.

From: https://www.webmd.com/infertility-and-reproduction/news/20171101/improve-your-odds-during-infertility-treatments?src=RSS_PUBLIC

ADA supports removing Part D requirement

The ADA said Nov. 1 that it is "pleased" to support the Protecting Seniors Access to Proper Care Act of 2017, legislation that supports removing the mandate for dentists — and other providers who are low prescribers and do not participate in Medicare — requiring they be enrolled in or opted-out of Medicare Part B in order for their written prescriptions to be covered under Medicare Part D.

From: By Jennifer Garvin http://www.ada.org/en/publications/ada-news/2017-archive/november/ada-supports-removing-part-d-requirement

Dentists can help spot early signs of eating disorders

When it comes to the early detection of eating disorders, dentists are in a unique position for spotting the early warning signs and referring patients to the proper behavioral health professionals.

From: http://www.ada.org/en/publications/ada-news/2017-archive/november/dentists-can-help-spot-early-signs-of-eating-disorders

New Clinical Trial for Ebstein’s Anomaly

From: Mayo Clinic https://www.youtube.com/watch?v=IqRDNttlFF0

More U.S. babies born preterm as progress stalls

A new report from the March of Dimes finds that after years of decline, the U.S. rate of preterm births has once again increased

From: http://www.cbsnews.com/news/preterm-birth-on-the-rise-second-year-in-a-row-march-of-dimes/

Mayo Clinic Minute: Why early detection of Alzheimer’s disease matters

From: Mayo Clinic https://www.youtube.com/watch?v=FSC0mlZWUFU

Leucine Transamination Is Lower in Middle-Aged Compared with Younger Adults [Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions]

Background: Insulin and age affect leucine (and protein) kinetics in vivo. However, to our knowledge, leucine transamination and the effects of insulin have not been studied in participants of different ages.

Objective: The aims of the study were to measure whole-body leucine deamination to α-ketoisocaproate (KIC) and KIC reamination to leucine in middle-aged and younger healthy adults, both in the postabsorptive state and after hyperinsulinemia.

Methods: Younger (mean ± SE age: 26 ± 2 y) and middle-aged (54 ± 3 y) healthy men and women were enrolled. Isotope dilution methods with 2 independent leucine and KIC tracers, a dual isotope model and the euglycemic, hyperinsulinemic clamp technique, were used.

Results: Leucine deamination [expressed as μmol/(kg x min)] was consistently greater than KIC reamination. In middle-aged adults, postabsorptive leucine deamination (0.77 ± 0.05), reamination (0.49 ± 0.04), and net deamination (0.28 ± 0.04) were ~30% lower than in the younger group (deamination: 1.12 ± 0.07; reamination: 0.70 ± 0.09; net deamination: 0.42 ± 0.04) (P < 0.002, P < 0.05, and P < 0.015, respectively). After the hyperinsulinemic clamp, plasma leucine and KIC concentrations were reduced by ~50% in both groups. Deamination and reamination also were suppressed by ~40–50% in both groups (P < 0.001); however, they remained lower [–35% (P = 0.02) and –25% (P = 0.036), respectively] in the middle-aged than in the younger participants. The leucine rate of appearance and its suppression by insulin were similar in the middle-aged and in the younger subjects. By using both the basal and the clamp data, deamination was directly correlated with the plasma leucine concentration (r = 0.61, P < 0.0025) and reamination to that of plasma KIC (r = 0.79, P < 0.00002). Expressing the data relative to lean body mass did not substantially alter the results.

Conclusions: Leucine deamination and reamination are lower in middle-aged than in younger adults, both in the postabsorptive and in the insulin-stimulated state. In middle age, a decreased net leucine transamination may represent a mechanism to spare this essential amino acid.

From: Tessari, P. http://jn.nutrition.org/cgi/content/short/147/11/2025?rss=1

Whole-Grain Starch and Fiber Composition Modifies Ileal Flow of Nutrients and Nutrient Availability in the Hindgut, Shifting Fecal Microbial Profiles in Pigs [Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions]

Background: Changes in whole-grain chemical composition can affect the site of nutrient digestion, which may alter substrate availability and gut microbiota composition.

Objective: This study elucidated the function of whole-grain fermentable fiber composition on ileal substrate flow, hindgut substrate availability, and subsequent gut microbial profiles in pigs.

Methods: Five whole grains—1) high-fermentability, high–β-glucan hull-less barley (HFB); 2) high-fermentability, high-amylose hull-less barley (HFA); 3) moderate-fermentability hull-less barley (MFB); 4) low-fermentability hulled barley (LFB); or 5) low-fermentability hard red spring wheat (LFW)—were included at 800 g/kg into diets fed to ileal-cannulated growing pigs for 9 d in a 6 (periods) x 5 (diets) Youden square. Digesta were analyzed for nutrient flow and microbial composition via 16S ribosomal RNA gene sequencing.

Results: The consumption of fermentable whole grains, HFB, and HFA increased (P < 0.05) ileal starch flow by 69% and dry matter flow by 37% compared with LFB and LFW intakes. The consumption of HFB and HFA increased (P < 0.05) fecal Firmicutes phylum abundance by 26% and 21% compared with LFB intake and increased (P < 0.05) fecal Dialister genus abundance, on average, by 98% compared with LFB and LFW intakes. Fecal Sharpea and Ruminococcus genera abundances increased (P < 0.05) with HFB intake compared with LFB and LFW intakes. In contrast, the consumption of LFB increased (P < 0.05) fecal Bacteroidetes phylum abundance by 43% compared with MFB intake. Ileal starch flow and fecal Firmicutes abundance were positively correlated and determined by using principal components analysis.

Conclusions: Increasing dietary fermentable fiber from whole grains can increase ileal substrate flow and hindgut substrate availability, shifting the fecal microbiota toward Firmicutes phylum members. Thus, digesta substrate flow is important to shape gut microbial profiles in pigs, which indicates that the manipulation of substrate flow should be considered as a tool to modulate gut microbiota composition.

From: Fouhse, J. M., Gänzle, M. G., Beattie, A. D., Vasanthan, T., Zijlstra, R. T. http://jn.nutrition.org/cgi/content/short/147/11/2031?rss=1

Can brain scans predict suicidal tendencies?

Small but intriguing study suggests certain tests may be able to identify when people are having suicidal thoughts

From: http://www.cbsnews.com/news/can-brain-scans-predict-suicidal-tendencies/

Bad Hot Flashes, Sleep Apnea Often Go Together

As if severe hot flashes alone weren't enough of a problem for menopausal women, a new study finds  these symptoms may also be tied to a greater risk for sleep apnea and related heart issues.

From: https://www.webmd.com/sleep-disorders/sleep-apnea/news/20171101/bad-hot-flashes-sleep-apnea-often-go-together?src=RSS_PUBLIC

Lack of Awareness May Spur Spread of Hep C

Only about half of people in the United States with hepatitis C know they have the curable disease, new data shows.

From: https://www.webmd.com/hepatitis/news/20171101/lack-of-awareness-may-spur-spread-of-hep-c?src=RSS_PUBLIC

#DearDiabetes: Martha Clark

Dear Diabetes,

You moved in 42 years ago… unexpectedly, uninvited and unwelcome… like a high-maintenance relative who requires my constant attention.

At first they told me to be patient… that they knew how to get you to leave… a cure is close, they said… be patient, they said… it will be soon, they said. But you wouldn’t budge; you just had to have it your way. You took some getting used to, and I have learned to be patient.

Let’s face it, our relationship has been up and down… I’ve often resented you, tried to ignore you, resisted you and eventually embraced you. Somewhere along the way I accepted that you are here to stay. So, like many who are in lifelong relationships, I’ve chosen our song… one that captures the truth about our relationship… Willie Nelson’s “Always on My Mind.”

You come with me everywhere I go—intruding on my social life and limiting my flexibility. You’re Always on My Mind.

To be fair, you’ve taught me a lot… discipline, managing risks, empathy for others and patience with myself.

But seriously, feel free to leave anytime. Anytime. Really.

In the meantime, I will continue to thrive and will do what I can to help others do the same. That’s my sweet revenge!

Thinking of You Always,

Martha Clark, MBA
Interim Chief Executive Officer, American Diabetes Association

From: American Diabetes Association http://diabetesstopshere.org/2017/11/01/deardiabetes-martha-clark/

Taking an anticlotting drug? If you need a procedure, be prepared

Millions of people with cardiovascular disease take drugs that help prevent blood clots, which can lodge in a vessel and choke off the blood supply to part of a leg, lung, or the brain. These potentially lifesaving medications include warfarin (Coumadin) and a class of drugs called non-vitamin K antagonist oral anticoagulants or NOACs. Examples include dabigatran (Pradaxa) and rivaroxaban (Xarelto).

However, if you’re taking one of these drugs and need an invasive procedure — anything from a tooth extraction to a hip replacement — managing the risks can be tricky, says cardiologist Dr. Gregory Piazza, assistant professor of medicine at Harvard Medical School. “There’s a higher-than-normal risk of bleeding during and after the procedure, because your blood doesn’t clot as easily,” he says.

But stopping an anticlotting drug is also risky. Doing so increases the chance of a blood clot, especially if you have surgery, which also leaves you more prone to a clot. “Walking the tightrope between these two extremes can be a challenge for clinicians,” says Dr. Piazza. They need to consider if, when, and how long a person might need to stop taking their anticlotting medication. And the answer hinges on many different factors.

Different risk levels

Each year, about one in 10 people taking a NOAC requires a planned invasive procedure. These include diagnostic tests and treatments that require a doctor to use an instrument to enter the body. Some are more risky than others, of course. Minor procedures such as a skin biopsy aren’t very worrisome, because you can compress and bandage the wound, says Dr. Piazza.

Tooth extractions can bleed a fair amount. Compresses and topical treatments are usually sufficient for controlling the bleeding, although your doctor might suggest skipping your anticoagulant the day of the procedure.

Biopsies, injections, and surgeries

Deciding to stop an anticoagulant for a colonoscopy is more complicated. A diagnostic colonoscopy isn’t likely to cause bleeding. But if the doctor has to remove any polyps from the colon, the risk of bleeding rises. Other procedures that require careful planning for people on anticoagulants include breast and prostate biopsies, as well biopsies of internal organs, such as the kidney or liver, which can lead to hard-to-detect internal bleeding.

Another common procedure (especially in older people) is a steroid injection in the spinal column to treat back pain. This, too, may cause undetected and potentially dangerous bleeding around the spinal column in people taking anticoagulants.

People nearly always have to stop taking anticlotting medications a few days prior to any type of elective surgery. Sometimes, doctors will use injectable, short-acting anticlotting drugs right before and immediately after the operation. This technique, called bridging, helps them better balance the degree of blood clotting during that critical window of time.

A key conversation

In addition to the procedure itself, other factors that affect anticoagulant decisions include a person’s age, any other health problems or medications they take, and whether they’re taking warfarin (which stays in the body for days) or a NOAC (which may lose some of its effect after about 12 hours). Because of all these variables, the best strategy is to make sure that the doctor slated to perform your procedure talks directly with the doctor who prescribed your anticoagulant, says Dr. Piazza. “If that conversation doesn’t take place, patients can have problems with either bleeding or clotting,” he says. Many physicians who do procedures aren’t as familiar with NOAC prescribing guidelines, so they may mistakenly keep people off these medications for a week or more, putting them at risk for a clot.

The post Taking an anticlotting drug? If you need a procedure, be prepared appeared first on Harvard Health Blog.

From: Julie Corliss https://www.health.harvard.edu/blog/anticlotting-drug-procedure-safety-2017110112659

Speed Up the 'Cancer Moonshot,' Doctors Urge

The Cancer Moonshot Initiative now has a detailed road map designed to cram a decade's worth of medical advancement into half that time.

From: https://www.webmd.com/cancer/news/20171031/speed-up-the-cancer-moonshot-doctors-urge?src=RSS_PUBLIC

Rheumatoid Arthritis Linked to Risk of COPD

People with rheumatoid arthritis appear to have a higher risk of the lung condition chronic obstructive pulmonary disease (COPD), researchers report.

From: https://www.webmd.com/rheumatoid-arthritis/news/20171031/rheumatoid-arthritis-linked-to-risk-of-copd?src=RSS_PUBLIC

Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology

G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferases in the cytoplasm, and, thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiological responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR-miRNA interactions related to gastrointestinal pathophysiology, such as inflammatory bowel diseases, irritable bowel syndrome, and gastrointestinal cancers. Given that the presence of different types of cells in the gastrointestinal tract suggests the importance of cell-cell interactions in maintaining gastrointestinal homeostasis, we also discuss how GPCR-miRNA interactions regulate gene expression at the cellular level and subsequently modulate gastrointestinal pathophysiology through molecular regulatory circuits and cell-cell interactions. These studies helped identify novel molecular pathways leading to the discovery of potential biomarkers for gastrointestinal diseases.

From: Law, I. K. M., Padua, D. M., Iliopoulos, D., Pothoulakis, C. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G361?rss=1

Impact of prevailing thiamin levels on thiamin pyrophosphate uptake in pancreatic acinar cells: do the shuttle!

From: Kennedy, L., Francis, H., Alpini, G. http://ajpgi.physiology.org/cgi/content/full/313/5/G373?rss=1

Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver.

NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases.

From: Malhotra, P., Aloman, C., Ankireddy, A., Khadra, H., Ooka, K., Gill, R. K., Saksena, S., Dudeja, P. K., Alrefai, W. A. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G376?rss=1

Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis

Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transporter (SERT), which increases and prolongs effects of 5-HT, was found to increase the severity of systemic manifestations, intestinal inflammation, and associated hepatotoxicity of experimental NEC. In contrast, genetic deletion of tryptophan hydroxylase 1 (TPH1), which is responsible for 5-HT biosynthesis in enterochromaffin (EC) cells of the intestinal mucosa, and TPH inhibition with LP-920540 both decrease the severity of experimental NEC in the small intestine and liver. These observations suggest that 5-HT from EC cells helps to drive the inflammatory damage to the gut and liver that occurs in the murine NEC model. Administration of OT decreased, while the OT receptor antagonist atosiban exacerbated, the intestinal inflammation of experimental NEC. Data from the current investigation are consistent with the tested hypotheses—that the enteric signaling molecules, 5-HT (positively) and OT (negatively) regulate severity of inflammation in a mouse model of NEC. Moreover, we suggest that mucosally restricted inhibition of 5-HT biosynthesis and/or administration of OT may be useful in the treatment of NEC.

NEW & NOTEWORTHY Serotonin (5-HT) and oxytocin reciprocally regulate the severity of intestinal inflammation and hepatotoxicity in a murine model of necrotizing enterocolitis (NEC). Selective depletion of mucosal 5-HT through genetic deletion or inhibition of tryptophan hydroxylase-1 ameliorates, while deletion of the 5-HT uptake transporter, which increases 5-HT availability, exacerbates the severity of NEC. In contrast, oxytocin reduces, while the oxytocin receptor antagonist atosiban enhances, NEC severity. Peripheral tryptophan hydroxylase inhibition may be useful in treatment of NEC.

From: Gross Margolis, K., Vittorio, J., Talavera, M., Gluck, K., Li, Z., Iuga, A., Stevanovic, K., Saurman, V., Israelyan, N., Welch, M. G., Gershon, M. D. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G386?rss=1

PARP2 deficiency affects invariant-NKT-cell maturation and protects mice from concanavalin A-induced liver injury

Excessive or persistent inflammation and hepatocyte death are the key triggers of liver diseases. The poly(ADP-ribose) polymerase (PARP) proteins induce cell death and inflammation. Chemical inhibition of PARP activity protects against liver injury during concanavalin A (ConA)-induced hepatitis. In this mice model, ConA activates immune cells, which promote inflammation and induce hepatocyte death, mediated by the activated invariant natural killer T (iNKT) lymphocyte population. We analyzed immune cell populations in the liver and several lymphoid organs, such as the spleen, thymus, and bone marrow in Parp2-deficient mice to better define the role of PARP proteins in liver immunity and inflammation at steady state and during ConA-induced hepatitis. We show that 1) the genetic inactivation of Parp2, but not Parp1, protected mice from ConA hepatitis without deregulating cytokine expression and leucocyte recruitment; 2) cellularity was lower in the thymus, but not in spleen, liver, or bone marrow of Parp2^–/– mice; 3) spleen and liver iNKT lymphocytes, as well as thymic T and NKT lymphocytes were reduced in Parp2 knockout mice. In conclusion, our results suggest that the defect of T-lymphocyte maturation in Parp2 knockout mice leads to a systemic reduction of iNKT cells, reducing hepatocyte death during ConA-mediated liver damage, thus protecting the mice from hepatitis.

NEW & NOTEWORTHY The genetic inactivation of Parp2, but not Parp1, protects mice from concanavalin A hepatitis. Immune cell populations are lower in the thymus, but not in the spleen, liver, or bone marrow of Parp2-deficient mice compared with wild-type mice. Spleen and liver invariant natural killer T (NKT) lymphocytes, as well as thymic T and NKT lymphocytes, are reduced in Parp2-deficient mice.

From: Filliol, A., Piquet-Pellorce, C., Dion, S., Genet, V., Lucas-Clerc, C., Dantzer, F., Samson, M. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G399?rss=1

Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats

Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.

NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.

From: McMillin, M., DeMorrow, S., Glaser, S., Venter, J., Kyritsi, K., Zhou, T., Grant, S., Giang, T., Greene, J. F., Wu, N., Jefferson, B., Meng, F., Alpini, G. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G410?rss=1

Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal

Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα⁺) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in Kit^W/Kit^W-v (W/W^v) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We used small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD⁺)/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5'-triphosphate (ATP), and metabolites from the tunica muscularis of human, monkey, and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from W/W^v, Nos1^–/–, and Prkg1^–/– mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from W/W^v mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. W/W^v mouse colons demonstrated reduced Nos1 expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provide novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility.

NEW & NOTEWORTHY This is the first study investigating the role of nitric oxide (NO) and intramuscular interstitial cells of Cajal (ICC-IM) in modulating neural release of purines in colon. We found that NO inhibited release of purines in human, monkey, and murine colons and that colons from Kit^W/Kit^W-v (W/W^v) mice, which present with partial loss of ICC-IM, demonstrated augmented neural release of purines. Interactions between nitrergic and purinergic neurotransmission may affect motility in disease conditions with ICC-IM deficiencies.

From: Durnin, L., Lees, A., Manzoor, S., Sasse, K. C., Sanders, K. M., Mutafova-Yambolieva, V. N. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G419?rss=1

Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat

Relationship of gastric emptying or accommodation with satiation, satiety, and postprandial symptoms in health

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m²): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank (r_s) and Pearson (R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal (r_s = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T_1/2) and VTF (r_s = –0.317, P < 0.001) and the calorie intake at buffet meal (r_s = –0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF (r_s = –0.273, P < 0.001 and r_s = –0.248, P < 0.001, respectively). GE T_1/2 was significantly associated with satiation (MTV, R = –0.234, P < 0.0001), nausea (R = 0.145, P = 0.023), pain (R = 0.149, P = 0.012), and higher aggregate symptom score (R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants.

NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

From: Halawi, H., Camilleri, M., Acosta, A., Vazquez-Roque, M., Oduyebo, I., Burton, D., Busciglio, I., Zinsmeister, A. R. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G442?rss=1

Adaptive regulation of pancreatic acinar mitochondrial thiamin pyrophosphate uptake process: possible involvement of epigenetic mechanism(s)

The essentiality of thiamin stems from its roles as a cofactor [mainly in the form of thiamin pyrophosphate (TPP)] in critical metabolic reactions including oxidative energy metabolism and reduction of cellular oxidative stress. Like other mammalian cells, pancreatic acinar cells (PAC) obtain thiamin from their surroundings and convert it to TPP; mitochondria then take up TPP by a carrier-mediated process that involves the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). Previous studies have characterized different physiological/biological aspects of the MTPP uptake process, but little is known about its possible adaptive regulation. We addressed this issue using pancreatic acinar 266-6 cells (PAC 266-6) maintained under thiamin-deficient (DEF) and oversupplemented (OS) conditions, as well as thiamin-DEF and -OS transgenic mice carrying the SLC25A19 promoter. We found that maintaining PAC 266-6 under the thiamin-DEF condition leads to a significant induction in mitochondrial [³H]TPP uptake, as well as in the level of expression of the MTPPT protein and mRNA compared with thiamin-OS cells. Similar findings were observed in mitochondria from thiamin-DEF mice compared with thiamin-OS. Subsequently, we demonstrated that adaptive regulation of MTTP protein was partly mediated via transcriptional mechanism(s) via studies with PAC 266-6 transfected with the SLC25A19 promoter and transgenic mice carrying the SLC25A19 promoter. This transcriptional regulation appeared to be, at least in part, mediated via epigenetic mechanism(s) involving histone modifications. These studies report, for the first time, that the PAC mitochondrial TPP uptake process is adaptively regulated by the prevailing thiamin level and that this regulation is transcriptionally mediated and involves epigenetic mechanism(s).

NEW & NOTEWORTHY Our findings show, for the first time, that the mitochondrial thiamin pyrophosphate (MTPP) uptake process is adaptively regulated by the prevailing thiamin level in pancreatic acinar cells and this regulation is mediated, at least in part, by transcriptional and epigenetic mechanism(s) affecting the SLC25A19 promoter.

From: Sabui, S., Subramanian, V. S., Kapadia, R., Said, H. M. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G448?rss=1

A novel mouse model of radiation-induced cancer survivorship diseases of the gut

A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury.

NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.

From: Bull, C., Malipatlolla, D., Kalm, M., Sjöberg, F., Alevronta, E., Grander, R., Sultanian, P., Persson, L., Boström, M., Eriksson, Y., Swanpalmer, J., Wold, A. E., Blomgren, K., Björk-Eriksson, T., Steineck, G. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G456?rss=1

A simple, cost-effective method for generating murine colonic 3D enteroids and 2D monolayers for studies of primary epithelial cell function

Cancer cell lines have been the mainstay of intestinal epithelial experimentation for decades, due primarily to their immortality and ease of culture. However, because of the inherent biological abnormalities of cancer cell lines, many cellular biologists are currently transitioning away from these models and toward more representative primary cells. This has been particularly challenging, but recent advances in the generation of intestinal organoids have brought the routine use of primary cells within reach of most epithelial biologists. Nevertheless, even with the proliferation of publications that use primary intestinal epithelial cells, there is still a considerable amount of trial and error required for laboratories to establish a consistent and reliable method to culture three-dimensional (3D) intestinal organoids and primary epithelial monolayers. We aim to minimize the time other laboratories spend troubleshooting the technique and present a standard method for culturing primary epithelial cells. Therefore, we have described our optimized, high-yield, cost-effective protocol to grow 3D murine colonoids for more than 20 passages and our detailed methods to culture these cells as confluent monolayers for at least 14 days, enabling a wide variety of potential future experiments. By supporting and expanding on the current literature of primary epithelial culture optimization and detailed use in experiments, we hope to help enable the widespread adoption of these innovative methods and allow consistency of results obtained across laboratories and institutions.

NEW & NOTEWORTHY Primary intestinal epithelial monolayers are notoriously difficult to maintain culture, even with the recent advances in the field. We describe, in detail, the protocols required to maintain three-dimensional cultures of murine colonoids and passage these primary epithelial cells to confluent monolayers in a standardized, high-yield and cost-effective manner.

From: Fernando, E. H., Dicay, M., Stahl, M., Gordon, M. H., Vegso, A., Baggio, C., Alston, L., Lopes, F., Baker, K., Hirota, S., McKay, D. M., Vallance, B., MacNaughton, W. K. http://ajpgi.physiology.org/cgi/content/abstract/313/5/G467?rss=1

Are Some Heartburn Meds Tied to Stomach Cancer?

Popping certain heartburn drugs like they're candy might up your odds for stomach cancer, new research suggests.

From: https://www.webmd.com/heartburn-gerd/news/20171031/are-some-heartburn-meds-tied-to-stomach-cancer?src=RSS_PUBLIC